Review ArticleA Pathophysiologic Approach to Biomarkers in AcuteRespiratory Distress Syndrome

Raiko Blondonnet12 Jean-Michel Constantin12

Vincent Sapin23 and Matthieu Jabaudon12

1CHU Clermont-Ferrand Intensive Care Unit Department of Perioperative Medicine Estaing University Hospital63000 Clermont-Ferrand France2Clermont Universite Universite drsquoAuvergne EA 7281 R2D2 63000 Clermont-Ferrand France3Department of Medical Biochemistry and Molecular Biology CHU Clermont-Ferrand 63000 Clermont-Ferrand France

Correspondence should be addressed to Matthieu Jabaudon mjabaudonchu-clermontferrandfr

Received 2 December 2015 Accepted 10 January 2016

Academic Editor George Perry

Copyright copy 2016 Raiko Blondonnet et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Acute respiratory distress syndrome (ARDS) is an acute-onset hypoxic condition with radiographic bilateral lung infiltration It ischaracterized by an acute exudative phase combining diffuse alveolar damage and lung edema followed by a later fibroproliferativephase Despite an improved understanding of ARDS pathobiology our ability to predict the development of ARDS and risk-stratifypatients with the disease remains limited Biomarkers may help to identify patients at the highest risk of developing ARDS assessresponse to therapy predict outcome and optimize enrollment in clinical trials After a short description of ARDS pathobiologyhere we review the scientific evidence that supports the value of variousARDSbiomarkerswith regard to theirmajor biological rolesin ARDS-associated lung injury andor repair Ongoing research aims at identifying and characterizing novel biomarkers in orderto highlight relevantmechanistic explorations of lung injury and repair and to ultimately develop innovative therapeutic approachesfor ARDS patientsThis review will focus on the pathophysiologic diagnostic and therapeutic implications of biomarkers in ARDSand on their utility to ultimately improve patient care

1 Introduction

The acute respiratory distress syndrome (ARDS) is a het-erogeneous syndrome defined by the association of bilateralradiographic pulmonary opacities arterial hypoxemia (par-tial pressure of arterial oxygen (PaO

2) to fraction of inspired

oxygen (FiO2) ratio lt300 with a positive end-expiratory

pressure of 5 cm H2O or more) and exclusion of cardiac

failure as a primary cause [1] It is characterized by diffusealveolar epithelial and lung endothelial injury leading toincreased permeability pulmonary edema and alveolar filling[2] By definition ARDS occurs within one week of a knownclinical insult or new or worsening respiratory symptoms asa consequence of various risk factors including either direct(eg bacterial or viral pneumonia gastric aspiration lungcontusion toxic inhalation and near drowning) or indirect

(eg sepsis pancreatitis severe trauma massive blood trans-fusion and burn) lung injury [1] Despite improvements inintensive care during the last fifteen years ARDS is stilla frequent (60100000 inhabitantsyear) morbid and life-threatening condition with a mortality rate around 30 [3ndash5] In addition there has been recent recognition of theclinical and biological heterogeneity within ARDS [6ndash8]thus reflecting our incomplete understanding of the biologyof ARDS and hampering the successful clinical translationof new diagnostic preventive and therapeutic strategies[9] Some investigators have further proposed subdividingARDS for example on the basis of clinical risk factors[10] by direct versus indirect lung injury [7] or by focalversus nonfocal lung morphology as assessed by CT-scan[11 12] Characterizing ARDS phenotypes may help to betterunderstand genetic genomic and protein risk factors for

Hindawi Publishing CorporationDisease MarkersVolume 2016 Article ID 3501373 20 pageshttpdxdoiorg10115520163501373

2 Disease Markers

ARDS predict the syndrome identify mechanism-definedsubgroups of ARDS andor to better target therapy [10 13]The subtype (or phenotype) of a condition is ideally definedby a distinct functionalpathobiological mechanism namedendotype that may explain at least in part response totreatment [13]

2 Pathogenesis of ARDS

The pathogenesis of ARDS is characterized by two phasesthat may sometimes overlap temporally and spatially [2]exudative and proliferative [14] phases An alveolar-capillarybarrier dysfunction resulting in altered permeability ofepithelial and endothelial alveolar cells characterizes the earlyexudative phase Due to loss of cellular integrity alveoliare filled with proteinaceous edema fluid that results inimpaired gas exchange Initially there is an early exudativephase associated with diffuse alveolar damage microvascularinjury with subsequent pulmonary edema alveolar type 1(AT1) epithelial cell necrosis and influx of inflammatory cellswhich then release active mediators [2] During this earlyphase alveolar inflammation ismainlymediated by polymor-phonuclear neutrophils (PMN) [2] but recent findings alsosupport a key role for monocytes and macrophages [15 16]Other proinflammatory mechanisms are also involved asthe significant release of proinflammatory cytokines by lungscells inflammatory cells and fibroblasts

The association of persistent injury and failure to repairlung damage in a timely manner mainly contributes to thepathological fibroproliferative response during which thereare proliferation of fibroblasts hyperplasia of AT2 cells andlung repair The repair of the injured alveolar epitheliumremains incompletely understood it involves hyperplasia ofAT2 (and maybe AT1) cells migration along the basementmembrane by AT2 cells to form a new epithelial barrier andcomplex interactions with ECM and other cells includingalveolar macrophages In the absence of recovery processesleading to fibrosing alveolitis may occur during a fibroticphase resulting in some cases in marked changes in lungstructure and function [17]

3 Biomarkers of ARDSA Pathophysiologic Approach

The discovery and validation of biomarkers of myocardialinjury and ventricular overload such as troponin and brain-natriuretic peptide (BNP) have transformed the diagnosismanagement and design of clinical trials in conditions suchas myocardial infarction and congestive heart failure [18 19]In a similar way identification of plasma biomarkers thatmayfacilitate diagnosis of ARDS could at least in theory improveclinical care enhance our understanding of pathophysiologyand be used to enroll more homogeneous groups of patientsin clinical trials of new therapies increasing the likelihood ofdetecting a treatment effect [20] Pathophysiologic changescan probably be used as a framework to better understandvarious biomarkers that have been studied in ARDS includ-ing the cellular injury pathways that are central to lung injury

endothelial injury epithelial injury proinflammatory injurycoagulation fibrosis and apoptosis [21]

Among multiple potential applications biomarkers maybe used to better identify patients with risk factors of ARDSwho are most likely to develop the syndrome Subsequentlythey may also be useful to improve risk stratification onceARDS criteria are present Biomarkers may also play apivotal role in the design of future clinical trials throughthe identification of patients at high risk of poor outcomethus decreasing the required sample size needed to showa therapeutic benefit [92] More recently biomarkers havealso been proven useful to evaluate the response to therapy[13 93] Finally the study of biomarkers in ARDS playsa fundamental role in understanding the mechanisms andpathophysiology underlying lung injury thus serving as asolid basis to develop future therapeutic strategies [9]

We will now review the biomarkers that have beeninvestigated in ARDS with a focus on biomarkers in groupsthat reflect their primary function (Figure 1 and Table 1)

31 Exudative Phase of ARDS ARDS is characterized byan initial exudative phase with diffuse alveolar damageassociated with the formation of lung inflammatory edemaAlveolar injury is predominant during this phase and variousproteins that are specific to lung injury are therefore releasedin both the blood and the alveolar compartment thus servingas markers of the disease or of its resolution

311 Lung Injury

(1) Alveolar Epithelium The alveolar epithelial lining iscomposed of AT1 and AT2 epithelial cells and plays a criticalrole in barrier function regulating surfactant productionand in vectorial transport of alveolar fluid During the acutephase of ARDS alveolar epithelial cells undergo neutrophil-mediated damage and effects of proinflammatory cytokinesor of hypoxic injury thus accounting for the clinical syn-drome [2] Lung-secreted proteins may be found in both thebronchoalveolar (BAL) fluid and the systemic blood becausethey can move passively across the epithelial barrier intoserum where they may serve as peripheral indicators ofepithelial damage Several markers of lung epithelial damagehave been studied as markers of ARDS as supported by thefact that they should be more specific to lung injury thanother markers for example inflammatory cytokines [94]

(a) Alveolar Type 1 Cells They are of two types

RAGE AT1 epithelial cells cover 90ndash95 of the alveolar sur-face and contribute to both alveolar fluid clearance (AFC) andbarrier integrity The receptor for advanced glycation end-products (RAGE) is a transmembrane pattern-recognitionreceptor of the immunoglobulin superfamily that is constitu-tively expressed at low levels in all cells but abundantly in thelung RAGE is primarily located on the basal surface of AT1cells [22 23] Activation of RAGE modulates cell signalingculminating in a sustained inflammatory response throughvarious intracellular signaling pathways such as cytokinesreactive oxygen species (ROS) or proteases and leading to

Disease Markers 3

Exudative

Epithelium damage

Endothelium damage

Inflammatory cascade

IL-6 and IL-8

IL-10Additional markers HMGB1 LBP NO CRP

Anti-inflammatory IL-1RA sTNF-RIII and

albumin and LDHPulmonary vascular permeability

EFPL ratioLung matrix alteration

LamininElastindesmosineMMPs 2 3 8 9 and 13

PA-1Protein C

Coagulation and fibrinolysis

phase

ATI cells sRAGE HTI56ATII cells surfactant KL-6Club cells CC16

Ang-1 Ang-2ICAM-1SelectinsVEGFvWF

Epithelial apoptosis

Fibroproliferative phase

FasFasL

VEGF

KGFHGF

N-PCP-III

Epithelial proliferation

Fibroblast proliferation

Endothelial proliferationProinflammatory IL1-120573TNF-120572 IL-18

ThrombomodulinTissue factorCell-free hemoglobin

Club cell

Alveolar type I cell

Alveolar type II cell

Red cell

Alveolarmacrophage

Neutrophil

CapillaryInterstitium

Protein-richedema fluid

differentiation ofalveolar type II cells

Alveolus

Necrotic alveolartype I cell

Proliferation and

m Fibroblast

Figure 1 Biomarkers of acute respiratory distress syndrome organized by pathways and phases of lung injury (left early exudative phaseright fibroproliferative phase)

proinflammatory activation of nuclear transcription factorNF-120581B [95 96] RAGE is implicated in ARDS as an importantpathway to innate immunity and alveolar inflammation [97]and when the soluble form (sRAGE for soluble RAGE) isassayed in plasma or pulmonary edema fluid as a markerof alveolar injury [98ndash101] Full-length RAGE is a transmem-brane receptor but it can also be found as soluble isoformsgenerally referred to as soluble RAGE (sRAGE comprisingthe extracellular domain of RAGE and produced through thecleavage of full-length RAGE by matrix metalloproteinases)[102 103] and endogenous secretory RAGE (esRAGE pro-duced after alternative splicing) [104] Full-length RAGE andits isoforms are abundantly and constitutively expressed inthe lungs in normal conditions [103 105ndash107] and sRAGEis now considered as a promising novel marker of AT1 cellinjury and a key mediator of alveolar inflammation [22 95108] It is shown that sRAGE expression appears enhancedduring the early stage of ARDS Our team with others hasrecently reported in both ARDS patients and a mouse modelof ARDS that the extent of sRAGE elevation in plasma andalveolar fluid correlates with markers of severity assessed byPaO2FiO2 lung injury and alveolar fluid clearance (AFC)

[98ndash101 109] A role for RAGE pathway in the regulation ofAFC has been recently described for the first time [110] and isunder active investigation by our team and others [101 111]Interestingly plasma and BAL sRAGE levels are elevatedduring ARDS independently of any associated severe sepsis[100] In addition plasma levels of sRAGE are correlated with

diffuse damage as assessed by lungCT-scan and are correlatedwith the extent of alveolar damage [100 112] suggesting thatsRAGEmay serve as a useful biomarker of AT1 cell injury andlung damage during ARDS Plasma levels of sRAGE are alsoassociated with 28-day and 90-day mortality in patients withARDS [99 106 112]

Calfee et al recently compared biomarker levels inpatients with direct versus indirect ARDS enrolled in a singlecenter study of 100 patients and in a secondary analysis of 853ARDS patients drawn from a multicenter randomized con-trolled trial [7] levels of biomarkers of lung epithelial injury(sRAGE surfactant protein-D) were significantly higher indirect ARDS compared to indirect ARDS

A recent observational study also supports an ARDSphenotype based on levels of RAGE ligands and solubleforms as elevated sRAGE high mobility group box-1 pro-tein (HMGB1) and S100A12 with decreased esRAGE andadvanced glycation end-products (AGEs) were found todistinguish patients with ARDS from those without [109]Although these recent findings warrant further validation inmulticenter studies monitoring sRAGE levels may be usefulin assessing the response to strategies in ventilator settingsincluding alveolar recruitment maneuvers in patients withARDS [113] or in patients without lung injury at risk of post-operative respiratory complications after major surgery [24]The predictive value of 4 single-nucleotide polymorphisms inRAGE gene (AGER) in the development of ARDS in at-riskpatients is currently under study by our team [114]

4 Disease Markers

Table 1 Biomarkers of acute respiratory distress syndrome organized by phases and pathways of lung injury

Pathophysiologic feature of ARDS Biomarker ReferencesExudative phase

Epithelium damage

(i) Alveolar type 1 cells RAGE [22ndash24]HTI56

[25 26]

(ii) Alveolar type 2 cells Surfactant [27 28]KL-6 [29 30]

(iii) Clara cells CC16 [31 32]Endothelium damage

Ang-1 Ang-2 [33 34]ICAM-1 [35 138ndash140]Selectins [36 37]VEGF [38 39]vWF [40ndash42]

Lung matrix alterationLaminin [43 44]

Elastindesmosine [45 46]MMPs [47ndash49]

Inflammatory cascade

(i) Proinflammatory

IL-1120573TNF-120572 [17 161ndash164 167]IL-18 [50 51]IL-6 [52ndash55]IL-8 [169ndash171]

(ii) Anti-inflammatoryIL-1RA [56 57]

sTNF-RIsTNF-RII [6 54 58]IL-10 [59ndash61]

(iii) Additional markers

HMGB1 [62 63]LBP [64 65]NO [46 66 67]CRP [68]

Albumin [69]LDH [69]

Coagulation and fibrinolysisPA-1 [32 53 70ndash72]

Protein C [75 76 182]Thrombomodulin [73 74]

Tissue factor [75ndash78]Cell-free hemoglobin [75 76 79 80]

Pulmonary vascular permeabilityEFPL ratio [81 82]

Fibroproliferative phaseEndothelial proliferation

VEGF [39 83ndash86]Epithelial proliferation

KGF [87]HGF [88 194 195 197]

Epithelial apoptosisFasFasL [25 88ndash91]

Fibroblast proliferationN-PCP-III [88 194 195 203 207]

Disease Markers 5

HTI56 Human type I cell-specificmembrane protein (HTI56)

is a 56-kDa glycosylated lung protein specific to the apicalmembrane of human AT1 cells HTI

56has biochemical char-

acteristics of an integral membrane protein [25] Althoughthe precise functions of HTI

56remain unknown HTI

56is

an analog to RTI40 a 40ndash42 kDa integral membrane protein

specific to the apical membrane of rat AT1 cells [26] Patientswith ARDS had higher levels of HTI

56in both lung edema

fluid and plasma as compared to patients with hydrostaticlung edema [94] but no study assessing the associationbetween HTI

56levels and other endpoints in patients with

ARDS (eg prognosis) has been published to date

(b) Alveolar Type 2 Cells AT2 cells have important homeo-static functions in the lung including AFC and productionof alveolar surfactant (involved in lung compliance keepingthe alveolus open) AT2 cells are also known as keymediatorsof the epithelial repair process [115]

Surfactant Proteins Surfactant has a vital role in maintainingthe integrity of the alveolar-capillary interface Its essentialfunction is to decrease surface tension into the alveoli thusstabilizing lung volume at low transpulmonary pressuresSurfactant is composed of approximately 80 phospholipids8 other lipids (cholesterol triacylglycerol and free fattyacids) and 12 proteins Four surfactant-associated proteins(SP) designated SP-A SP-B SP-C and SP-D representapproximately half of proteins composing surfactant SP-Aand SP-D easily dissociate from lipids and are hydrosolubleThey belong to the lung innate immune system therebyenhancing phagocytosis of bacteria and virus They alsoexert regulatory effects on AT2 cells SP-B and SP-C aresmall extremely hydrophobic proteins that are important inthe formation of the surfactant monolayer in the terminalairspaces and in the reduction of surface tension thuspreventing end-expiratory alveolar collapse [116]

Early observations in ARDS revealed a loss in surfacetension suggesting a functional loss of the surfactant proteins[117] In a first case report of three patients the ratioof plasma SP-BSP-A was inversely associated with bothblood oxygenation and static respiratory system compliancesuggesting that SP-B breaches the alveolocapillary barriermore readily than SP-A and may therefore provide a moresensitive marker of lung injury [118] Plasma levels of SP-Aand SP-B are increased in patients with ARDS [70] and in at-risk patients [119 120] whereas lower SP-A and SP-B levelswere found in the BAL fluid of patients at risk for ARDSprior to the onset of the clinical syndrome SP-A and SP-Blevels remained low for as long as 14 days in patients withsustained ARDS Interestingly this decrease in BAL SP-A andSP-B does not result simply from dilution of alveolar fluids byplasma entering the alveolar spaces as SP-D levels remainedstable in parallel [119] In a cohort of 38 patients reducedpulmonary edema fluid SP-D and elevated plasma SP-A atthe onset of ARDS were associated with poor prognosis [27]Nevertheless in a study of 259 patients from the ARDSNettrial of low versus high end-expiratory pressure in ARDS(ALVEOLI) as well as in 75 patients enrolled in a randomized

trial of activated protein C for ARDS plasma SP-D was notassociated with 28-day mortality or ventilator-free days [28]

KL-6 Krebs von den Lungen-6 (KL-6) is a human MUC1mucin that belongs to the high-molecular-weight glyco-protein family After the cleavage of S-S bond KL-6 canspread into the pulmonary epithelial lining fluid In thenormal lung this glycoprotein can be predominantly foundin AT2 cells and its expression is enhanced during AT2proliferation regeneration or injury thus representing anattractive biomarker in ARDS Plasma KL-6 is elevated inARDS patients and correlates with lung injury and mortality[29 121ndash123] Plasma levels of SP-D and KL-6 increase overtime in patients with ARDS and may represent biologicalmarkers of ventilator-associated lung injury because theirincrease is attenuated by lung-protective ventilation [30]

(c) CC16 Clara cell protein (CC16) is a 158 kDa homod-imeric protein that is abundantly secreted in airways by thenonciliated bronchiolar Clara cells Clara cells are devotedto the protection of the respiratory tract against toxicinhaled agents the repair of damaged epithelium xenobioticsdetoxification and the secretion of proteins with importantbiological activities CC16 is highly expressed in the epitheliallining fluid with antioxidantinflammatory roles notably bymodulating the production andor activity of phospholipase-A2 interferon-120574 and tumor necrosis factor-120572 [31] Availablestudies found contradictory inconclusive findings duringARDS Although higher levels of CC16 are associated withlung injury and inflammation in some experimental andclinical studies patients with ARDS had lower plasma andpulmonary edema fluid levels of CC16 than patients withacute cardiogenic pulmonary edema and no correlation wasfound between CC16 and prognosis So many conflictingfindings do not currently support the association of CC16with the diagnosis or prognosis of ARDS

(2) Vascular Endothelium Vascular endothelial injury ischaracterized by the disruption of cell components leadingto increased microvascular permeability and alveolar edemaEndothelial injury is mainly driven by the activation ofinflammation and coagulation cascades The activation ofendothelial cells by circulating mediators leads to increasedexpression of cell surface molecules that are importantmediators of leukocyte adhesion and contribute to leuko-cyte accumulation and transmigration [124] Activated lym-phocytes can also release mediators in microvessels thatincrease vascular permeability Along with these leukocytesignals inflammatory mediators such as tumor necrosis fac-tor (TNF) thrombin and vascular endothelial growth factor(VEGF) disrupt endothelial-cadherin bonds and contributeto the vascular leak underlying edema formation in ARDSPlatelets also contribute to endothelial injury through therelease of cytokines and through fibrin clotting [92]

(a) Angiopoietin Angiogenic agents along with VEGF andangiopoietin-1 (Ang-1) play key roles in vascular develop-ment VEGF stimulates the generation of new immature

6 Disease Markers

and leaky blood vessels whereas Ang-1 enhances angiogene-sis inducing vascularmaturation anddecreases vascular per-meability [33] The most encouraging data result from recentstudies of angiopoietin-2 (Ang-2) an endothelial protein thathas been studied extensively during sepsis [125] Ang-2 has animportant role as it increases endothelial junction instabilityenhances vascular leak naturally antagonizes Ang-1 and inthe absence of other angiogenic stimuli induces vascularregression and endothelial cell apoptosis Both Ang-1 andAng-2 are ligands for the tyrosine kinase receptor Tie-2 [126] and a link between Ang-2 and inflammation hasbeen reported [127] Therefore such vascular growth factorshave been proposed as biomarkers for ARDS [128] Firsttwo single-nucleotide polymorphisms within the Ang-2 gene(rs1868554 and rs2442598) were associated with the riskof developing ARDS in trauma patients [129] In additionAgrawal et al found in a prospective study of 230 patientsadmitted to the intensive care unit (ICU) without ARDSthat higher levels of Ang-2 were significantly associatedwith increased development of ARDS [130] In surgical ICUpatients levels of Ang-2 were higher in patients with ARDSthan in those without the syndrome [131] A higher Ang-2Ang-1 ratio was also an independent predictor of mortalityin ARDS patients [131 132] and patients with infection-related ARDS whose Ang-2 levels increased between day 0and day 3 doubled their odds of death suggesting that Ang-2kinetics may be particularly valuable by reflecting evolvinglung injury [34] Finally in a large study of 931 patientsenrolled in the ARDSNet fluid and catheter treatment trialbaseline plasma levels of Ang-2 were associated with 90-daymortality in patients with noninfectious ARDS whereas thisassociation was not found in patients with infection as theirprimary ARDS risk factor Based on a secondary analysisof two large studies Calfee et al further demonstrated thatindirect lung injury is characterized by a molecular pheno-type consistent with more severe lung endothelial injury asassessed by plasma Ang-2 and less severe epithelial injury[7]

(b) ICAM-1 The soluble intercellular adhesion molecule-1 (sICAM-1) is an inducible glycoprotein expressed onthe surface of vascular endothelial cells and other cells(eg hematopoietic cells AT1 cells) [35] Under physiologicconditions sICAM-1 is not constitutively expressed or isexpressed at low levels in most tissues During inflammationand in response to stimuli such as interferon-120574 (IFN-120574) orinterleukin-1 (IL-1) levels of sICAM-1 are upregulated [133]Elevated levels have also been found in both plasma andlung edema fluid from patients with ARDS as compared topatients with hydrostatic lung edema [134] In a multicenterstudy the increase of sICAM-1 from baseline to day 3was associated with poor clinical outcome [135] and in aprospective cohort of 65 patients with ARDS baseline plasmalevels of sICAM-1 were also associated with mortality [136]In pediatric patients with ARDS early elevated plasma levelsof sICAM-1 were associated with increased risks of death andof prolongedmechanical ventilation [137] In traumapatientshigher plasma levels of sICAM-1 at baseline were correlated

with future development of multiple organ dysfunction syn-drome (MODS) but not with the development of ARDS [138ndash140]

(c) Selectins Selectins are membrane-associated glycopro-teins that mediate the adhesion of leukocytes and plateletsto vascular surface L-selectin is mainly expressed by leuko-cytes P-selectin is rapidly redistributed from membranoussecretory granules to the surface of activated platelets andendothelial cells [36] E-selectin is expressed by cytokine-activated endothelial cells It has been shown that plasmalevels of such soluble adhesion molecules were markedlyhigher in nonsurvivors among critically ill patients and thatthey were negatively correlated with lung function (egPaO2FiO2ratio) [141] Other studies found that plasma P-

selectin was elevated in patients with ARDS especially inthose who subsequently died as compared with patients withother pulmonary diseases or sepsis but without ARDS [142]Interestingly patients with ARDS with chronic alcohol con-sumption had elevated levels of soluble E-selectin in both theplasma and epithelial fluid consistent with altered endothe-lial and alveolar-capillary function [143] More recently E-selectin was measured in the plasma levels from 50 individ-uals admitted to the emergency department and who wereat-risk for developing ARDS with higher E-selectin levelsbeing associated with both ARDS development and 28-daymortality [144] Circulating soluble E-selectin levels wereelevated in pneumonia patientswithARDS and plasma levelsdecreased along with the treatment of pneumonia [37]

(d) VEGF One of the most extensively studied endothelialmarkers in ARDS is VEGF albeit its value as a biomarkerremains unclear Vascular endothelial growth factors belongto the platelet-derived growth factor supergene family Theyplay central roles in the regulation of angiogenesis andlymphangiogenesis [38] Alternative splicing of the VEGFgene (6p213) transcript leads to the generation of severalsplice variants or isoforms with various sizes [145] VEGF-Ais a 34ndash46 kDa glycoprotein acting as the major factor impli-cated in angiogenesis It binds to two tyrosine kinase (TK)receptors named VEGFR-1 (Flt-1) and VEGFR-2 (KDRFlk-1) and regulates endothelial cell proliferationmigration vas-cular permeability secretion and other endothelial functions[146] The expression of VEGF in ARDS varies dependingon the degree of epithelial and endothelial damage Manylung cells release VEGF for example AT2 cells neutrophilsalveolar macrophages and activated T cells Thus VEGFis potentially capable of having an effect on both alveolarepithelial and endothelial barriers Interestingly overexpres-sion of VEGF induces pulmonary edema in animal models[147] In a single center study plasma levels of VEGF wereincreased in subjects with ARDS compared to controls andelevated plasma VEGF as measured on day 4 was associatedwith mortality in patients with ARDS [83] Neverthelessseveral studies suggest that plasma and alveolar VEGF mayhelp to predict the development of ARDS and its recoveryWhereas plasma VEGF is increased in ARDS patients VEGFlevels were decreased in the BAL fluid from ARDS patients

Disease Markers 7

as compared to controls [84 148 149] In order to betterunderstand such differences between plasma and alveolarexpression of VEGF Ware et al conducted a study with theaim to determine whether changes in alveolar levels of VEGFwere specific to ARDS or not [39] the authors found thatalveolar levels of VEGF were decreased in both patients withARDS and those with hydrostatic edema The mechanismsimplicated in this alveolar decrease in VEGF during ARDSmight not depend on the degree of lung injury but rather onthe degree of alveolar flooding [39]

(e) vWF Early studies of endothelial markers focused on vonWillebrand Factor (vWF) a macromolecular antigen that isproduced predominantly by endothelial cells and to a lesserextent by platelets In the setting of endothelial activationor injury vWF is released from preformed stocks into thecirculation [40 41] VWFhas been investigated as a biologicalmarker of endothelial injury in patients both at-risk forARDSand with established ARDS [40 150] In a prospective studyof 45 ICU patients with sepsis patients with nonpulmonarysepsis had higher levels of plasma vWF with good predictiveand prognostic values for ARDS Indeed elevated plasmalevels of vWF had a sensitivity of 87 and a specificity of77 for the prediction of ARDS development in the settingof nonpulmonary sepsis [151] However subsequent studiesin patients at-risk for ARDS did not confirm these findings[42 152 153] In another study of 559 patients with ARDSenrolled in the National Heart Lung and Blood InstituteARDS Network trial of lower tidal volume nonsurvivorshad higher plasma levels of vWF compared to survivors[40] Higher vWF levels were significantly associated withfewer organ failure-free days suggesting that the degree ofendothelial activation and injury is strongly associated withoutcomes in ARDS nevertheless ventilator settings had noimpact on vWF levels in this study [40]

(f) Lung ExtracellularMatrixThe extracellularmatrix (ECM)forms the region of the lung situated between the alveo-lar epithelium and the vascular endothelium ECM playsa mechanical role as it supports and maintains tissularstructures ECM also represents a complex and dynamicmeshwork influencing many biological cell functions such asdevelopment proliferation and migration [154] Collagensare the main component of ECM along with glycoproteinsand proteoglycans including hyaluronic acid

Laminin Laminins (LM) are ECM proteins with high molec-ular weights that deposit in basal membranes Lamininsare involved in cell processes such as cellular adhesiongrowth and differentiation [43] Laminin-5 (LM-5) plays animportant role in cell migration and in the remodeling ofepithelial tissue LM-5 is activated through its cleavage bymatrix metalloproteinases (MMPs) thus releasing a solubleLN 1205742 NH2-terminal fragment (G2F) that does not depositin the ECM and can therefore be detected in the peripheralblood In a small single center study lamininwasmeasured inthe plasma and lung edema fluid from 17 patients with ARDSwith higher levels found in patients with ARDS as comparedto healthy volunteers [44] Interestingly nonsurvivors had

higher plasma levels of laminin as measured 5 days afterARDS onset than survivors and survivors had decreasinglevels of the marker over time suggesting that its secretionis suppressed during ARDS recovery

ElastinDesmosine Elastin is another critical protein of theECM that gives the lung its elastic recoil ability In adultselastin which is expressed by lungs and other tissues isusually excreted in the urine During lung epithelial andendothelial injury elastin can be broken down by proteasessuch as neutrophil elastase [45] Elastin breakdown results insmaller fragments containing desmosine and isodesmosine[155] In a large study of 579 patients with ARDS thoseventilated with lower tidal volumes had lower urine desmo-sine levels a finding that may reflect reduced extracellularmatrix breakdown however no correlation with mortalitywas found in patients with ARDS [46]

MMPs Matrix metalloproteinases (MMPs) are zinc-depend-ent endopeptidases that are able to degrade almost allextracellular matrix components MMP-8 a member of theleukocyte-derived MMPs contributes to the degradationturnover and remodeling of the extracellular matrix digest-ing type I collagen [47 48] MMPs are major actors inalmost all phases of the inflammatory response and theirfunction is highly regulated At the tissue level most impor-tant inhibitors are the tissue inhibitors of metalloproteinases(TIMPs) In fulminant inflammation the inhibitory capacityof TIMPs may be overwhelmed leading to excessive tissuedamage and adverse outcome [47] Previous studies suggestthat MMPs may have an important role in ARDS althoughthis role may be either harmful or beneficial [156 157] In arecent study despiteMMP-8 levels did not predict outcome inARDS patients higher levels of TIMP-1 were independentlyassociated with increased 90-day mortality in a large groupof critically ill mechanically ventilated patients [47] Thesefindings are in contradiction to those from a study inpediatric ARDS patients in which higher MMP-8 and activeMMP-9 levels as measured 48 hours after disease onset wereassociated with longer durations of mechanical ventilationand fewer ventilator-free days [158] ElevatedMMP-2 MMP-8 and MMP-9 in the BAL fluid from ARDS patients wereassociated with patterns of acute inflammation but with pooroutcome [157] Interestingly MMP-3 and MMP-13 may beprotective against lung injury by cleaving transmembranereceptor RAGE into sRAGE thus regulating RAGE activationby its ligands [48 49]

312 Inflammatory Cascades During ARDS inflammatoryresponses can either be related to an ongoing primaryinfectious stimulus such as pneumonia or to systemic inflam-mation such as in sepsis or in pancreatitis [2] The inflam-matory cascade involves inflammatory cells and the releaseof inflammatory mediators as driven by a complex networkof cytokines A comparison between blood and alveolarcytokines suggests that most inflammatory mediators orig-inate from the lung [17] Alarmins or damage-associatedmolecular patterns (DAMPs) are released by dead cells orlocal inflammatory cells (eg alveolar macrophages) They

8 Disease Markers

activate and recruit immune cells via binding to differentreceptors such as TLR IL-1 receptor (IL-1R) or RAGEthereby initiating and perpetuating multiple proinflamma-tory pathways [21 159]

Regulation of the inflammatory response is a complexprocess that requires interplay between several immunemediators [160] Both pro- and anti-inflammatory biomark-ers have been studied in ARDS

(1) Proinflammatory Cytokines

(a) IL-1120573 and TNF-120572 IL-1120573 and TNF-120572 are the most biolog-ically potent cytokines secreted by activated macrophages inthe early phase of ARDS They cause the release of a varietyof proinflammatory chemokines such as monocyte chemo-tactic protein-1 (MCP-1) macrophage inflammatory protein-1120572 (MIP-1120572) IL-6 and IL-8 with subsequent recruitmentof inflammatory cells into the air spaces alteration of theendothelial-epithelial barrier permeability and impairmentof fluid transport leading to alveolar edema [17] TNF-120572 alsopromotes lung edema indirectly through the production ofreactive oxygen species (ROS) and a decreased expressionof epithelial sodium (ENaC) and Na+-K+-ATPase channels[161] Finally TNF-120572 a potent chemoattractant for fibrob-lasts is a promoter of lung fibrosis in experimental studies[162 163] Interestingly the ratio of BAL to serum levelsof both TNF-120572 and IL-1120573 is typically high suggesting thatsuch cytokines may originate from the lung in the settingof ARDS [164] Persistent elevation of plasma and BAL IL-1120573 is associated with worse outcome [165 166] Both TNF-120572 and IL-1120573 are elevated in the plasma and BAL fluid frompatients at risk of and with ARDS [164 167] and associatedwith mortality [166]

(b) IL-18 Inflammasomes are intracellular macromolecularcomplexes that serve as platforms for the activation of theproinflammatory enzyme caspase-1 which in turn cleavespro-IL-1120573 and pro-IL-18 into IL-1120573 and IL-18 [50] Theseinflammasome-activated cytokines play central roles in thepropagation of the acute inflammatory response IL-18 andcaspase-1 play critical roles in the development of lunginjury and higher levels of IL-18 are correlated with diseaseseverity and mortality in patients with ARDS [168] Among38 patients with acute respiratory failure those with ARDShad significantly higher serum levels of IL-18 and serum IL-18 was significantly higher in nonsurvivors [51]

(c) IL-6 IL-6 is produced by a wide range of cells includingmonocytesmacrophages endothelial cells fibroblasts andsmoothmuscle cells in response to stimulation by endotoxinIL-1120573 and TNF-120572 [52] IL-6 is one of the most importantmediators of fever and is critical for B-cell differentiation andmaturation with secretion of immunoglobulins cytotoxic Tcell differentiation macrophage and monocyte function andproduction of acute phase proteins Although IL-6 activatesboth proinflammatory and anti-inflammatory mechanismsIL-6 primarily correlates with a proinflammatory profileduring the early phase of ARDS Plasma IL-6 increases earlyin patients at risk of developing ARDS [53] IL-6 is elevated in

both plasma and BAL fluid during ARDS [59] and correlateswith mortality [54 55]

(d) IL-8 IL-8 is a proinflammatory cytokine with a role inneutrophilmonocyte chemotaxis and neutrophil apoptosisinhibitionHighplasma andBAL levels of IL-8 are found earlyduring ARDS and predict outcome [169] However previousstudies did not support such findings [170 171] In a recentmonocenter study of 100 patients only baseline IL-8 (among6 other biomarkers) was associated with the development ofmultiorgan failure even after adjustment for other relevantvariables [32] Also several studies have evaluated the roleof the anti-IL-8 autoantibodyIL-8 immune complexes inARDS a pathway that could lead to the identification of novelbiomarkers and therapeutic targets [17 172ndash175]

In a recent study Calfee et al used latent class analysisto integrate both clinical and biological data to identifytwo ARDS endotypes in an analysis of 1022 patients fromtwo ARDSNet trials (ARMA and ALVEOLI) [13] A firstendotype was categorized by more severe inflammation asassessed by both IL-6 and IL-8 levels and worse clinicaloutcomes whereas a second endotype had less inflammationless shock and better clinical outcomes Based on the datafrom the ALVEOLI trial a ldquoproinflammatoryrdquo endotypewas associated with higher mortality and better response tohigher levels of positive end-expiratory pressure [176]

(2) Anti-Inflammatory Cytokines The inflammatory responseis also strongly influenced by anti-inflammatory systemsincluding nonspecific (eg 2-macroglobulin IL-10) andspecific (eg IL-1 receptor antagonist (IL-1RA) antagonistssoluble IL-1 receptor II (sIL-1RII) soluble TNF receptorI (sTNF-RI) and soluble TNF receptor II (sTNF-RII)) ofproinflammatory cytokines

(a) IL-1RA Circulating IL-1RA levels are increased but donot predict the development of ARDS in at-risk patients[56] Studies of gene expression in alveolar macrophagesand circulating leukocytes from healthy control subjects andpatients with ARDS revealed that sIL-1RII may be valuable asa biomarker because of increased levels in both the lung andcirculation during ARDS [57]

(b) sTNF-RIsTNF-RII Soluble TNF-120572 receptors (sTNF-R)I and II can bind TNF and compete with its binding tothe cellular receptor thus reducing its bioavailability SolubleTNF-RI and TNF-II are associated with morbidity andmortality in patients with ARDS [54] and a strategy of lowtidal volume ventilation is associated with decreased sTNF-RI levels [54] Trauma-associated ARDS differs clinically andbiologically from ARDS due to other clinical disorders withlower levels of sTNF-RI patients with trauma as a primarycause of ARDS [6 58]

(c) IL-10 Interleukin-10 (IL-10) is an anti-inflammatorycytokine that is produced by several cells including B lym-phocytes monocytes and alveolar macrophages [60] Asidefrom inhibiting the production of IL-1 and TNF-120572 IL-10

Disease Markers 9

upregulates TNF receptors [177] and stimulates the produc-tion of the naturally occurring IL-1RAand the release of sTNFreceptors [178] IL-10 inhibits the production of proinflam-matory mediators by alveolar macrophages involved duringARDS [179] ARDS patients have lower plasma and BALlevels of IL-10 than at-risk patients who did not develop thesyndrome [61] Higher baseline IL-10 levels were associatedwith higher morbidity and mortality [59]

(3) Additional Markers Other markers with potential clinicalimportance in ARDS-associated inflammation have beenidentified as putative biomarkers during ARDS

High mobility group box nuclear protein 1 (HMGB1) is aDNAnuclear binding protein that is secreted by immune cellsincluding monocytes and macrophages HMGB1 increasesearly after severe trauma and correlates with systemic inflam-matory response and development of ARDS [62] Alveolarand plasma levels of HMGB1 (as measured in the arterial orcentral venous blood) are elevated in patients with ARDS andassociated with outcome [109] In 20 patients with ARDSplasma levels of HMGB1 were also higher in nonsurvivorsand correlated with levels of sRAGE [63]

Lipopolysaccharide binding protein (LBP) is an acutephase protein that is correlated with lung inflammationduring ARDS [64] More recently it has also been demon-strated that serum levels of LBPwere strongly associated withincreasedmortality and the development of ARDS in patientswith severe sepsis [65]

Nitric oxide (NO) is a marker of oxidative stress thathas also been investigated as a marker of ARDS In patientswith persistent ARDS higher levels of nitric oxide andof its end-products (eg nitrotyrosine) are associated withmortality [66] In contrast higher urine NO levels werestrongly associated with better clinical outcomes includingmortality and ventilator-free days in patients enrolled in theARDSNet low tidal volume trial [46] Extracellular citrullinethe effective precursor of NO is lower in the plasma frompatients with severe sepsis and lower plasma citrulline isassociated with the presence of ARDS [67] Mechanismsinvolved in the regulation of lung injury by NO-dependentpathways remain unknown

Although C-reactive protein (CRP) is widely consideredas a marker of systemic inflammation higher levels of CRPare associated with better outcome among patients withARDS [68] Nevertheless a recent study found that albuminlevels rather than CRP may help to predict and monitor theseverity and course of ARDS in febrile critically ill patientswith ARDS or at risk for the syndrome [69] In the samestudy levels of lactate dehydrogenase (LDH) predicted 28-day mortality but were not correlated with severity [69]

313 Coagulation and Fibrinolysis During early ARDS acti-vation of the inflammatory cascades results in the activationof the coagulation system which in turn can influenceinflammatory responses by affecting the expression of variouscytokines such as IL-1 IL-6 and IL-8 Activation of coagula-tion pathways induces migration of inflammatory cells intoalveoli through the endothelial and epithelial barriers and

generates thrombin formation In addition proinflammatoryevents may also inhibit fibrinolysis and induce platelet acti-vation [17]

Extravascular fibrin deposition when localized predomi-nantly in the alveolar compartment is found in several acuteinflammatory lung diseases and enhanced alveolar procoag-ulant activity is reported inARDS patients [180] Fibrin depo-sition may be beneficial for gas exchange by sealing leakagesites when lung capillary endothelial and epithelial barriersare disrupted Nevertheless fibrin alveolar deposition maybe harmful since it can lead to activation of neutrophilsand fibroblasts endothelial injury loss of surfactant activityfavoring alveolar collapse impaired alveolar fluid clearanceand thrombotic obstruction of the microcirculation [180]

(1) PAI-1 The balance between activation of coagulationand activation of fibrinolysis is an important determinantof the amount and duration of fibrin deposition duringlung injury Plasminogen activator (PA) and plasminogenactivator inhibitor-1 (PAI-1) regulate fibrinolysis through theconversion of plasminogen to plasmin a fibrinolytic enzymePA-1 is amajor endogenous inhibitor of PA Both PA and PA-1are secreted by various cells including macrophages fibrob-lasts and lung endothelial and epithelial cells [71] DuringARDS alveolar epithelial cells and activated macrophagesoverexpress PAI-1 thus contributing to decreased alveolarfibrinolytic activity Nevertheless the value of PAI-1 asa biomarker in ARDS remains controversial PAI-1 levelswere higher in patients with ARDS than in patients withhydrostatic lung edema [72] and higher PAI-1 levels areassociated withmortality and higher durations ofmechanicalventilation in patients with ARDS [72 169] In a large Finnishstudy PAI-1 levels were not correlated with mortality ordevelopment of ARDS in critically ill patients undermechan-ical ventilation but low baseline plasma levels of the solubleurokinase plasminogen activator receptor (suPAR) were pre-dictive of survival [181] In a secondary analysis of two largerandomized controlled trials PAI-1 was associated with lunginjury (as defined as decreased oxygenation index) but notwithmortality [28] Nevertheless in another study of patientsfrom the ARDSNet ARMA study higher levels of PAI-1were independently associated with higher mortality andclinical outcomes including organ failure [182] Howeverthis association between PAI-1 levels and the development ofmultiorgan failure was not confirmed in a recent study of 100ARDS patients [32]

(2) Protein C Protein C system is an important endogenousregulator of coagulation and fibrinolysis Protein C is synthe-sized by the liver and circulates as an inactive compoundIt is transformed to its active form on cell surface by thethrombomodulin- (TM-) thrombin complex [75 76] Theendothelial cell protein C receptor (EPCR) is another cellsurface protein that can further enhance protein activationby binding the TM-thrombin complex [183] In additionto suppressing thrombin formation activated protein C hasanti-inflammatory properties such as decreasing the levelsof proinflammatory cytokines [184] Protein C can improveendothelial permeability and exert antiapoptotic effects via

10 Disease Markers

p53 pathways [185] Activated protein C can also inactivatePAI-1 thus promoting fibrinolysis [186] Plasma protein Cwas significantly lower in patients with ARDS as comparedto controls and it was associated with worse clinical out-comes including higher hospital mortality shorter durationof unassisted ventilation and increased risk ofmultiple organfailure [73] In a larger cohort of patients with early ARDSlow plasma levels of protein C were again associated withmortality and adverse clinical outcomes [182] Decreasedlevels of protein C during ARDS suggest a link betweenhypercoagulability and mortality

(3) Thrombomodulin Thrombomodulin (TM) is a mul-tidomain transmembrane-bound glycoprotein found on thesurface of endothelial cell Its main role is to neutralize theprocoagulant effects of thrombin and accelerate activationof protein C In addition to its membrane-bound form TMalso exists as a circulating soluble isoform in the plasmaIn patients with ARDS levels of soluble thrombomodulin(sTM) are higher in the pulmonary edema fluid than inplasma [73] suggesting an alveolar source but no correlationwas found between plasma sTM and the development ofARDS yet higher levels of sTM were observed in patientsat high risk for ARDS In patients with established ARDShigher plasma and alveolar levels of sTM were correlatedwith severity of illness and multiple organ failure [73] Ina larger analysis of 449 patients elevated levels of plasmasTM were associated with increased mortality thus possiblyreflecting an increased degree of inflammation and both lungand systemic endothelial damage [74]

(4) Tissue Factor (TF) Tissue factor (TF) is a 47 kDa trans-membrane glycoprotein that is the most potent stimulator ofthe extrinsic coagulation cascade TF initiates the coagulationcascade by binding and allosterically activating coagulationfactor VIIa The resulting TF-VIIa complex binds the sub-strate coagulation factor X via multiple interactions alongan extended interface to produce the TF-VIIa-X complexThis complex leads eventually to thrombin formation andfibrin deposition [77] Levels of TF in lung edema fluid arehigher than plasma levels in patients with ARDS supportinga lung origin for TF in this setting and both plasma andalveolar levels of TF are higher in ARDS patients as comparedto patients with hydrostatic edema [187] Notably patientswith sepsis-induced ARDS may have higher levels of TF ascompared to patients without ARDS [78]

(5) Cell-Free Hb Levels of cell-free hemoglobin (Hb) arehigher in the air space of ARDS patients as comparedto critically ill patients with hydrostatic lung edema [79]Instillation of red blood cells or cell-free hemoglobin causeslung injury in rats [188] and intra-alveolar hemorrhage isassociated with high levels of intra-alveolar cell-free Hbmore severe lung injury and increased lipid peroxidationin the lung from mice with tissue factor deficiency [79]Precise cellular and molecular mechanisms by which cell-free hemoglobin in the air space could mediate or potenti-ate ARDS are currently under investigation [189] Cell-freeHb could activate chemokine release within the lung and

decompartmentalization of hemoglobin is likely to provide asignificant proinflammatory stimulus in the setting of diffusealveolar damage and hemorrhage during ARDS [80]

314 EFPL Protein Ratio The pathophysiology of ARDSincludes disruption of several physical barriers includingendothelial and epithelial cell layers the basement mem-brane and the extracellularmatrix resulting in increased pul-monary microvascular permeability The pulmonary edemafluid-to-plasma protein (EFPL) ratio is a rapid safe andnoninvasive measure of alveolar-capillary membrane per-meability The EFPL ratio was first proposed as a tool todetermine the etiology of acute pulmonary edema [81] Morerecently in a large study of 390 critically ill patientsWare et aldemonstrated that the EFPL ratio had an excellent discrimi-native value in distinguishing ARDS from hydrostatic edemaand was strongly associated with clinical outcomes Using acutoff of 065 the EFPL ratio had a sensitivity of 81 and aspecificity of 81 for the diagnosis of ARDS [82]

32 Fibroproliferative Phase of ARDS In some patientsimportant and persistent accumulation of macrophagesfibrocytes fibroblasts and myofibroblasts in the alveolarcompartment leads to excessive deposition of ECM com-ponents including fibronectin and collagen types I and IIIamong other proteins An imbalance between profibrotic andantifibrotic mediators may subsequently drive this fibropro-liferative response [190] Growth factors play a major rolein the resolution of ARDS [17] Lung endothelial repair ispromoted by vascular endothelial growth factor (VEGF)A variety of growth factors promote repair of the alveo-lar epithelium including keratinocyte growth factor (KGF)hepatocyte growth factor (HGF) fibroblast growth factor(FGF) and transforming growth factor-120572 (TGF-120572) [17] Twomajor pathways with opposite effects involve growth factorsduring ARDS tyrosine kinase receptor mediation (eg KGFHGF FGF and VEGF) and serine-threonine kinase receptorssuch as TGF-1205731 which tend to have opposed effect on theupregulation that occurs when the tyrosine kinase receptorpathway is involved [85 191 192]

321 Endothelial Proliferation Novel evidence points to apotential role of VEGF in promoting repair of the alveolar-capillarymembrane during recovery fromARDS and under-standing the role of VEGF in this disease process couldbe crucial for developing new therapeutic strategies [85193] In the lung VEGF is produced primarily by epithelialcells it increases microvascular permeability [83] but has animportant role also during the repair phase by stimulatingendothelial cell proliferation and survival [86 149] Thelevels of VEGF are increased in plasma from patients withARDS but are decreased in BAL fluid compared to healthycontrols subsequently BAL levels of VEGF increase duringthe resolution of lung injury [39 84 149]

322 Epithelial Proliferation and Apoptosis KGF also knownas FGF-7 is a potent mitogenic factor for alveolar epithelialcells that is primarily produced by fibroblasts and other

Disease Markers 11

cells such as T lymphocytes KGF regulates transepithelialtransport of sodium by stimulating the epithelial channelNa+-K+-ATPase in alveolar epithelial cells [87]

HGF is a nonspecific mitogen secreted by fibroblastsalveolar macrophages endothelial cells and epithelial cellsSeveral animal and human studies suggest that KGF andHGFcould protect the alveolar space against injury and couldfacilitate the repair of alveolar structures after injury [88 194195] KGF levels could be measured in the BAL from patientswith ARDS but not in the BAL from those without ARDS inaddition BALKGFwas associated with poor prognosis [196]Elevated HGF levels were also associated with outcome [196]In 36 patients with ARDS and 11 patients with hydrostaticlung edema HGF and KGF were proven biologically activein the edema fluid of patients with ARDS and higher levelsof HGFwere associated withmortality in these patients [197]

Apoptosis of alveolar epithelial cells is a major phe-nomenon in the initiation and perpetuation of lung injury[89] The FasFasL system plays an important role in theregulation of cell life and death through its ability to initiateapoptosis [198] This system combines the cell membranesurface receptor Fas (CD95) and its natural ligand FasL(CD95L) Membrane-bound FasL mediates lymphocyte-dependent cytotoxicity clonal deletion of alloreactive T cellsand activation-induced suicide of T cells [199] Its solubleform (sFasL) results from cleavage of membrane FasL byMMPs and induces apoptosis in susceptible cells [200]Apoptosis is inducedwhenmembrane-bound or soluble FasLbinds to Fas-bearing cells By contrast apoptosis is inhibitedwhen soluble Fas binds to either membrane-bound FasL orsFasL thus preventing FasL from interacting withmembrane-bound Fas receptors [201] In patients with ARDS sFasL wasdetectable in the lung before and after the onset of clinicallydefined ARDS and nonsurvivors had significantly higherBAL levels of sFasL on day 1 as compared with survivors[200] Both soluble Fas and soluble FasL were associated withoutcome and higher in the lung edema fluid from patientswith ARDS compared to control patients with hydrostaticpulmonary edema [202] Nevertheless recent findings sug-gested limited role for FasFasL system and apoptosis inairway epithelial cell death during ARDS [90]

323 Fibroblast Proliferation Pulmonary fibroblasts pro-duce procollagen III peptide (PCP-III) that is a precursorof collagen The NT part of procollagen III resulting fromthe enzymatic cleavage of procollagen by specific proteases inthe extracellular space is considered as a marker of collagensynthesis Alveolar levels of N-PCP-III are higher in ARDSpatient as compared with controls [203] The elevation ofN-PCP-III in pulmonary edema fluid begins within the first24 h of ARDS that is during the acute phase of increasedendothelial and epithelial permeability to protein suggestingthat fibrosing alveolitis could begin very early in the course ofclinical ARDS [203] In another study high levels of N-PCP-III were early predictors of poor outcome [204 205] Morerecently Forel et al measured alveolar N-PCP-III in patientswith nonresolving ARDS thus identifying patients who haddeveloped lung fibroproliferation [206] Unfortunately it

is still unknown whether N-PCP-III measurements couldbe useful in selecting patients who would benefit fromglucocorticoid therapy among others to reduce the ARDS-associated lung fibrosis [207]

4 Perspectives

41 Combining Biomarkers Despite advances in the identi-fication of biomarker candidate and better understanding ofARDS pathogenesis no single clinical or biological markerreliably predicts clinical outcomes inARDSThe combinationof clinical and biological marker is attractive in order toimprove the sensitivity andor the specificity of the testespecially through a recent approach aimed at measuring8 biological markers that reflect endothelial and epithelialinjury inflammation and coagulation vWF SP-D TNF-R1IL-6 IL-8 ICAM-1 protein C and PAI-1 in 549 patientsenrolled in the the ARDSNet trial of low versus high positiveend-expiratory pressure [208] Clinical predictors predictedmortality with an area under the ROC curve (AUC) of082 whereas a combination of these 8 biomarkers and theclinical predictors had an AUC of 085 The best performingbiomarkers were the neutrophil chemotactic factor IL-8 andSP-D a product of AT2 cells [208] supporting the conceptthat acute inflammation and alveolar epithelial injury areimportant pathogenetic pathways in human ARDS Morerecently a panel of biomarkers of lung epithelial injuryand inflammation (SP-D sRAGE IL-8 CC16 and IL-6)provided excellent discrimination for diagnosis of ARDSin patients with severe sepsis [20] Therefore and beyondtheir better diagnostic and prognostic values the use of suchbiomarker panels may be useful for selecting patients forclinical trials that are designed to reduce lung epithelial injury[113] Nevertheless whether a therapeutic strategy based onbiomarker measurements would benefit patient outcome hasnever been investigated

42 Lung Imaging as an ARDS Biomarker Studies of lungimaging during ARDS have revealed that adequate ventilatorsettings may vary among patients with the same syndromeIn a large study gas and tissue distribution in the lungs ofARDS patients were assessed using computed tomography(CT) and compared to those of healthy volunteers [11] Lungmorphology in ARDS is characterized by marked excess oflung tissue associated with a major decrease in aerated lungregions and in functional residual capacity Some patientswith ARDS exhibit preserved aeration of the upper lobesdespite the presence of an overall excess of lung tissue (ldquofocalrdquoARDS) as opposed to other patients with more diffuse lossof aeration and excessive lung tissue (ldquodiffuserdquo or ldquononfocalrdquoARDS) [209]

Lung morphology may influence the response to pos-itive end-expiratory pressure (PEEP) recruitment maneu-vers (RM) prone position and patient outcome [12 210]In a prospective study of nineteen patients with ARDSConstantin et al found that lung morphology at zero end-expiratory pressure could predict the response to a RM withcontinuous positive airway pressure of 40 cm H

2O for 40

12 Disease Markers

seconds Nonfocal morphology was associated with higherlung recruitability and PaO

2FiO2was significantly increased

by the RM [12 211] In contrast patients with focal lungmorphology were at risk of significant hyperinflation duringthe RM with no improvement of arterial oxygenation

It has also been hypothesized that the effects of PEEPmay depend on lung morphology Puybasset et al assessedthe responses to PEEP among patients with focal or nonfocalARDS [210] The regional distribution of intrapulmonarygas and lung tissue influences the effects of PEEP in ARDSpatients maximal alveolar recruitment without evidenceof overdistension was observed in patients with nonfocalARDS Nevertheless PEEP induced mild alveolar recruit-ment in patients with focal ARDS along with overdistensionof previously aerated lung regions

Interestingly phenotyping patients with ARDS basedon their lung morphology might be possible by measuringplasma sRAGEwith commercially available kits even thoughthese findings need further validation [100 112] HoweverRAGE pathway is a promising candidate for subphenotypingpatients with ARDS as it is believed to play a major rolein the mechanisms leading to AFC and their regulation[110] Recent findings that support a relationship betweenimpaired AFC and lung morphology may therefore fill a gapin the full recognition of an ARDS phenotype based on lungmorphology that could be linked to an endotype of impairedAFC and activated RAGE pathway [12 100 101 112 113 212]

43 Biomarkers in ARDS Can They Improve Patient CareBiomarkers are broadly used in critically ill patientsespecially during inflammatory andor infectious diseasesBiomarkers have been commonly defined as characteristicsthat are objectively measured and evaluated as indicatorsof normal biological processes pathogenic processes orpharmacologic responses to therapeutic interventions [213214] Biomarkers provide a powerful approach to understanda disease with multiple applications in observational andanalytic epidemiology randomized clinical trials screeningand diagnosis or prognosis [215]

Nevertheless there are important technical attributes fora relevant biomarker First the marker must be present inperipheral body tissue andor fluid (eg blood urine salivabreath or cerebrospinal fluid) second it must be easy todetect or quantify in assays that are both affordable androbust and third its regulation should be associated asspecifically as possible with damage of a particular tissuepreferably in a quantifiable manner Prior to the widespreaduse of a marker of interest it is essential that validation andconfirmation of candidate biomarkers by robust statisticalmethods are performed during biomarker discovery [215]Sensitivity and specificity are common quality parametersfor biomarkers Sensitivity describes the probability of apositive test in cases and specificity describes probability ofnegative test in controls An association between sensitivityand specificity is represented in the ROC curve by graphingsensitivity versus 100 minus specificity Area under the ROC curve(AUROC) is therefore a measure of performance of a markerThere is no absolute cutoff value of AUROC for robustness of

a marker but aminimum of 07 is required and values greaterthan 08 are good particularly in a heterogeneous critically illpatient population [216 217]

To summarize an ideal biomarker should indicate aclear relationship with the pathophysiologic event needsto be reliable reproducible disease specific and sensitiveand should be sampled by simple methods and relativelyinexpensive with little or no diurnal variation DuringARDS no single marker has been validated with all thesecriteria to date yet we believe that sRAGE may fulfill allprerequisites of a biomarker of ARDS First plasma sRAGEhas good diagnostic and prognostic values [96 99 100109 112] Second it is very well correlated with lung injuryseverity and specific pathophysiologic features of ARDS forexample alveolar fluid clearance and lung morphology [9699ndash101 109 112] Previous studies of the predictive value ofearly levels of sRAGE for the development of ARDS in ageneral population of patients admitted to the emergencydepartment were negative [130] but current research focuseson both the kinetics of sRAGE and esRAGE and RAGE genepolymorphisms as predictors of the development of ARDSin at-risk critically ill patients [114] Finally there is someevidence suggesting that monitoring sRAGE could informat least partially on therapeutic responses in patients with orwithout ARDS [24 99 113] If these data are confirmed byfuture studies such findingswould definitely help to reinforcesRAGE a real biomarker of ARDS

5 Conclusion

Biomarker research provides an important translational linkto our understanding of lung pathobiology Through theidentification and testing of candidate biomarkers we havegained insight into the pathogenic importance of endothelialand epithelial injury and have started to unravel the complexpathways that contribute to endothelial and epithelial celldysfunction inflammation fibrosis and apoptosis in ARDSIn addition biomarker studies may help us to explore thecellular and molecular mechanisms of various therapeuticstrategies for ARDS and to better understand the potentialproinflammatory effects of mechanical ventilation Giventhe clinical heterogeneity of patients with ARDS and thecomplexity of the underlying pathobiology it is unlikely thata single biomarker will emerge for ARDS as cardiac-specifictroponin did for myocardial infarction but the develop-ment of small biomarker panels reflecting each importantlung injury pathway would provide valuable predictive andprognostic information for both clinicians and investigatorsWhile biomarkers are currently not recommended for usein clinical practice in ARDS biomarker discovery mayhold significant promise in order to develop and applytargeted therapies and to identify candidates for enrollmentin patient-tailored clinical trials of novel therapies for ARDS

Disclosure

The funders had no influence on the study design conductand analysis or on the preparation of this paper

Disease Markers 13

Conflict of Interests

No conflict of interests other sources of financial supportcorporate involvement patent holdings and so forth are tobe declared for all authors

Authorsrsquo Contribution

Raiko Blondonnet was involved in the conception and designof the review in writing the paper and in its revision priorto submission Jean-Michel Constantin was involved in theconception and design of the review in writing the paperand in its revision prior to submission Vincent Sapin wasinvolved in the conception and design of the review inwriting the paper and in its revision prior to submissionMatthieu Jabaudon takes responsibility for the content ofthe paper and was involved in the conception and design ofthe review in writing the paper and in its revision prior tosubmission

Acknowledgments

This work was supported by grants from the AuvergneRegional Council (ldquoProgramme Nouveau Chercheur de laRegion Auvergnerdquo 2013) the french Agence Nationale de laRecherche and the Direction Generale de lrsquoOffre de Soins(ldquoProgramme de Recherche Translationnelle en Santerdquo ANR-13-PRTS-0010)

References

[1] VM Ranieri G D Rubenfeld P TThompson et al ldquoAcute res-piratory distress syndrome the Berlin definitionrdquo The Journalof the American Medical Association vol 307 no 23 pp 2526ndash2533 2012

[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000

[3] C Brun-Buisson C Minelli G Bertolini et al ldquoEpidemiologyand outcome of acute lung injury in European intensive careunitsrdquo Intensive Care Medicine vol 30 no 1 pp 51ndash61 2004

[4] G D Rubenfeld E Caldwell E Peabody et al ldquoIncidence andoutcomes of acute lung injuryrdquo The New England Journal ofMedicine vol 353 no 16 pp 1685ndash1693 2005

[5] D W Dowdy M P Eid C R Dennison et al ldquoQuality oflife after acute respiratory distress syndrome a meta-analysisrdquoIntensive Care Medicine vol 32 no 8 pp 1115ndash1124 2006

[6] C S Calfee M D Eisner L B Ware et al ldquoTrauma-associatedlung injury differs clinically and biologically from acute lunginjury due to other clinical disordersrdquo Critical Care Medicinevol 35 no 10 pp 2243ndash2250 2007

[7] C S Calfee D R Janz G R Bernard et al ldquoDistinct molecularphenotypes of direct versus indirect ARDS in single and multi-center studiesrdquo Chest vol 147 no 6 pp 1539ndash1548 2015

[8] P Tejera N J Meyer F Chen et al ldquoDistinct and replicablegenetic risk factors for acute respiratory distress syndromeof pulmonary or extrapulmonary originrdquo Journal of MedicalGenetics vol 49 no 11 pp 671ndash680 2012

[9] M A Matthay G A Zimmerman C Esmon et al ldquoFutureresearch directions in acute lung injury summary of a National

Heart Lung and Blood Institute Working Grouprdquo AmericanJournal of Respiratory and Critical Care Medicine vol 167 no7 pp 1027ndash1035 2003

[10] J P Reilly S Bellamy M G S Shashaty et al ldquoHeterogeneousphenotypes of acute respiratory distress syndrome after majortraumardquo Annals of the American Thoracic Society vol 11 no 5pp 728ndash736 2014

[11] L Puybasset P Cluzel N Chao et al ldquoA computed tomographyscan assessment of regional lung volume in acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol158 no 5 pp 1644ndash1655 1998

[12] J-M Constantin S Grasso G Chanques et al ldquoLungmorphol-ogy predicts response to recruitment maneuver in patients withacute respiratory distress syndromerdquo Critical Care Medicinevol 38 no 4 pp 1108ndash1117 2010

[13] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoSubphenotypes in acute respiratorydistress syndrome latent class analysis of data from tworandomised controlled trialsrdquoThe Lancet Respiratory Medicinevol 2 no 8 pp 611ndash620 2014

[14] R Marshall G Bellingan and G Laurent ldquoThe acute respira-tory distress syndrome fibrosis in the fast lanerdquoThorax vol 53no 10 pp 815ndash817 1998

[15] R B Henderson J A R Hobbs M Mathies and N HoggldquoRapid recruitment of inflammatory monocytes is independentof neutrophil migrationrdquo Blood vol 102 no 1 pp 328ndash3352003

[16] HMMarriott andDH Dockrell ldquoThe role of themacrophagein lung disease mediated by bacteriardquo Experimental LungResearch vol 33 no 10 pp 493ndash505 2007

[17] L J M Cross and M A Matthay ldquoBiomarkers in acute lunginjury insights into the pathogenesis of acute lung injuryrdquoCritical Care Clinics vol 27 no 2 pp 355ndash377 2011

[18] H K Gaggin and J L Januzzi ldquoBiomarkers and diagnostics inheart failurerdquo Biochimica et Biophysica Acta (BBA)mdashMolecularBasis of Disease vol 1832 no 12 pp 2442ndash2450 2013

[19] E Christenson and R H Christenson ldquoThe role of cardiacbiomarkers in the diagnosis and management of patientspresenting with suspected acute coronary syndromerdquo Annals ofLaboratory Medicine vol 33 no 5 pp 309ndash318 2013

[20] L B Ware T Koyama Z Zhao et al ldquoBiomarkers of lungepithelial injury and inflammation distinguish severe sepsispatientswith acute respiratory distress syndromerdquoCritical Carevol 17 no 5 article R253 2013

[21] M A Matthay L B Ware and G A Zimmerman ldquoTheacute respiratory distress syndromerdquo The Journal of ClinicalInvestigation vol 122 no 8 pp 2731ndash2740 2012

[22] M Shirasawa N Fujiwara S Hirabayashi et al ldquoReceptor foradvanced glycation end-products is a marker of type I lungalveolar cellsrdquo Genes to Cells vol 9 no 2 pp 165ndash174 2004

[23] M Neeper A M Schmidt J Brett et al ldquoCloning andexpression of a cell surface receptor for advanced glycosylationend products of proteinsrdquo The Journal of Biological Chemistryvol 267 no 21 pp 14998ndash15004 1992

[24] M Jabaudon E Futier L Roszyk V Sapin B Pereira andJ Constantin ldquoAssociation between intraoperative ventilatorsettings and plasma levels of soluble receptor for advancedglycation end-products in patients without pre-existing lunginjuryrdquo Respirology vol 20 no 7 pp 1131ndash1138 2015

[25] L G Dobbs R F Gonzalez L Allen and D K Froh ldquoHTI56an integral membrane protein specific to human alveolar type

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Research and TreatmentAIDS

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 Disease Markers

ARDS predict the syndrome identify mechanism-definedsubgroups of ARDS andor to better target therapy [10 13]The subtype (or phenotype) of a condition is ideally definedby a distinct functionalpathobiological mechanism namedendotype that may explain at least in part response totreatment [13]

2 Pathogenesis of ARDS

The pathogenesis of ARDS is characterized by two phasesthat may sometimes overlap temporally and spatially [2]exudative and proliferative [14] phases An alveolar-capillarybarrier dysfunction resulting in altered permeability ofepithelial and endothelial alveolar cells characterizes the earlyexudative phase Due to loss of cellular integrity alveoliare filled with proteinaceous edema fluid that results inimpaired gas exchange Initially there is an early exudativephase associated with diffuse alveolar damage microvascularinjury with subsequent pulmonary edema alveolar type 1(AT1) epithelial cell necrosis and influx of inflammatory cellswhich then release active mediators [2] During this earlyphase alveolar inflammation ismainlymediated by polymor-phonuclear neutrophils (PMN) [2] but recent findings alsosupport a key role for monocytes and macrophages [15 16]Other proinflammatory mechanisms are also involved asthe significant release of proinflammatory cytokines by lungscells inflammatory cells and fibroblasts

The association of persistent injury and failure to repairlung damage in a timely manner mainly contributes to thepathological fibroproliferative response during which thereare proliferation of fibroblasts hyperplasia of AT2 cells andlung repair The repair of the injured alveolar epitheliumremains incompletely understood it involves hyperplasia ofAT2 (and maybe AT1) cells migration along the basementmembrane by AT2 cells to form a new epithelial barrier andcomplex interactions with ECM and other cells includingalveolar macrophages In the absence of recovery processesleading to fibrosing alveolitis may occur during a fibroticphase resulting in some cases in marked changes in lungstructure and function [17]

3 Biomarkers of ARDSA Pathophysiologic Approach

The discovery and validation of biomarkers of myocardialinjury and ventricular overload such as troponin and brain-natriuretic peptide (BNP) have transformed the diagnosismanagement and design of clinical trials in conditions suchas myocardial infarction and congestive heart failure [18 19]In a similar way identification of plasma biomarkers thatmayfacilitate diagnosis of ARDS could at least in theory improveclinical care enhance our understanding of pathophysiologyand be used to enroll more homogeneous groups of patientsin clinical trials of new therapies increasing the likelihood ofdetecting a treatment effect [20] Pathophysiologic changescan probably be used as a framework to better understandvarious biomarkers that have been studied in ARDS includ-ing the cellular injury pathways that are central to lung injury

endothelial injury epithelial injury proinflammatory injurycoagulation fibrosis and apoptosis [21]

Among multiple potential applications biomarkers maybe used to better identify patients with risk factors of ARDSwho are most likely to develop the syndrome Subsequentlythey may also be useful to improve risk stratification onceARDS criteria are present Biomarkers may also play apivotal role in the design of future clinical trials throughthe identification of patients at high risk of poor outcomethus decreasing the required sample size needed to showa therapeutic benefit [92] More recently biomarkers havealso been proven useful to evaluate the response to therapy[13 93] Finally the study of biomarkers in ARDS playsa fundamental role in understanding the mechanisms andpathophysiology underlying lung injury thus serving as asolid basis to develop future therapeutic strategies [9]

We will now review the biomarkers that have beeninvestigated in ARDS with a focus on biomarkers in groupsthat reflect their primary function (Figure 1 and Table 1)

31 Exudative Phase of ARDS ARDS is characterized byan initial exudative phase with diffuse alveolar damageassociated with the formation of lung inflammatory edemaAlveolar injury is predominant during this phase and variousproteins that are specific to lung injury are therefore releasedin both the blood and the alveolar compartment thus servingas markers of the disease or of its resolution

311 Lung Injury

(1) Alveolar Epithelium The alveolar epithelial lining iscomposed of AT1 and AT2 epithelial cells and plays a criticalrole in barrier function regulating surfactant productionand in vectorial transport of alveolar fluid During the acutephase of ARDS alveolar epithelial cells undergo neutrophil-mediated damage and effects of proinflammatory cytokinesor of hypoxic injury thus accounting for the clinical syn-drome [2] Lung-secreted proteins may be found in both thebronchoalveolar (BAL) fluid and the systemic blood becausethey can move passively across the epithelial barrier intoserum where they may serve as peripheral indicators ofepithelial damage Several markers of lung epithelial damagehave been studied as markers of ARDS as supported by thefact that they should be more specific to lung injury thanother markers for example inflammatory cytokines [94]

(a) Alveolar Type 1 Cells They are of two types

RAGE AT1 epithelial cells cover 90ndash95 of the alveolar sur-face and contribute to both alveolar fluid clearance (AFC) andbarrier integrity The receptor for advanced glycation end-products (RAGE) is a transmembrane pattern-recognitionreceptor of the immunoglobulin superfamily that is constitu-tively expressed at low levels in all cells but abundantly in thelung RAGE is primarily located on the basal surface of AT1cells [22 23] Activation of RAGE modulates cell signalingculminating in a sustained inflammatory response throughvarious intracellular signaling pathways such as cytokinesreactive oxygen species (ROS) or proteases and leading to

Disease Markers 3

Exudative

Epithelium damage

Endothelium damage

Inflammatory cascade

IL-6 and IL-8

IL-10Additional markers HMGB1 LBP NO CRP

Anti-inflammatory IL-1RA sTNF-RIII and

albumin and LDHPulmonary vascular permeability

EFPL ratioLung matrix alteration

LamininElastindesmosineMMPs 2 3 8 9 and 13

PA-1Protein C

Coagulation and fibrinolysis

phase

ATI cells sRAGE HTI56ATII cells surfactant KL-6Club cells CC16

Ang-1 Ang-2ICAM-1SelectinsVEGFvWF

Epithelial apoptosis

Fibroproliferative phase

FasFasL

VEGF

KGFHGF

N-PCP-III

Epithelial proliferation

Fibroblast proliferation

Endothelial proliferationProinflammatory IL1-120573TNF-120572 IL-18

ThrombomodulinTissue factorCell-free hemoglobin

Club cell

Alveolar type I cell

Alveolar type II cell

Red cell

Alveolarmacrophage

Neutrophil

CapillaryInterstitium

Protein-richedema fluid

differentiation ofalveolar type II cells

Alveolus

Necrotic alveolartype I cell

Proliferation and

m Fibroblast

Figure 1 Biomarkers of acute respiratory distress syndrome organized by pathways and phases of lung injury (left early exudative phaseright fibroproliferative phase)

proinflammatory activation of nuclear transcription factorNF-120581B [95 96] RAGE is implicated in ARDS as an importantpathway to innate immunity and alveolar inflammation [97]and when the soluble form (sRAGE for soluble RAGE) isassayed in plasma or pulmonary edema fluid as a markerof alveolar injury [98ndash101] Full-length RAGE is a transmem-brane receptor but it can also be found as soluble isoformsgenerally referred to as soluble RAGE (sRAGE comprisingthe extracellular domain of RAGE and produced through thecleavage of full-length RAGE by matrix metalloproteinases)[102 103] and endogenous secretory RAGE (esRAGE pro-duced after alternative splicing) [104] Full-length RAGE andits isoforms are abundantly and constitutively expressed inthe lungs in normal conditions [103 105ndash107] and sRAGEis now considered as a promising novel marker of AT1 cellinjury and a key mediator of alveolar inflammation [22 95108] It is shown that sRAGE expression appears enhancedduring the early stage of ARDS Our team with others hasrecently reported in both ARDS patients and a mouse modelof ARDS that the extent of sRAGE elevation in plasma andalveolar fluid correlates with markers of severity assessed byPaO2FiO2 lung injury and alveolar fluid clearance (AFC)

[98ndash101 109] A role for RAGE pathway in the regulation ofAFC has been recently described for the first time [110] and isunder active investigation by our team and others [101 111]Interestingly plasma and BAL sRAGE levels are elevatedduring ARDS independently of any associated severe sepsis[100] In addition plasma levels of sRAGE are correlated with

diffuse damage as assessed by lungCT-scan and are correlatedwith the extent of alveolar damage [100 112] suggesting thatsRAGEmay serve as a useful biomarker of AT1 cell injury andlung damage during ARDS Plasma levels of sRAGE are alsoassociated with 28-day and 90-day mortality in patients withARDS [99 106 112]

Calfee et al recently compared biomarker levels inpatients with direct versus indirect ARDS enrolled in a singlecenter study of 100 patients and in a secondary analysis of 853ARDS patients drawn from a multicenter randomized con-trolled trial [7] levels of biomarkers of lung epithelial injury(sRAGE surfactant protein-D) were significantly higher indirect ARDS compared to indirect ARDS

A recent observational study also supports an ARDSphenotype based on levels of RAGE ligands and solubleforms as elevated sRAGE high mobility group box-1 pro-tein (HMGB1) and S100A12 with decreased esRAGE andadvanced glycation end-products (AGEs) were found todistinguish patients with ARDS from those without [109]Although these recent findings warrant further validation inmulticenter studies monitoring sRAGE levels may be usefulin assessing the response to strategies in ventilator settingsincluding alveolar recruitment maneuvers in patients withARDS [113] or in patients without lung injury at risk of post-operative respiratory complications after major surgery [24]The predictive value of 4 single-nucleotide polymorphisms inRAGE gene (AGER) in the development of ARDS in at-riskpatients is currently under study by our team [114]

4 Disease Markers

Table 1 Biomarkers of acute respiratory distress syndrome organized by phases and pathways of lung injury

Pathophysiologic feature of ARDS Biomarker ReferencesExudative phase

Epithelium damage

(i) Alveolar type 1 cells RAGE [22ndash24]HTI56

[25 26]

(ii) Alveolar type 2 cells Surfactant [27 28]KL-6 [29 30]

(iii) Clara cells CC16 [31 32]Endothelium damage

Ang-1 Ang-2 [33 34]ICAM-1 [35 138ndash140]Selectins [36 37]VEGF [38 39]vWF [40ndash42]

Lung matrix alterationLaminin [43 44]

Elastindesmosine [45 46]MMPs [47ndash49]

Inflammatory cascade

(i) Proinflammatory

IL-1120573TNF-120572 [17 161ndash164 167]IL-18 [50 51]IL-6 [52ndash55]IL-8 [169ndash171]

(ii) Anti-inflammatoryIL-1RA [56 57]

sTNF-RIsTNF-RII [6 54 58]IL-10 [59ndash61]

(iii) Additional markers

HMGB1 [62 63]LBP [64 65]NO [46 66 67]CRP [68]

Albumin [69]LDH [69]

Coagulation and fibrinolysisPA-1 [32 53 70ndash72]

Protein C [75 76 182]Thrombomodulin [73 74]

Tissue factor [75ndash78]Cell-free hemoglobin [75 76 79 80]

Pulmonary vascular permeabilityEFPL ratio [81 82]

Fibroproliferative phaseEndothelial proliferation

VEGF [39 83ndash86]Epithelial proliferation

KGF [87]HGF [88 194 195 197]

Epithelial apoptosisFasFasL [25 88ndash91]

Fibroblast proliferationN-PCP-III [88 194 195 203 207]

Disease Markers 5

HTI56 Human type I cell-specificmembrane protein (HTI56)

is a 56-kDa glycosylated lung protein specific to the apicalmembrane of human AT1 cells HTI

56has biochemical char-

acteristics of an integral membrane protein [25] Althoughthe precise functions of HTI

56remain unknown HTI

56is

an analog to RTI40 a 40ndash42 kDa integral membrane protein

specific to the apical membrane of rat AT1 cells [26] Patientswith ARDS had higher levels of HTI

56in both lung edema

fluid and plasma as compared to patients with hydrostaticlung edema [94] but no study assessing the associationbetween HTI

56levels and other endpoints in patients with

ARDS (eg prognosis) has been published to date

(b) Alveolar Type 2 Cells AT2 cells have important homeo-static functions in the lung including AFC and productionof alveolar surfactant (involved in lung compliance keepingthe alveolus open) AT2 cells are also known as keymediatorsof the epithelial repair process [115]

Surfactant Proteins Surfactant has a vital role in maintainingthe integrity of the alveolar-capillary interface Its essentialfunction is to decrease surface tension into the alveoli thusstabilizing lung volume at low transpulmonary pressuresSurfactant is composed of approximately 80 phospholipids8 other lipids (cholesterol triacylglycerol and free fattyacids) and 12 proteins Four surfactant-associated proteins(SP) designated SP-A SP-B SP-C and SP-D representapproximately half of proteins composing surfactant SP-Aand SP-D easily dissociate from lipids and are hydrosolubleThey belong to the lung innate immune system therebyenhancing phagocytosis of bacteria and virus They alsoexert regulatory effects on AT2 cells SP-B and SP-C aresmall extremely hydrophobic proteins that are important inthe formation of the surfactant monolayer in the terminalairspaces and in the reduction of surface tension thuspreventing end-expiratory alveolar collapse [116]

Early observations in ARDS revealed a loss in surfacetension suggesting a functional loss of the surfactant proteins[117] In a first case report of three patients the ratioof plasma SP-BSP-A was inversely associated with bothblood oxygenation and static respiratory system compliancesuggesting that SP-B breaches the alveolocapillary barriermore readily than SP-A and may therefore provide a moresensitive marker of lung injury [118] Plasma levels of SP-Aand SP-B are increased in patients with ARDS [70] and in at-risk patients [119 120] whereas lower SP-A and SP-B levelswere found in the BAL fluid of patients at risk for ARDSprior to the onset of the clinical syndrome SP-A and SP-Blevels remained low for as long as 14 days in patients withsustained ARDS Interestingly this decrease in BAL SP-A andSP-B does not result simply from dilution of alveolar fluids byplasma entering the alveolar spaces as SP-D levels remainedstable in parallel [119] In a cohort of 38 patients reducedpulmonary edema fluid SP-D and elevated plasma SP-A atthe onset of ARDS were associated with poor prognosis [27]Nevertheless in a study of 259 patients from the ARDSNettrial of low versus high end-expiratory pressure in ARDS(ALVEOLI) as well as in 75 patients enrolled in a randomized

trial of activated protein C for ARDS plasma SP-D was notassociated with 28-day mortality or ventilator-free days [28]

KL-6 Krebs von den Lungen-6 (KL-6) is a human MUC1mucin that belongs to the high-molecular-weight glyco-protein family After the cleavage of S-S bond KL-6 canspread into the pulmonary epithelial lining fluid In thenormal lung this glycoprotein can be predominantly foundin AT2 cells and its expression is enhanced during AT2proliferation regeneration or injury thus representing anattractive biomarker in ARDS Plasma KL-6 is elevated inARDS patients and correlates with lung injury and mortality[29 121ndash123] Plasma levels of SP-D and KL-6 increase overtime in patients with ARDS and may represent biologicalmarkers of ventilator-associated lung injury because theirincrease is attenuated by lung-protective ventilation [30]

(c) CC16 Clara cell protein (CC16) is a 158 kDa homod-imeric protein that is abundantly secreted in airways by thenonciliated bronchiolar Clara cells Clara cells are devotedto the protection of the respiratory tract against toxicinhaled agents the repair of damaged epithelium xenobioticsdetoxification and the secretion of proteins with importantbiological activities CC16 is highly expressed in the epitheliallining fluid with antioxidantinflammatory roles notably bymodulating the production andor activity of phospholipase-A2 interferon-120574 and tumor necrosis factor-120572 [31] Availablestudies found contradictory inconclusive findings duringARDS Although higher levels of CC16 are associated withlung injury and inflammation in some experimental andclinical studies patients with ARDS had lower plasma andpulmonary edema fluid levels of CC16 than patients withacute cardiogenic pulmonary edema and no correlation wasfound between CC16 and prognosis So many conflictingfindings do not currently support the association of CC16with the diagnosis or prognosis of ARDS

(2) Vascular Endothelium Vascular endothelial injury ischaracterized by the disruption of cell components leadingto increased microvascular permeability and alveolar edemaEndothelial injury is mainly driven by the activation ofinflammation and coagulation cascades The activation ofendothelial cells by circulating mediators leads to increasedexpression of cell surface molecules that are importantmediators of leukocyte adhesion and contribute to leuko-cyte accumulation and transmigration [124] Activated lym-phocytes can also release mediators in microvessels thatincrease vascular permeability Along with these leukocytesignals inflammatory mediators such as tumor necrosis fac-tor (TNF) thrombin and vascular endothelial growth factor(VEGF) disrupt endothelial-cadherin bonds and contributeto the vascular leak underlying edema formation in ARDSPlatelets also contribute to endothelial injury through therelease of cytokines and through fibrin clotting [92]

(a) Angiopoietin Angiogenic agents along with VEGF andangiopoietin-1 (Ang-1) play key roles in vascular develop-ment VEGF stimulates the generation of new immature

6 Disease Markers

and leaky blood vessels whereas Ang-1 enhances angiogene-sis inducing vascularmaturation anddecreases vascular per-meability [33] The most encouraging data result from recentstudies of angiopoietin-2 (Ang-2) an endothelial protein thathas been studied extensively during sepsis [125] Ang-2 has animportant role as it increases endothelial junction instabilityenhances vascular leak naturally antagonizes Ang-1 and inthe absence of other angiogenic stimuli induces vascularregression and endothelial cell apoptosis Both Ang-1 andAng-2 are ligands for the tyrosine kinase receptor Tie-2 [126] and a link between Ang-2 and inflammation hasbeen reported [127] Therefore such vascular growth factorshave been proposed as biomarkers for ARDS [128] Firsttwo single-nucleotide polymorphisms within the Ang-2 gene(rs1868554 and rs2442598) were associated with the riskof developing ARDS in trauma patients [129] In additionAgrawal et al found in a prospective study of 230 patientsadmitted to the intensive care unit (ICU) without ARDSthat higher levels of Ang-2 were significantly associatedwith increased development of ARDS [130] In surgical ICUpatients levels of Ang-2 were higher in patients with ARDSthan in those without the syndrome [131] A higher Ang-2Ang-1 ratio was also an independent predictor of mortalityin ARDS patients [131 132] and patients with infection-related ARDS whose Ang-2 levels increased between day 0and day 3 doubled their odds of death suggesting that Ang-2kinetics may be particularly valuable by reflecting evolvinglung injury [34] Finally in a large study of 931 patientsenrolled in the ARDSNet fluid and catheter treatment trialbaseline plasma levels of Ang-2 were associated with 90-daymortality in patients with noninfectious ARDS whereas thisassociation was not found in patients with infection as theirprimary ARDS risk factor Based on a secondary analysisof two large studies Calfee et al further demonstrated thatindirect lung injury is characterized by a molecular pheno-type consistent with more severe lung endothelial injury asassessed by plasma Ang-2 and less severe epithelial injury[7]

(b) ICAM-1 The soluble intercellular adhesion molecule-1 (sICAM-1) is an inducible glycoprotein expressed onthe surface of vascular endothelial cells and other cells(eg hematopoietic cells AT1 cells) [35] Under physiologicconditions sICAM-1 is not constitutively expressed or isexpressed at low levels in most tissues During inflammationand in response to stimuli such as interferon-120574 (IFN-120574) orinterleukin-1 (IL-1) levels of sICAM-1 are upregulated [133]Elevated levels have also been found in both plasma andlung edema fluid from patients with ARDS as compared topatients with hydrostatic lung edema [134] In a multicenterstudy the increase of sICAM-1 from baseline to day 3was associated with poor clinical outcome [135] and in aprospective cohort of 65 patients with ARDS baseline plasmalevels of sICAM-1 were also associated with mortality [136]In pediatric patients with ARDS early elevated plasma levelsof sICAM-1 were associated with increased risks of death andof prolongedmechanical ventilation [137] In traumapatientshigher plasma levels of sICAM-1 at baseline were correlated

with future development of multiple organ dysfunction syn-drome (MODS) but not with the development of ARDS [138ndash140]

(c) Selectins Selectins are membrane-associated glycopro-teins that mediate the adhesion of leukocytes and plateletsto vascular surface L-selectin is mainly expressed by leuko-cytes P-selectin is rapidly redistributed from membranoussecretory granules to the surface of activated platelets andendothelial cells [36] E-selectin is expressed by cytokine-activated endothelial cells It has been shown that plasmalevels of such soluble adhesion molecules were markedlyhigher in nonsurvivors among critically ill patients and thatthey were negatively correlated with lung function (egPaO2FiO2ratio) [141] Other studies found that plasma P-

selectin was elevated in patients with ARDS especially inthose who subsequently died as compared with patients withother pulmonary diseases or sepsis but without ARDS [142]Interestingly patients with ARDS with chronic alcohol con-sumption had elevated levels of soluble E-selectin in both theplasma and epithelial fluid consistent with altered endothe-lial and alveolar-capillary function [143] More recently E-selectin was measured in the plasma levels from 50 individ-uals admitted to the emergency department and who wereat-risk for developing ARDS with higher E-selectin levelsbeing associated with both ARDS development and 28-daymortality [144] Circulating soluble E-selectin levels wereelevated in pneumonia patientswithARDS and plasma levelsdecreased along with the treatment of pneumonia [37]

(d) VEGF One of the most extensively studied endothelialmarkers in ARDS is VEGF albeit its value as a biomarkerremains unclear Vascular endothelial growth factors belongto the platelet-derived growth factor supergene family Theyplay central roles in the regulation of angiogenesis andlymphangiogenesis [38] Alternative splicing of the VEGFgene (6p213) transcript leads to the generation of severalsplice variants or isoforms with various sizes [145] VEGF-Ais a 34ndash46 kDa glycoprotein acting as the major factor impli-cated in angiogenesis It binds to two tyrosine kinase (TK)receptors named VEGFR-1 (Flt-1) and VEGFR-2 (KDRFlk-1) and regulates endothelial cell proliferationmigration vas-cular permeability secretion and other endothelial functions[146] The expression of VEGF in ARDS varies dependingon the degree of epithelial and endothelial damage Manylung cells release VEGF for example AT2 cells neutrophilsalveolar macrophages and activated T cells Thus VEGFis potentially capable of having an effect on both alveolarepithelial and endothelial barriers Interestingly overexpres-sion of VEGF induces pulmonary edema in animal models[147] In a single center study plasma levels of VEGF wereincreased in subjects with ARDS compared to controls andelevated plasma VEGF as measured on day 4 was associatedwith mortality in patients with ARDS [83] Neverthelessseveral studies suggest that plasma and alveolar VEGF mayhelp to predict the development of ARDS and its recoveryWhereas plasma VEGF is increased in ARDS patients VEGFlevels were decreased in the BAL fluid from ARDS patients

Disease Markers 7

as compared to controls [84 148 149] In order to betterunderstand such differences between plasma and alveolarexpression of VEGF Ware et al conducted a study with theaim to determine whether changes in alveolar levels of VEGFwere specific to ARDS or not [39] the authors found thatalveolar levels of VEGF were decreased in both patients withARDS and those with hydrostatic edema The mechanismsimplicated in this alveolar decrease in VEGF during ARDSmight not depend on the degree of lung injury but rather onthe degree of alveolar flooding [39]

(e) vWF Early studies of endothelial markers focused on vonWillebrand Factor (vWF) a macromolecular antigen that isproduced predominantly by endothelial cells and to a lesserextent by platelets In the setting of endothelial activationor injury vWF is released from preformed stocks into thecirculation [40 41] VWFhas been investigated as a biologicalmarker of endothelial injury in patients both at-risk forARDSand with established ARDS [40 150] In a prospective studyof 45 ICU patients with sepsis patients with nonpulmonarysepsis had higher levels of plasma vWF with good predictiveand prognostic values for ARDS Indeed elevated plasmalevels of vWF had a sensitivity of 87 and a specificity of77 for the prediction of ARDS development in the settingof nonpulmonary sepsis [151] However subsequent studiesin patients at-risk for ARDS did not confirm these findings[42 152 153] In another study of 559 patients with ARDSenrolled in the National Heart Lung and Blood InstituteARDS Network trial of lower tidal volume nonsurvivorshad higher plasma levels of vWF compared to survivors[40] Higher vWF levels were significantly associated withfewer organ failure-free days suggesting that the degree ofendothelial activation and injury is strongly associated withoutcomes in ARDS nevertheless ventilator settings had noimpact on vWF levels in this study [40]

(f) Lung ExtracellularMatrixThe extracellularmatrix (ECM)forms the region of the lung situated between the alveo-lar epithelium and the vascular endothelium ECM playsa mechanical role as it supports and maintains tissularstructures ECM also represents a complex and dynamicmeshwork influencing many biological cell functions such asdevelopment proliferation and migration [154] Collagensare the main component of ECM along with glycoproteinsand proteoglycans including hyaluronic acid

Laminin Laminins (LM) are ECM proteins with high molec-ular weights that deposit in basal membranes Lamininsare involved in cell processes such as cellular adhesiongrowth and differentiation [43] Laminin-5 (LM-5) plays animportant role in cell migration and in the remodeling ofepithelial tissue LM-5 is activated through its cleavage bymatrix metalloproteinases (MMPs) thus releasing a solubleLN 1205742 NH2-terminal fragment (G2F) that does not depositin the ECM and can therefore be detected in the peripheralblood In a small single center study lamininwasmeasured inthe plasma and lung edema fluid from 17 patients with ARDSwith higher levels found in patients with ARDS as comparedto healthy volunteers [44] Interestingly nonsurvivors had

higher plasma levels of laminin as measured 5 days afterARDS onset than survivors and survivors had decreasinglevels of the marker over time suggesting that its secretionis suppressed during ARDS recovery

ElastinDesmosine Elastin is another critical protein of theECM that gives the lung its elastic recoil ability In adultselastin which is expressed by lungs and other tissues isusually excreted in the urine During lung epithelial andendothelial injury elastin can be broken down by proteasessuch as neutrophil elastase [45] Elastin breakdown results insmaller fragments containing desmosine and isodesmosine[155] In a large study of 579 patients with ARDS thoseventilated with lower tidal volumes had lower urine desmo-sine levels a finding that may reflect reduced extracellularmatrix breakdown however no correlation with mortalitywas found in patients with ARDS [46]

MMPs Matrix metalloproteinases (MMPs) are zinc-depend-ent endopeptidases that are able to degrade almost allextracellular matrix components MMP-8 a member of theleukocyte-derived MMPs contributes to the degradationturnover and remodeling of the extracellular matrix digest-ing type I collagen [47 48] MMPs are major actors inalmost all phases of the inflammatory response and theirfunction is highly regulated At the tissue level most impor-tant inhibitors are the tissue inhibitors of metalloproteinases(TIMPs) In fulminant inflammation the inhibitory capacityof TIMPs may be overwhelmed leading to excessive tissuedamage and adverse outcome [47] Previous studies suggestthat MMPs may have an important role in ARDS althoughthis role may be either harmful or beneficial [156 157] In arecent study despiteMMP-8 levels did not predict outcome inARDS patients higher levels of TIMP-1 were independentlyassociated with increased 90-day mortality in a large groupof critically ill mechanically ventilated patients [47] Thesefindings are in contradiction to those from a study inpediatric ARDS patients in which higher MMP-8 and activeMMP-9 levels as measured 48 hours after disease onset wereassociated with longer durations of mechanical ventilationand fewer ventilator-free days [158] ElevatedMMP-2 MMP-8 and MMP-9 in the BAL fluid from ARDS patients wereassociated with patterns of acute inflammation but with pooroutcome [157] Interestingly MMP-3 and MMP-13 may beprotective against lung injury by cleaving transmembranereceptor RAGE into sRAGE thus regulating RAGE activationby its ligands [48 49]

312 Inflammatory Cascades During ARDS inflammatoryresponses can either be related to an ongoing primaryinfectious stimulus such as pneumonia or to systemic inflam-mation such as in sepsis or in pancreatitis [2] The inflam-matory cascade involves inflammatory cells and the releaseof inflammatory mediators as driven by a complex networkof cytokines A comparison between blood and alveolarcytokines suggests that most inflammatory mediators orig-inate from the lung [17] Alarmins or damage-associatedmolecular patterns (DAMPs) are released by dead cells orlocal inflammatory cells (eg alveolar macrophages) They

8 Disease Markers

activate and recruit immune cells via binding to differentreceptors such as TLR IL-1 receptor (IL-1R) or RAGEthereby initiating and perpetuating multiple proinflamma-tory pathways [21 159]

Regulation of the inflammatory response is a complexprocess that requires interplay between several immunemediators [160] Both pro- and anti-inflammatory biomark-ers have been studied in ARDS

(1) Proinflammatory Cytokines

(a) IL-1120573 and TNF-120572 IL-1120573 and TNF-120572 are the most biolog-ically potent cytokines secreted by activated macrophages inthe early phase of ARDS They cause the release of a varietyof proinflammatory chemokines such as monocyte chemo-tactic protein-1 (MCP-1) macrophage inflammatory protein-1120572 (MIP-1120572) IL-6 and IL-8 with subsequent recruitmentof inflammatory cells into the air spaces alteration of theendothelial-epithelial barrier permeability and impairmentof fluid transport leading to alveolar edema [17] TNF-120572 alsopromotes lung edema indirectly through the production ofreactive oxygen species (ROS) and a decreased expressionof epithelial sodium (ENaC) and Na+-K+-ATPase channels[161] Finally TNF-120572 a potent chemoattractant for fibrob-lasts is a promoter of lung fibrosis in experimental studies[162 163] Interestingly the ratio of BAL to serum levelsof both TNF-120572 and IL-1120573 is typically high suggesting thatsuch cytokines may originate from the lung in the settingof ARDS [164] Persistent elevation of plasma and BAL IL-1120573 is associated with worse outcome [165 166] Both TNF-120572 and IL-1120573 are elevated in the plasma and BAL fluid frompatients at risk of and with ARDS [164 167] and associatedwith mortality [166]

(b) IL-18 Inflammasomes are intracellular macromolecularcomplexes that serve as platforms for the activation of theproinflammatory enzyme caspase-1 which in turn cleavespro-IL-1120573 and pro-IL-18 into IL-1120573 and IL-18 [50] Theseinflammasome-activated cytokines play central roles in thepropagation of the acute inflammatory response IL-18 andcaspase-1 play critical roles in the development of lunginjury and higher levels of IL-18 are correlated with diseaseseverity and mortality in patients with ARDS [168] Among38 patients with acute respiratory failure those with ARDShad significantly higher serum levels of IL-18 and serum IL-18 was significantly higher in nonsurvivors [51]

(c) IL-6 IL-6 is produced by a wide range of cells includingmonocytesmacrophages endothelial cells fibroblasts andsmoothmuscle cells in response to stimulation by endotoxinIL-1120573 and TNF-120572 [52] IL-6 is one of the most importantmediators of fever and is critical for B-cell differentiation andmaturation with secretion of immunoglobulins cytotoxic Tcell differentiation macrophage and monocyte function andproduction of acute phase proteins Although IL-6 activatesboth proinflammatory and anti-inflammatory mechanismsIL-6 primarily correlates with a proinflammatory profileduring the early phase of ARDS Plasma IL-6 increases earlyin patients at risk of developing ARDS [53] IL-6 is elevated in

both plasma and BAL fluid during ARDS [59] and correlateswith mortality [54 55]

(d) IL-8 IL-8 is a proinflammatory cytokine with a role inneutrophilmonocyte chemotaxis and neutrophil apoptosisinhibitionHighplasma andBAL levels of IL-8 are found earlyduring ARDS and predict outcome [169] However previousstudies did not support such findings [170 171] In a recentmonocenter study of 100 patients only baseline IL-8 (among6 other biomarkers) was associated with the development ofmultiorgan failure even after adjustment for other relevantvariables [32] Also several studies have evaluated the roleof the anti-IL-8 autoantibodyIL-8 immune complexes inARDS a pathway that could lead to the identification of novelbiomarkers and therapeutic targets [17 172ndash175]

In a recent study Calfee et al used latent class analysisto integrate both clinical and biological data to identifytwo ARDS endotypes in an analysis of 1022 patients fromtwo ARDSNet trials (ARMA and ALVEOLI) [13] A firstendotype was categorized by more severe inflammation asassessed by both IL-6 and IL-8 levels and worse clinicaloutcomes whereas a second endotype had less inflammationless shock and better clinical outcomes Based on the datafrom the ALVEOLI trial a ldquoproinflammatoryrdquo endotypewas associated with higher mortality and better response tohigher levels of positive end-expiratory pressure [176]

(2) Anti-Inflammatory Cytokines The inflammatory responseis also strongly influenced by anti-inflammatory systemsincluding nonspecific (eg 2-macroglobulin IL-10) andspecific (eg IL-1 receptor antagonist (IL-1RA) antagonistssoluble IL-1 receptor II (sIL-1RII) soluble TNF receptorI (sTNF-RI) and soluble TNF receptor II (sTNF-RII)) ofproinflammatory cytokines

(a) IL-1RA Circulating IL-1RA levels are increased but donot predict the development of ARDS in at-risk patients[56] Studies of gene expression in alveolar macrophagesand circulating leukocytes from healthy control subjects andpatients with ARDS revealed that sIL-1RII may be valuable asa biomarker because of increased levels in both the lung andcirculation during ARDS [57]

(b) sTNF-RIsTNF-RII Soluble TNF-120572 receptors (sTNF-R)I and II can bind TNF and compete with its binding tothe cellular receptor thus reducing its bioavailability SolubleTNF-RI and TNF-II are associated with morbidity andmortality in patients with ARDS [54] and a strategy of lowtidal volume ventilation is associated with decreased sTNF-RI levels [54] Trauma-associated ARDS differs clinically andbiologically from ARDS due to other clinical disorders withlower levels of sTNF-RI patients with trauma as a primarycause of ARDS [6 58]

(c) IL-10 Interleukin-10 (IL-10) is an anti-inflammatorycytokine that is produced by several cells including B lym-phocytes monocytes and alveolar macrophages [60] Asidefrom inhibiting the production of IL-1 and TNF-120572 IL-10

Disease Markers 9

upregulates TNF receptors [177] and stimulates the produc-tion of the naturally occurring IL-1RAand the release of sTNFreceptors [178] IL-10 inhibits the production of proinflam-matory mediators by alveolar macrophages involved duringARDS [179] ARDS patients have lower plasma and BALlevels of IL-10 than at-risk patients who did not develop thesyndrome [61] Higher baseline IL-10 levels were associatedwith higher morbidity and mortality [59]

(3) Additional Markers Other markers with potential clinicalimportance in ARDS-associated inflammation have beenidentified as putative biomarkers during ARDS

High mobility group box nuclear protein 1 (HMGB1) is aDNAnuclear binding protein that is secreted by immune cellsincluding monocytes and macrophages HMGB1 increasesearly after severe trauma and correlates with systemic inflam-matory response and development of ARDS [62] Alveolarand plasma levels of HMGB1 (as measured in the arterial orcentral venous blood) are elevated in patients with ARDS andassociated with outcome [109] In 20 patients with ARDSplasma levels of HMGB1 were also higher in nonsurvivorsand correlated with levels of sRAGE [63]

Lipopolysaccharide binding protein (LBP) is an acutephase protein that is correlated with lung inflammationduring ARDS [64] More recently it has also been demon-strated that serum levels of LBPwere strongly associated withincreasedmortality and the development of ARDS in patientswith severe sepsis [65]

Nitric oxide (NO) is a marker of oxidative stress thathas also been investigated as a marker of ARDS In patientswith persistent ARDS higher levels of nitric oxide andof its end-products (eg nitrotyrosine) are associated withmortality [66] In contrast higher urine NO levels werestrongly associated with better clinical outcomes includingmortality and ventilator-free days in patients enrolled in theARDSNet low tidal volume trial [46] Extracellular citrullinethe effective precursor of NO is lower in the plasma frompatients with severe sepsis and lower plasma citrulline isassociated with the presence of ARDS [67] Mechanismsinvolved in the regulation of lung injury by NO-dependentpathways remain unknown

Although C-reactive protein (CRP) is widely consideredas a marker of systemic inflammation higher levels of CRPare associated with better outcome among patients withARDS [68] Nevertheless a recent study found that albuminlevels rather than CRP may help to predict and monitor theseverity and course of ARDS in febrile critically ill patientswith ARDS or at risk for the syndrome [69] In the samestudy levels of lactate dehydrogenase (LDH) predicted 28-day mortality but were not correlated with severity [69]

313 Coagulation and Fibrinolysis During early ARDS acti-vation of the inflammatory cascades results in the activationof the coagulation system which in turn can influenceinflammatory responses by affecting the expression of variouscytokines such as IL-1 IL-6 and IL-8 Activation of coagula-tion pathways induces migration of inflammatory cells intoalveoli through the endothelial and epithelial barriers and

generates thrombin formation In addition proinflammatoryevents may also inhibit fibrinolysis and induce platelet acti-vation [17]

Extravascular fibrin deposition when localized predomi-nantly in the alveolar compartment is found in several acuteinflammatory lung diseases and enhanced alveolar procoag-ulant activity is reported inARDS patients [180] Fibrin depo-sition may be beneficial for gas exchange by sealing leakagesites when lung capillary endothelial and epithelial barriersare disrupted Nevertheless fibrin alveolar deposition maybe harmful since it can lead to activation of neutrophilsand fibroblasts endothelial injury loss of surfactant activityfavoring alveolar collapse impaired alveolar fluid clearanceand thrombotic obstruction of the microcirculation [180]

(1) PAI-1 The balance between activation of coagulationand activation of fibrinolysis is an important determinantof the amount and duration of fibrin deposition duringlung injury Plasminogen activator (PA) and plasminogenactivator inhibitor-1 (PAI-1) regulate fibrinolysis through theconversion of plasminogen to plasmin a fibrinolytic enzymePA-1 is amajor endogenous inhibitor of PA Both PA and PA-1are secreted by various cells including macrophages fibrob-lasts and lung endothelial and epithelial cells [71] DuringARDS alveolar epithelial cells and activated macrophagesoverexpress PAI-1 thus contributing to decreased alveolarfibrinolytic activity Nevertheless the value of PAI-1 asa biomarker in ARDS remains controversial PAI-1 levelswere higher in patients with ARDS than in patients withhydrostatic lung edema [72] and higher PAI-1 levels areassociated withmortality and higher durations ofmechanicalventilation in patients with ARDS [72 169] In a large Finnishstudy PAI-1 levels were not correlated with mortality ordevelopment of ARDS in critically ill patients undermechan-ical ventilation but low baseline plasma levels of the solubleurokinase plasminogen activator receptor (suPAR) were pre-dictive of survival [181] In a secondary analysis of two largerandomized controlled trials PAI-1 was associated with lunginjury (as defined as decreased oxygenation index) but notwithmortality [28] Nevertheless in another study of patientsfrom the ARDSNet ARMA study higher levels of PAI-1were independently associated with higher mortality andclinical outcomes including organ failure [182] Howeverthis association between PAI-1 levels and the development ofmultiorgan failure was not confirmed in a recent study of 100ARDS patients [32]

(2) Protein C Protein C system is an important endogenousregulator of coagulation and fibrinolysis Protein C is synthe-sized by the liver and circulates as an inactive compoundIt is transformed to its active form on cell surface by thethrombomodulin- (TM-) thrombin complex [75 76] Theendothelial cell protein C receptor (EPCR) is another cellsurface protein that can further enhance protein activationby binding the TM-thrombin complex [183] In additionto suppressing thrombin formation activated protein C hasanti-inflammatory properties such as decreasing the levelsof proinflammatory cytokines [184] Protein C can improveendothelial permeability and exert antiapoptotic effects via

10 Disease Markers

p53 pathways [185] Activated protein C can also inactivatePAI-1 thus promoting fibrinolysis [186] Plasma protein Cwas significantly lower in patients with ARDS as comparedto controls and it was associated with worse clinical out-comes including higher hospital mortality shorter durationof unassisted ventilation and increased risk ofmultiple organfailure [73] In a larger cohort of patients with early ARDSlow plasma levels of protein C were again associated withmortality and adverse clinical outcomes [182] Decreasedlevels of protein C during ARDS suggest a link betweenhypercoagulability and mortality

(3) Thrombomodulin Thrombomodulin (TM) is a mul-tidomain transmembrane-bound glycoprotein found on thesurface of endothelial cell Its main role is to neutralize theprocoagulant effects of thrombin and accelerate activationof protein C In addition to its membrane-bound form TMalso exists as a circulating soluble isoform in the plasmaIn patients with ARDS levels of soluble thrombomodulin(sTM) are higher in the pulmonary edema fluid than inplasma [73] suggesting an alveolar source but no correlationwas found between plasma sTM and the development ofARDS yet higher levels of sTM were observed in patientsat high risk for ARDS In patients with established ARDShigher plasma and alveolar levels of sTM were correlatedwith severity of illness and multiple organ failure [73] Ina larger analysis of 449 patients elevated levels of plasmasTM were associated with increased mortality thus possiblyreflecting an increased degree of inflammation and both lungand systemic endothelial damage [74]

(4) Tissue Factor (TF) Tissue factor (TF) is a 47 kDa trans-membrane glycoprotein that is the most potent stimulator ofthe extrinsic coagulation cascade TF initiates the coagulationcascade by binding and allosterically activating coagulationfactor VIIa The resulting TF-VIIa complex binds the sub-strate coagulation factor X via multiple interactions alongan extended interface to produce the TF-VIIa-X complexThis complex leads eventually to thrombin formation andfibrin deposition [77] Levels of TF in lung edema fluid arehigher than plasma levels in patients with ARDS supportinga lung origin for TF in this setting and both plasma andalveolar levels of TF are higher in ARDS patients as comparedto patients with hydrostatic edema [187] Notably patientswith sepsis-induced ARDS may have higher levels of TF ascompared to patients without ARDS [78]

(5) Cell-Free Hb Levels of cell-free hemoglobin (Hb) arehigher in the air space of ARDS patients as comparedto critically ill patients with hydrostatic lung edema [79]Instillation of red blood cells or cell-free hemoglobin causeslung injury in rats [188] and intra-alveolar hemorrhage isassociated with high levels of intra-alveolar cell-free Hbmore severe lung injury and increased lipid peroxidationin the lung from mice with tissue factor deficiency [79]Precise cellular and molecular mechanisms by which cell-free hemoglobin in the air space could mediate or potenti-ate ARDS are currently under investigation [189] Cell-freeHb could activate chemokine release within the lung and

decompartmentalization of hemoglobin is likely to provide asignificant proinflammatory stimulus in the setting of diffusealveolar damage and hemorrhage during ARDS [80]

314 EFPL Protein Ratio The pathophysiology of ARDSincludes disruption of several physical barriers includingendothelial and epithelial cell layers the basement mem-brane and the extracellularmatrix resulting in increased pul-monary microvascular permeability The pulmonary edemafluid-to-plasma protein (EFPL) ratio is a rapid safe andnoninvasive measure of alveolar-capillary membrane per-meability The EFPL ratio was first proposed as a tool todetermine the etiology of acute pulmonary edema [81] Morerecently in a large study of 390 critically ill patientsWare et aldemonstrated that the EFPL ratio had an excellent discrimi-native value in distinguishing ARDS from hydrostatic edemaand was strongly associated with clinical outcomes Using acutoff of 065 the EFPL ratio had a sensitivity of 81 and aspecificity of 81 for the diagnosis of ARDS [82]

32 Fibroproliferative Phase of ARDS In some patientsimportant and persistent accumulation of macrophagesfibrocytes fibroblasts and myofibroblasts in the alveolarcompartment leads to excessive deposition of ECM com-ponents including fibronectin and collagen types I and IIIamong other proteins An imbalance between profibrotic andantifibrotic mediators may subsequently drive this fibropro-liferative response [190] Growth factors play a major rolein the resolution of ARDS [17] Lung endothelial repair ispromoted by vascular endothelial growth factor (VEGF)A variety of growth factors promote repair of the alveo-lar epithelium including keratinocyte growth factor (KGF)hepatocyte growth factor (HGF) fibroblast growth factor(FGF) and transforming growth factor-120572 (TGF-120572) [17] Twomajor pathways with opposite effects involve growth factorsduring ARDS tyrosine kinase receptor mediation (eg KGFHGF FGF and VEGF) and serine-threonine kinase receptorssuch as TGF-1205731 which tend to have opposed effect on theupregulation that occurs when the tyrosine kinase receptorpathway is involved [85 191 192]

321 Endothelial Proliferation Novel evidence points to apotential role of VEGF in promoting repair of the alveolar-capillarymembrane during recovery fromARDS and under-standing the role of VEGF in this disease process couldbe crucial for developing new therapeutic strategies [85193] In the lung VEGF is produced primarily by epithelialcells it increases microvascular permeability [83] but has animportant role also during the repair phase by stimulatingendothelial cell proliferation and survival [86 149] Thelevels of VEGF are increased in plasma from patients withARDS but are decreased in BAL fluid compared to healthycontrols subsequently BAL levels of VEGF increase duringthe resolution of lung injury [39 84 149]

322 Epithelial Proliferation and Apoptosis KGF also knownas FGF-7 is a potent mitogenic factor for alveolar epithelialcells that is primarily produced by fibroblasts and other

Disease Markers 11

cells such as T lymphocytes KGF regulates transepithelialtransport of sodium by stimulating the epithelial channelNa+-K+-ATPase in alveolar epithelial cells [87]

HGF is a nonspecific mitogen secreted by fibroblastsalveolar macrophages endothelial cells and epithelial cellsSeveral animal and human studies suggest that KGF andHGFcould protect the alveolar space against injury and couldfacilitate the repair of alveolar structures after injury [88 194195] KGF levels could be measured in the BAL from patientswith ARDS but not in the BAL from those without ARDS inaddition BALKGFwas associated with poor prognosis [196]Elevated HGF levels were also associated with outcome [196]In 36 patients with ARDS and 11 patients with hydrostaticlung edema HGF and KGF were proven biologically activein the edema fluid of patients with ARDS and higher levelsof HGFwere associated withmortality in these patients [197]

Apoptosis of alveolar epithelial cells is a major phe-nomenon in the initiation and perpetuation of lung injury[89] The FasFasL system plays an important role in theregulation of cell life and death through its ability to initiateapoptosis [198] This system combines the cell membranesurface receptor Fas (CD95) and its natural ligand FasL(CD95L) Membrane-bound FasL mediates lymphocyte-dependent cytotoxicity clonal deletion of alloreactive T cellsand activation-induced suicide of T cells [199] Its solubleform (sFasL) results from cleavage of membrane FasL byMMPs and induces apoptosis in susceptible cells [200]Apoptosis is inducedwhenmembrane-bound or soluble FasLbinds to Fas-bearing cells By contrast apoptosis is inhibitedwhen soluble Fas binds to either membrane-bound FasL orsFasL thus preventing FasL from interacting withmembrane-bound Fas receptors [201] In patients with ARDS sFasL wasdetectable in the lung before and after the onset of clinicallydefined ARDS and nonsurvivors had significantly higherBAL levels of sFasL on day 1 as compared with survivors[200] Both soluble Fas and soluble FasL were associated withoutcome and higher in the lung edema fluid from patientswith ARDS compared to control patients with hydrostaticpulmonary edema [202] Nevertheless recent findings sug-gested limited role for FasFasL system and apoptosis inairway epithelial cell death during ARDS [90]

323 Fibroblast Proliferation Pulmonary fibroblasts pro-duce procollagen III peptide (PCP-III) that is a precursorof collagen The NT part of procollagen III resulting fromthe enzymatic cleavage of procollagen by specific proteases inthe extracellular space is considered as a marker of collagensynthesis Alveolar levels of N-PCP-III are higher in ARDSpatient as compared with controls [203] The elevation ofN-PCP-III in pulmonary edema fluid begins within the first24 h of ARDS that is during the acute phase of increasedendothelial and epithelial permeability to protein suggestingthat fibrosing alveolitis could begin very early in the course ofclinical ARDS [203] In another study high levels of N-PCP-III were early predictors of poor outcome [204 205] Morerecently Forel et al measured alveolar N-PCP-III in patientswith nonresolving ARDS thus identifying patients who haddeveloped lung fibroproliferation [206] Unfortunately it

is still unknown whether N-PCP-III measurements couldbe useful in selecting patients who would benefit fromglucocorticoid therapy among others to reduce the ARDS-associated lung fibrosis [207]

4 Perspectives

41 Combining Biomarkers Despite advances in the identi-fication of biomarker candidate and better understanding ofARDS pathogenesis no single clinical or biological markerreliably predicts clinical outcomes inARDSThe combinationof clinical and biological marker is attractive in order toimprove the sensitivity andor the specificity of the testespecially through a recent approach aimed at measuring8 biological markers that reflect endothelial and epithelialinjury inflammation and coagulation vWF SP-D TNF-R1IL-6 IL-8 ICAM-1 protein C and PAI-1 in 549 patientsenrolled in the the ARDSNet trial of low versus high positiveend-expiratory pressure [208] Clinical predictors predictedmortality with an area under the ROC curve (AUC) of082 whereas a combination of these 8 biomarkers and theclinical predictors had an AUC of 085 The best performingbiomarkers were the neutrophil chemotactic factor IL-8 andSP-D a product of AT2 cells [208] supporting the conceptthat acute inflammation and alveolar epithelial injury areimportant pathogenetic pathways in human ARDS Morerecently a panel of biomarkers of lung epithelial injuryand inflammation (SP-D sRAGE IL-8 CC16 and IL-6)provided excellent discrimination for diagnosis of ARDSin patients with severe sepsis [20] Therefore and beyondtheir better diagnostic and prognostic values the use of suchbiomarker panels may be useful for selecting patients forclinical trials that are designed to reduce lung epithelial injury[113] Nevertheless whether a therapeutic strategy based onbiomarker measurements would benefit patient outcome hasnever been investigated

42 Lung Imaging as an ARDS Biomarker Studies of lungimaging during ARDS have revealed that adequate ventilatorsettings may vary among patients with the same syndromeIn a large study gas and tissue distribution in the lungs ofARDS patients were assessed using computed tomography(CT) and compared to those of healthy volunteers [11] Lungmorphology in ARDS is characterized by marked excess oflung tissue associated with a major decrease in aerated lungregions and in functional residual capacity Some patientswith ARDS exhibit preserved aeration of the upper lobesdespite the presence of an overall excess of lung tissue (ldquofocalrdquoARDS) as opposed to other patients with more diffuse lossof aeration and excessive lung tissue (ldquodiffuserdquo or ldquononfocalrdquoARDS) [209]

Lung morphology may influence the response to pos-itive end-expiratory pressure (PEEP) recruitment maneu-vers (RM) prone position and patient outcome [12 210]In a prospective study of nineteen patients with ARDSConstantin et al found that lung morphology at zero end-expiratory pressure could predict the response to a RM withcontinuous positive airway pressure of 40 cm H

2O for 40

12 Disease Markers

seconds Nonfocal morphology was associated with higherlung recruitability and PaO

2FiO2was significantly increased

by the RM [12 211] In contrast patients with focal lungmorphology were at risk of significant hyperinflation duringthe RM with no improvement of arterial oxygenation

It has also been hypothesized that the effects of PEEPmay depend on lung morphology Puybasset et al assessedthe responses to PEEP among patients with focal or nonfocalARDS [210] The regional distribution of intrapulmonarygas and lung tissue influences the effects of PEEP in ARDSpatients maximal alveolar recruitment without evidenceof overdistension was observed in patients with nonfocalARDS Nevertheless PEEP induced mild alveolar recruit-ment in patients with focal ARDS along with overdistensionof previously aerated lung regions

Interestingly phenotyping patients with ARDS basedon their lung morphology might be possible by measuringplasma sRAGEwith commercially available kits even thoughthese findings need further validation [100 112] HoweverRAGE pathway is a promising candidate for subphenotypingpatients with ARDS as it is believed to play a major rolein the mechanisms leading to AFC and their regulation[110] Recent findings that support a relationship betweenimpaired AFC and lung morphology may therefore fill a gapin the full recognition of an ARDS phenotype based on lungmorphology that could be linked to an endotype of impairedAFC and activated RAGE pathway [12 100 101 112 113 212]

43 Biomarkers in ARDS Can They Improve Patient CareBiomarkers are broadly used in critically ill patientsespecially during inflammatory andor infectious diseasesBiomarkers have been commonly defined as characteristicsthat are objectively measured and evaluated as indicatorsof normal biological processes pathogenic processes orpharmacologic responses to therapeutic interventions [213214] Biomarkers provide a powerful approach to understanda disease with multiple applications in observational andanalytic epidemiology randomized clinical trials screeningand diagnosis or prognosis [215]

Nevertheless there are important technical attributes fora relevant biomarker First the marker must be present inperipheral body tissue andor fluid (eg blood urine salivabreath or cerebrospinal fluid) second it must be easy todetect or quantify in assays that are both affordable androbust and third its regulation should be associated asspecifically as possible with damage of a particular tissuepreferably in a quantifiable manner Prior to the widespreaduse of a marker of interest it is essential that validation andconfirmation of candidate biomarkers by robust statisticalmethods are performed during biomarker discovery [215]Sensitivity and specificity are common quality parametersfor biomarkers Sensitivity describes the probability of apositive test in cases and specificity describes probability ofnegative test in controls An association between sensitivityand specificity is represented in the ROC curve by graphingsensitivity versus 100 minus specificity Area under the ROC curve(AUROC) is therefore a measure of performance of a markerThere is no absolute cutoff value of AUROC for robustness of

a marker but aminimum of 07 is required and values greaterthan 08 are good particularly in a heterogeneous critically illpatient population [216 217]

To summarize an ideal biomarker should indicate aclear relationship with the pathophysiologic event needsto be reliable reproducible disease specific and sensitiveand should be sampled by simple methods and relativelyinexpensive with little or no diurnal variation DuringARDS no single marker has been validated with all thesecriteria to date yet we believe that sRAGE may fulfill allprerequisites of a biomarker of ARDS First plasma sRAGEhas good diagnostic and prognostic values [96 99 100109 112] Second it is very well correlated with lung injuryseverity and specific pathophysiologic features of ARDS forexample alveolar fluid clearance and lung morphology [9699ndash101 109 112] Previous studies of the predictive value ofearly levels of sRAGE for the development of ARDS in ageneral population of patients admitted to the emergencydepartment were negative [130] but current research focuseson both the kinetics of sRAGE and esRAGE and RAGE genepolymorphisms as predictors of the development of ARDSin at-risk critically ill patients [114] Finally there is someevidence suggesting that monitoring sRAGE could informat least partially on therapeutic responses in patients with orwithout ARDS [24 99 113] If these data are confirmed byfuture studies such findingswould definitely help to reinforcesRAGE a real biomarker of ARDS

5 Conclusion

Biomarker research provides an important translational linkto our understanding of lung pathobiology Through theidentification and testing of candidate biomarkers we havegained insight into the pathogenic importance of endothelialand epithelial injury and have started to unravel the complexpathways that contribute to endothelial and epithelial celldysfunction inflammation fibrosis and apoptosis in ARDSIn addition biomarker studies may help us to explore thecellular and molecular mechanisms of various therapeuticstrategies for ARDS and to better understand the potentialproinflammatory effects of mechanical ventilation Giventhe clinical heterogeneity of patients with ARDS and thecomplexity of the underlying pathobiology it is unlikely thata single biomarker will emerge for ARDS as cardiac-specifictroponin did for myocardial infarction but the develop-ment of small biomarker panels reflecting each importantlung injury pathway would provide valuable predictive andprognostic information for both clinicians and investigatorsWhile biomarkers are currently not recommended for usein clinical practice in ARDS biomarker discovery mayhold significant promise in order to develop and applytargeted therapies and to identify candidates for enrollmentin patient-tailored clinical trials of novel therapies for ARDS

Disclosure

The funders had no influence on the study design conductand analysis or on the preparation of this paper

Disease Markers 13

Conflict of Interests

No conflict of interests other sources of financial supportcorporate involvement patent holdings and so forth are tobe declared for all authors

Authorsrsquo Contribution

Raiko Blondonnet was involved in the conception and designof the review in writing the paper and in its revision priorto submission Jean-Michel Constantin was involved in theconception and design of the review in writing the paperand in its revision prior to submission Vincent Sapin wasinvolved in the conception and design of the review inwriting the paper and in its revision prior to submissionMatthieu Jabaudon takes responsibility for the content ofthe paper and was involved in the conception and design ofthe review in writing the paper and in its revision prior tosubmission

Acknowledgments

This work was supported by grants from the AuvergneRegional Council (ldquoProgramme Nouveau Chercheur de laRegion Auvergnerdquo 2013) the french Agence Nationale de laRecherche and the Direction Generale de lrsquoOffre de Soins(ldquoProgramme de Recherche Translationnelle en Santerdquo ANR-13-PRTS-0010)

References

[1] VM Ranieri G D Rubenfeld P TThompson et al ldquoAcute res-piratory distress syndrome the Berlin definitionrdquo The Journalof the American Medical Association vol 307 no 23 pp 2526ndash2533 2012

[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000

[3] C Brun-Buisson C Minelli G Bertolini et al ldquoEpidemiologyand outcome of acute lung injury in European intensive careunitsrdquo Intensive Care Medicine vol 30 no 1 pp 51ndash61 2004

[4] G D Rubenfeld E Caldwell E Peabody et al ldquoIncidence andoutcomes of acute lung injuryrdquo The New England Journal ofMedicine vol 353 no 16 pp 1685ndash1693 2005

[5] D W Dowdy M P Eid C R Dennison et al ldquoQuality oflife after acute respiratory distress syndrome a meta-analysisrdquoIntensive Care Medicine vol 32 no 8 pp 1115ndash1124 2006

[6] C S Calfee M D Eisner L B Ware et al ldquoTrauma-associatedlung injury differs clinically and biologically from acute lunginjury due to other clinical disordersrdquo Critical Care Medicinevol 35 no 10 pp 2243ndash2250 2007

[7] C S Calfee D R Janz G R Bernard et al ldquoDistinct molecularphenotypes of direct versus indirect ARDS in single and multi-center studiesrdquo Chest vol 147 no 6 pp 1539ndash1548 2015

[8] P Tejera N J Meyer F Chen et al ldquoDistinct and replicablegenetic risk factors for acute respiratory distress syndromeof pulmonary or extrapulmonary originrdquo Journal of MedicalGenetics vol 49 no 11 pp 671ndash680 2012

[9] M A Matthay G A Zimmerman C Esmon et al ldquoFutureresearch directions in acute lung injury summary of a National

Heart Lung and Blood Institute Working Grouprdquo AmericanJournal of Respiratory and Critical Care Medicine vol 167 no7 pp 1027ndash1035 2003

[10] J P Reilly S Bellamy M G S Shashaty et al ldquoHeterogeneousphenotypes of acute respiratory distress syndrome after majortraumardquo Annals of the American Thoracic Society vol 11 no 5pp 728ndash736 2014

[11] L Puybasset P Cluzel N Chao et al ldquoA computed tomographyscan assessment of regional lung volume in acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol158 no 5 pp 1644ndash1655 1998

[12] J-M Constantin S Grasso G Chanques et al ldquoLungmorphol-ogy predicts response to recruitment maneuver in patients withacute respiratory distress syndromerdquo Critical Care Medicinevol 38 no 4 pp 1108ndash1117 2010

[13] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoSubphenotypes in acute respiratorydistress syndrome latent class analysis of data from tworandomised controlled trialsrdquoThe Lancet Respiratory Medicinevol 2 no 8 pp 611ndash620 2014

[14] R Marshall G Bellingan and G Laurent ldquoThe acute respira-tory distress syndrome fibrosis in the fast lanerdquoThorax vol 53no 10 pp 815ndash817 1998

[15] R B Henderson J A R Hobbs M Mathies and N HoggldquoRapid recruitment of inflammatory monocytes is independentof neutrophil migrationrdquo Blood vol 102 no 1 pp 328ndash3352003

[16] HMMarriott andDH Dockrell ldquoThe role of themacrophagein lung disease mediated by bacteriardquo Experimental LungResearch vol 33 no 10 pp 493ndash505 2007

[17] L J M Cross and M A Matthay ldquoBiomarkers in acute lunginjury insights into the pathogenesis of acute lung injuryrdquoCritical Care Clinics vol 27 no 2 pp 355ndash377 2011

[18] H K Gaggin and J L Januzzi ldquoBiomarkers and diagnostics inheart failurerdquo Biochimica et Biophysica Acta (BBA)mdashMolecularBasis of Disease vol 1832 no 12 pp 2442ndash2450 2013

[19] E Christenson and R H Christenson ldquoThe role of cardiacbiomarkers in the diagnosis and management of patientspresenting with suspected acute coronary syndromerdquo Annals ofLaboratory Medicine vol 33 no 5 pp 309ndash318 2013

[20] L B Ware T Koyama Z Zhao et al ldquoBiomarkers of lungepithelial injury and inflammation distinguish severe sepsispatientswith acute respiratory distress syndromerdquoCritical Carevol 17 no 5 article R253 2013

[21] M A Matthay L B Ware and G A Zimmerman ldquoTheacute respiratory distress syndromerdquo The Journal of ClinicalInvestigation vol 122 no 8 pp 2731ndash2740 2012

[22] M Shirasawa N Fujiwara S Hirabayashi et al ldquoReceptor foradvanced glycation end-products is a marker of type I lungalveolar cellsrdquo Genes to Cells vol 9 no 2 pp 165ndash174 2004

[23] M Neeper A M Schmidt J Brett et al ldquoCloning andexpression of a cell surface receptor for advanced glycosylationend products of proteinsrdquo The Journal of Biological Chemistryvol 267 no 21 pp 14998ndash15004 1992

[24] M Jabaudon E Futier L Roszyk V Sapin B Pereira andJ Constantin ldquoAssociation between intraoperative ventilatorsettings and plasma levels of soluble receptor for advancedglycation end-products in patients without pre-existing lunginjuryrdquo Respirology vol 20 no 7 pp 1131ndash1138 2015

[25] L G Dobbs R F Gonzalez L Allen and D K Froh ldquoHTI56an integral membrane protein specific to human alveolar type

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ObesityJournal of

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Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Research and TreatmentAIDS

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Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Disease Markers 3

Exudative

Epithelium damage

Endothelium damage

Inflammatory cascade

IL-6 and IL-8

IL-10Additional markers HMGB1 LBP NO CRP

Anti-inflammatory IL-1RA sTNF-RIII and

albumin and LDHPulmonary vascular permeability

EFPL ratioLung matrix alteration

LamininElastindesmosineMMPs 2 3 8 9 and 13

PA-1Protein C

Coagulation and fibrinolysis

phase

ATI cells sRAGE HTI56ATII cells surfactant KL-6Club cells CC16

Ang-1 Ang-2ICAM-1SelectinsVEGFvWF

Epithelial apoptosis

Fibroproliferative phase

FasFasL

VEGF

KGFHGF

N-PCP-III

Epithelial proliferation

Fibroblast proliferation

Endothelial proliferationProinflammatory IL1-120573TNF-120572 IL-18

ThrombomodulinTissue factorCell-free hemoglobin

Club cell

Alveolar type I cell

Alveolar type II cell

Red cell

Alveolarmacrophage

Neutrophil

CapillaryInterstitium

Protein-richedema fluid

differentiation ofalveolar type II cells

Alveolus

Necrotic alveolartype I cell

Proliferation and

m Fibroblast

Figure 1 Biomarkers of acute respiratory distress syndrome organized by pathways and phases of lung injury (left early exudative phaseright fibroproliferative phase)

proinflammatory activation of nuclear transcription factorNF-120581B [95 96] RAGE is implicated in ARDS as an importantpathway to innate immunity and alveolar inflammation [97]and when the soluble form (sRAGE for soluble RAGE) isassayed in plasma or pulmonary edema fluid as a markerof alveolar injury [98ndash101] Full-length RAGE is a transmem-brane receptor but it can also be found as soluble isoformsgenerally referred to as soluble RAGE (sRAGE comprisingthe extracellular domain of RAGE and produced through thecleavage of full-length RAGE by matrix metalloproteinases)[102 103] and endogenous secretory RAGE (esRAGE pro-duced after alternative splicing) [104] Full-length RAGE andits isoforms are abundantly and constitutively expressed inthe lungs in normal conditions [103 105ndash107] and sRAGEis now considered as a promising novel marker of AT1 cellinjury and a key mediator of alveolar inflammation [22 95108] It is shown that sRAGE expression appears enhancedduring the early stage of ARDS Our team with others hasrecently reported in both ARDS patients and a mouse modelof ARDS that the extent of sRAGE elevation in plasma andalveolar fluid correlates with markers of severity assessed byPaO2FiO2 lung injury and alveolar fluid clearance (AFC)

[98ndash101 109] A role for RAGE pathway in the regulation ofAFC has been recently described for the first time [110] and isunder active investigation by our team and others [101 111]Interestingly plasma and BAL sRAGE levels are elevatedduring ARDS independently of any associated severe sepsis[100] In addition plasma levels of sRAGE are correlated with

diffuse damage as assessed by lungCT-scan and are correlatedwith the extent of alveolar damage [100 112] suggesting thatsRAGEmay serve as a useful biomarker of AT1 cell injury andlung damage during ARDS Plasma levels of sRAGE are alsoassociated with 28-day and 90-day mortality in patients withARDS [99 106 112]

Calfee et al recently compared biomarker levels inpatients with direct versus indirect ARDS enrolled in a singlecenter study of 100 patients and in a secondary analysis of 853ARDS patients drawn from a multicenter randomized con-trolled trial [7] levels of biomarkers of lung epithelial injury(sRAGE surfactant protein-D) were significantly higher indirect ARDS compared to indirect ARDS

A recent observational study also supports an ARDSphenotype based on levels of RAGE ligands and solubleforms as elevated sRAGE high mobility group box-1 pro-tein (HMGB1) and S100A12 with decreased esRAGE andadvanced glycation end-products (AGEs) were found todistinguish patients with ARDS from those without [109]Although these recent findings warrant further validation inmulticenter studies monitoring sRAGE levels may be usefulin assessing the response to strategies in ventilator settingsincluding alveolar recruitment maneuvers in patients withARDS [113] or in patients without lung injury at risk of post-operative respiratory complications after major surgery [24]The predictive value of 4 single-nucleotide polymorphisms inRAGE gene (AGER) in the development of ARDS in at-riskpatients is currently under study by our team [114]

4 Disease Markers

Table 1 Biomarkers of acute respiratory distress syndrome organized by phases and pathways of lung injury

Pathophysiologic feature of ARDS Biomarker ReferencesExudative phase

Epithelium damage

(i) Alveolar type 1 cells RAGE [22ndash24]HTI56

[25 26]

(ii) Alveolar type 2 cells Surfactant [27 28]KL-6 [29 30]

(iii) Clara cells CC16 [31 32]Endothelium damage

Ang-1 Ang-2 [33 34]ICAM-1 [35 138ndash140]Selectins [36 37]VEGF [38 39]vWF [40ndash42]

Lung matrix alterationLaminin [43 44]

Elastindesmosine [45 46]MMPs [47ndash49]

Inflammatory cascade

(i) Proinflammatory

IL-1120573TNF-120572 [17 161ndash164 167]IL-18 [50 51]IL-6 [52ndash55]IL-8 [169ndash171]

(ii) Anti-inflammatoryIL-1RA [56 57]

sTNF-RIsTNF-RII [6 54 58]IL-10 [59ndash61]

(iii) Additional markers

HMGB1 [62 63]LBP [64 65]NO [46 66 67]CRP [68]

Albumin [69]LDH [69]

Coagulation and fibrinolysisPA-1 [32 53 70ndash72]

Protein C [75 76 182]Thrombomodulin [73 74]

Tissue factor [75ndash78]Cell-free hemoglobin [75 76 79 80]

Pulmonary vascular permeabilityEFPL ratio [81 82]

Fibroproliferative phaseEndothelial proliferation

VEGF [39 83ndash86]Epithelial proliferation

KGF [87]HGF [88 194 195 197]

Epithelial apoptosisFasFasL [25 88ndash91]

Fibroblast proliferationN-PCP-III [88 194 195 203 207]

Disease Markers 5

HTI56 Human type I cell-specificmembrane protein (HTI56)

is a 56-kDa glycosylated lung protein specific to the apicalmembrane of human AT1 cells HTI

56has biochemical char-

acteristics of an integral membrane protein [25] Althoughthe precise functions of HTI

56remain unknown HTI

56is

an analog to RTI40 a 40ndash42 kDa integral membrane protein

specific to the apical membrane of rat AT1 cells [26] Patientswith ARDS had higher levels of HTI

56in both lung edema

fluid and plasma as compared to patients with hydrostaticlung edema [94] but no study assessing the associationbetween HTI

56levels and other endpoints in patients with

ARDS (eg prognosis) has been published to date

(b) Alveolar Type 2 Cells AT2 cells have important homeo-static functions in the lung including AFC and productionof alveolar surfactant (involved in lung compliance keepingthe alveolus open) AT2 cells are also known as keymediatorsof the epithelial repair process [115]

Surfactant Proteins Surfactant has a vital role in maintainingthe integrity of the alveolar-capillary interface Its essentialfunction is to decrease surface tension into the alveoli thusstabilizing lung volume at low transpulmonary pressuresSurfactant is composed of approximately 80 phospholipids8 other lipids (cholesterol triacylglycerol and free fattyacids) and 12 proteins Four surfactant-associated proteins(SP) designated SP-A SP-B SP-C and SP-D representapproximately half of proteins composing surfactant SP-Aand SP-D easily dissociate from lipids and are hydrosolubleThey belong to the lung innate immune system therebyenhancing phagocytosis of bacteria and virus They alsoexert regulatory effects on AT2 cells SP-B and SP-C aresmall extremely hydrophobic proteins that are important inthe formation of the surfactant monolayer in the terminalairspaces and in the reduction of surface tension thuspreventing end-expiratory alveolar collapse [116]

Early observations in ARDS revealed a loss in surfacetension suggesting a functional loss of the surfactant proteins[117] In a first case report of three patients the ratioof plasma SP-BSP-A was inversely associated with bothblood oxygenation and static respiratory system compliancesuggesting that SP-B breaches the alveolocapillary barriermore readily than SP-A and may therefore provide a moresensitive marker of lung injury [118] Plasma levels of SP-Aand SP-B are increased in patients with ARDS [70] and in at-risk patients [119 120] whereas lower SP-A and SP-B levelswere found in the BAL fluid of patients at risk for ARDSprior to the onset of the clinical syndrome SP-A and SP-Blevels remained low for as long as 14 days in patients withsustained ARDS Interestingly this decrease in BAL SP-A andSP-B does not result simply from dilution of alveolar fluids byplasma entering the alveolar spaces as SP-D levels remainedstable in parallel [119] In a cohort of 38 patients reducedpulmonary edema fluid SP-D and elevated plasma SP-A atthe onset of ARDS were associated with poor prognosis [27]Nevertheless in a study of 259 patients from the ARDSNettrial of low versus high end-expiratory pressure in ARDS(ALVEOLI) as well as in 75 patients enrolled in a randomized

trial of activated protein C for ARDS plasma SP-D was notassociated with 28-day mortality or ventilator-free days [28]

KL-6 Krebs von den Lungen-6 (KL-6) is a human MUC1mucin that belongs to the high-molecular-weight glyco-protein family After the cleavage of S-S bond KL-6 canspread into the pulmonary epithelial lining fluid In thenormal lung this glycoprotein can be predominantly foundin AT2 cells and its expression is enhanced during AT2proliferation regeneration or injury thus representing anattractive biomarker in ARDS Plasma KL-6 is elevated inARDS patients and correlates with lung injury and mortality[29 121ndash123] Plasma levels of SP-D and KL-6 increase overtime in patients with ARDS and may represent biologicalmarkers of ventilator-associated lung injury because theirincrease is attenuated by lung-protective ventilation [30]

(c) CC16 Clara cell protein (CC16) is a 158 kDa homod-imeric protein that is abundantly secreted in airways by thenonciliated bronchiolar Clara cells Clara cells are devotedto the protection of the respiratory tract against toxicinhaled agents the repair of damaged epithelium xenobioticsdetoxification and the secretion of proteins with importantbiological activities CC16 is highly expressed in the epitheliallining fluid with antioxidantinflammatory roles notably bymodulating the production andor activity of phospholipase-A2 interferon-120574 and tumor necrosis factor-120572 [31] Availablestudies found contradictory inconclusive findings duringARDS Although higher levels of CC16 are associated withlung injury and inflammation in some experimental andclinical studies patients with ARDS had lower plasma andpulmonary edema fluid levels of CC16 than patients withacute cardiogenic pulmonary edema and no correlation wasfound between CC16 and prognosis So many conflictingfindings do not currently support the association of CC16with the diagnosis or prognosis of ARDS

(2) Vascular Endothelium Vascular endothelial injury ischaracterized by the disruption of cell components leadingto increased microvascular permeability and alveolar edemaEndothelial injury is mainly driven by the activation ofinflammation and coagulation cascades The activation ofendothelial cells by circulating mediators leads to increasedexpression of cell surface molecules that are importantmediators of leukocyte adhesion and contribute to leuko-cyte accumulation and transmigration [124] Activated lym-phocytes can also release mediators in microvessels thatincrease vascular permeability Along with these leukocytesignals inflammatory mediators such as tumor necrosis fac-tor (TNF) thrombin and vascular endothelial growth factor(VEGF) disrupt endothelial-cadherin bonds and contributeto the vascular leak underlying edema formation in ARDSPlatelets also contribute to endothelial injury through therelease of cytokines and through fibrin clotting [92]

(a) Angiopoietin Angiogenic agents along with VEGF andangiopoietin-1 (Ang-1) play key roles in vascular develop-ment VEGF stimulates the generation of new immature

6 Disease Markers

and leaky blood vessels whereas Ang-1 enhances angiogene-sis inducing vascularmaturation anddecreases vascular per-meability [33] The most encouraging data result from recentstudies of angiopoietin-2 (Ang-2) an endothelial protein thathas been studied extensively during sepsis [125] Ang-2 has animportant role as it increases endothelial junction instabilityenhances vascular leak naturally antagonizes Ang-1 and inthe absence of other angiogenic stimuli induces vascularregression and endothelial cell apoptosis Both Ang-1 andAng-2 are ligands for the tyrosine kinase receptor Tie-2 [126] and a link between Ang-2 and inflammation hasbeen reported [127] Therefore such vascular growth factorshave been proposed as biomarkers for ARDS [128] Firsttwo single-nucleotide polymorphisms within the Ang-2 gene(rs1868554 and rs2442598) were associated with the riskof developing ARDS in trauma patients [129] In additionAgrawal et al found in a prospective study of 230 patientsadmitted to the intensive care unit (ICU) without ARDSthat higher levels of Ang-2 were significantly associatedwith increased development of ARDS [130] In surgical ICUpatients levels of Ang-2 were higher in patients with ARDSthan in those without the syndrome [131] A higher Ang-2Ang-1 ratio was also an independent predictor of mortalityin ARDS patients [131 132] and patients with infection-related ARDS whose Ang-2 levels increased between day 0and day 3 doubled their odds of death suggesting that Ang-2kinetics may be particularly valuable by reflecting evolvinglung injury [34] Finally in a large study of 931 patientsenrolled in the ARDSNet fluid and catheter treatment trialbaseline plasma levels of Ang-2 were associated with 90-daymortality in patients with noninfectious ARDS whereas thisassociation was not found in patients with infection as theirprimary ARDS risk factor Based on a secondary analysisof two large studies Calfee et al further demonstrated thatindirect lung injury is characterized by a molecular pheno-type consistent with more severe lung endothelial injury asassessed by plasma Ang-2 and less severe epithelial injury[7]

(b) ICAM-1 The soluble intercellular adhesion molecule-1 (sICAM-1) is an inducible glycoprotein expressed onthe surface of vascular endothelial cells and other cells(eg hematopoietic cells AT1 cells) [35] Under physiologicconditions sICAM-1 is not constitutively expressed or isexpressed at low levels in most tissues During inflammationand in response to stimuli such as interferon-120574 (IFN-120574) orinterleukin-1 (IL-1) levels of sICAM-1 are upregulated [133]Elevated levels have also been found in both plasma andlung edema fluid from patients with ARDS as compared topatients with hydrostatic lung edema [134] In a multicenterstudy the increase of sICAM-1 from baseline to day 3was associated with poor clinical outcome [135] and in aprospective cohort of 65 patients with ARDS baseline plasmalevels of sICAM-1 were also associated with mortality [136]In pediatric patients with ARDS early elevated plasma levelsof sICAM-1 were associated with increased risks of death andof prolongedmechanical ventilation [137] In traumapatientshigher plasma levels of sICAM-1 at baseline were correlated

with future development of multiple organ dysfunction syn-drome (MODS) but not with the development of ARDS [138ndash140]

(c) Selectins Selectins are membrane-associated glycopro-teins that mediate the adhesion of leukocytes and plateletsto vascular surface L-selectin is mainly expressed by leuko-cytes P-selectin is rapidly redistributed from membranoussecretory granules to the surface of activated platelets andendothelial cells [36] E-selectin is expressed by cytokine-activated endothelial cells It has been shown that plasmalevels of such soluble adhesion molecules were markedlyhigher in nonsurvivors among critically ill patients and thatthey were negatively correlated with lung function (egPaO2FiO2ratio) [141] Other studies found that plasma P-

selectin was elevated in patients with ARDS especially inthose who subsequently died as compared with patients withother pulmonary diseases or sepsis but without ARDS [142]Interestingly patients with ARDS with chronic alcohol con-sumption had elevated levels of soluble E-selectin in both theplasma and epithelial fluid consistent with altered endothe-lial and alveolar-capillary function [143] More recently E-selectin was measured in the plasma levels from 50 individ-uals admitted to the emergency department and who wereat-risk for developing ARDS with higher E-selectin levelsbeing associated with both ARDS development and 28-daymortality [144] Circulating soluble E-selectin levels wereelevated in pneumonia patientswithARDS and plasma levelsdecreased along with the treatment of pneumonia [37]

(d) VEGF One of the most extensively studied endothelialmarkers in ARDS is VEGF albeit its value as a biomarkerremains unclear Vascular endothelial growth factors belongto the platelet-derived growth factor supergene family Theyplay central roles in the regulation of angiogenesis andlymphangiogenesis [38] Alternative splicing of the VEGFgene (6p213) transcript leads to the generation of severalsplice variants or isoforms with various sizes [145] VEGF-Ais a 34ndash46 kDa glycoprotein acting as the major factor impli-cated in angiogenesis It binds to two tyrosine kinase (TK)receptors named VEGFR-1 (Flt-1) and VEGFR-2 (KDRFlk-1) and regulates endothelial cell proliferationmigration vas-cular permeability secretion and other endothelial functions[146] The expression of VEGF in ARDS varies dependingon the degree of epithelial and endothelial damage Manylung cells release VEGF for example AT2 cells neutrophilsalveolar macrophages and activated T cells Thus VEGFis potentially capable of having an effect on both alveolarepithelial and endothelial barriers Interestingly overexpres-sion of VEGF induces pulmonary edema in animal models[147] In a single center study plasma levels of VEGF wereincreased in subjects with ARDS compared to controls andelevated plasma VEGF as measured on day 4 was associatedwith mortality in patients with ARDS [83] Neverthelessseveral studies suggest that plasma and alveolar VEGF mayhelp to predict the development of ARDS and its recoveryWhereas plasma VEGF is increased in ARDS patients VEGFlevels were decreased in the BAL fluid from ARDS patients

Disease Markers 7

as compared to controls [84 148 149] In order to betterunderstand such differences between plasma and alveolarexpression of VEGF Ware et al conducted a study with theaim to determine whether changes in alveolar levels of VEGFwere specific to ARDS or not [39] the authors found thatalveolar levels of VEGF were decreased in both patients withARDS and those with hydrostatic edema The mechanismsimplicated in this alveolar decrease in VEGF during ARDSmight not depend on the degree of lung injury but rather onthe degree of alveolar flooding [39]

(e) vWF Early studies of endothelial markers focused on vonWillebrand Factor (vWF) a macromolecular antigen that isproduced predominantly by endothelial cells and to a lesserextent by platelets In the setting of endothelial activationor injury vWF is released from preformed stocks into thecirculation [40 41] VWFhas been investigated as a biologicalmarker of endothelial injury in patients both at-risk forARDSand with established ARDS [40 150] In a prospective studyof 45 ICU patients with sepsis patients with nonpulmonarysepsis had higher levels of plasma vWF with good predictiveand prognostic values for ARDS Indeed elevated plasmalevels of vWF had a sensitivity of 87 and a specificity of77 for the prediction of ARDS development in the settingof nonpulmonary sepsis [151] However subsequent studiesin patients at-risk for ARDS did not confirm these findings[42 152 153] In another study of 559 patients with ARDSenrolled in the National Heart Lung and Blood InstituteARDS Network trial of lower tidal volume nonsurvivorshad higher plasma levels of vWF compared to survivors[40] Higher vWF levels were significantly associated withfewer organ failure-free days suggesting that the degree ofendothelial activation and injury is strongly associated withoutcomes in ARDS nevertheless ventilator settings had noimpact on vWF levels in this study [40]

(f) Lung ExtracellularMatrixThe extracellularmatrix (ECM)forms the region of the lung situated between the alveo-lar epithelium and the vascular endothelium ECM playsa mechanical role as it supports and maintains tissularstructures ECM also represents a complex and dynamicmeshwork influencing many biological cell functions such asdevelopment proliferation and migration [154] Collagensare the main component of ECM along with glycoproteinsand proteoglycans including hyaluronic acid

Laminin Laminins (LM) are ECM proteins with high molec-ular weights that deposit in basal membranes Lamininsare involved in cell processes such as cellular adhesiongrowth and differentiation [43] Laminin-5 (LM-5) plays animportant role in cell migration and in the remodeling ofepithelial tissue LM-5 is activated through its cleavage bymatrix metalloproteinases (MMPs) thus releasing a solubleLN 1205742 NH2-terminal fragment (G2F) that does not depositin the ECM and can therefore be detected in the peripheralblood In a small single center study lamininwasmeasured inthe plasma and lung edema fluid from 17 patients with ARDSwith higher levels found in patients with ARDS as comparedto healthy volunteers [44] Interestingly nonsurvivors had

higher plasma levels of laminin as measured 5 days afterARDS onset than survivors and survivors had decreasinglevels of the marker over time suggesting that its secretionis suppressed during ARDS recovery

ElastinDesmosine Elastin is another critical protein of theECM that gives the lung its elastic recoil ability In adultselastin which is expressed by lungs and other tissues isusually excreted in the urine During lung epithelial andendothelial injury elastin can be broken down by proteasessuch as neutrophil elastase [45] Elastin breakdown results insmaller fragments containing desmosine and isodesmosine[155] In a large study of 579 patients with ARDS thoseventilated with lower tidal volumes had lower urine desmo-sine levels a finding that may reflect reduced extracellularmatrix breakdown however no correlation with mortalitywas found in patients with ARDS [46]

MMPs Matrix metalloproteinases (MMPs) are zinc-depend-ent endopeptidases that are able to degrade almost allextracellular matrix components MMP-8 a member of theleukocyte-derived MMPs contributes to the degradationturnover and remodeling of the extracellular matrix digest-ing type I collagen [47 48] MMPs are major actors inalmost all phases of the inflammatory response and theirfunction is highly regulated At the tissue level most impor-tant inhibitors are the tissue inhibitors of metalloproteinases(TIMPs) In fulminant inflammation the inhibitory capacityof TIMPs may be overwhelmed leading to excessive tissuedamage and adverse outcome [47] Previous studies suggestthat MMPs may have an important role in ARDS althoughthis role may be either harmful or beneficial [156 157] In arecent study despiteMMP-8 levels did not predict outcome inARDS patients higher levels of TIMP-1 were independentlyassociated with increased 90-day mortality in a large groupof critically ill mechanically ventilated patients [47] Thesefindings are in contradiction to those from a study inpediatric ARDS patients in which higher MMP-8 and activeMMP-9 levels as measured 48 hours after disease onset wereassociated with longer durations of mechanical ventilationand fewer ventilator-free days [158] ElevatedMMP-2 MMP-8 and MMP-9 in the BAL fluid from ARDS patients wereassociated with patterns of acute inflammation but with pooroutcome [157] Interestingly MMP-3 and MMP-13 may beprotective against lung injury by cleaving transmembranereceptor RAGE into sRAGE thus regulating RAGE activationby its ligands [48 49]

312 Inflammatory Cascades During ARDS inflammatoryresponses can either be related to an ongoing primaryinfectious stimulus such as pneumonia or to systemic inflam-mation such as in sepsis or in pancreatitis [2] The inflam-matory cascade involves inflammatory cells and the releaseof inflammatory mediators as driven by a complex networkof cytokines A comparison between blood and alveolarcytokines suggests that most inflammatory mediators orig-inate from the lung [17] Alarmins or damage-associatedmolecular patterns (DAMPs) are released by dead cells orlocal inflammatory cells (eg alveolar macrophages) They

8 Disease Markers

activate and recruit immune cells via binding to differentreceptors such as TLR IL-1 receptor (IL-1R) or RAGEthereby initiating and perpetuating multiple proinflamma-tory pathways [21 159]

Regulation of the inflammatory response is a complexprocess that requires interplay between several immunemediators [160] Both pro- and anti-inflammatory biomark-ers have been studied in ARDS

(1) Proinflammatory Cytokines

(a) IL-1120573 and TNF-120572 IL-1120573 and TNF-120572 are the most biolog-ically potent cytokines secreted by activated macrophages inthe early phase of ARDS They cause the release of a varietyof proinflammatory chemokines such as monocyte chemo-tactic protein-1 (MCP-1) macrophage inflammatory protein-1120572 (MIP-1120572) IL-6 and IL-8 with subsequent recruitmentof inflammatory cells into the air spaces alteration of theendothelial-epithelial barrier permeability and impairmentof fluid transport leading to alveolar edema [17] TNF-120572 alsopromotes lung edema indirectly through the production ofreactive oxygen species (ROS) and a decreased expressionof epithelial sodium (ENaC) and Na+-K+-ATPase channels[161] Finally TNF-120572 a potent chemoattractant for fibrob-lasts is a promoter of lung fibrosis in experimental studies[162 163] Interestingly the ratio of BAL to serum levelsof both TNF-120572 and IL-1120573 is typically high suggesting thatsuch cytokines may originate from the lung in the settingof ARDS [164] Persistent elevation of plasma and BAL IL-1120573 is associated with worse outcome [165 166] Both TNF-120572 and IL-1120573 are elevated in the plasma and BAL fluid frompatients at risk of and with ARDS [164 167] and associatedwith mortality [166]

(b) IL-18 Inflammasomes are intracellular macromolecularcomplexes that serve as platforms for the activation of theproinflammatory enzyme caspase-1 which in turn cleavespro-IL-1120573 and pro-IL-18 into IL-1120573 and IL-18 [50] Theseinflammasome-activated cytokines play central roles in thepropagation of the acute inflammatory response IL-18 andcaspase-1 play critical roles in the development of lunginjury and higher levels of IL-18 are correlated with diseaseseverity and mortality in patients with ARDS [168] Among38 patients with acute respiratory failure those with ARDShad significantly higher serum levels of IL-18 and serum IL-18 was significantly higher in nonsurvivors [51]

(c) IL-6 IL-6 is produced by a wide range of cells includingmonocytesmacrophages endothelial cells fibroblasts andsmoothmuscle cells in response to stimulation by endotoxinIL-1120573 and TNF-120572 [52] IL-6 is one of the most importantmediators of fever and is critical for B-cell differentiation andmaturation with secretion of immunoglobulins cytotoxic Tcell differentiation macrophage and monocyte function andproduction of acute phase proteins Although IL-6 activatesboth proinflammatory and anti-inflammatory mechanismsIL-6 primarily correlates with a proinflammatory profileduring the early phase of ARDS Plasma IL-6 increases earlyin patients at risk of developing ARDS [53] IL-6 is elevated in

both plasma and BAL fluid during ARDS [59] and correlateswith mortality [54 55]

(d) IL-8 IL-8 is a proinflammatory cytokine with a role inneutrophilmonocyte chemotaxis and neutrophil apoptosisinhibitionHighplasma andBAL levels of IL-8 are found earlyduring ARDS and predict outcome [169] However previousstudies did not support such findings [170 171] In a recentmonocenter study of 100 patients only baseline IL-8 (among6 other biomarkers) was associated with the development ofmultiorgan failure even after adjustment for other relevantvariables [32] Also several studies have evaluated the roleof the anti-IL-8 autoantibodyIL-8 immune complexes inARDS a pathway that could lead to the identification of novelbiomarkers and therapeutic targets [17 172ndash175]

In a recent study Calfee et al used latent class analysisto integrate both clinical and biological data to identifytwo ARDS endotypes in an analysis of 1022 patients fromtwo ARDSNet trials (ARMA and ALVEOLI) [13] A firstendotype was categorized by more severe inflammation asassessed by both IL-6 and IL-8 levels and worse clinicaloutcomes whereas a second endotype had less inflammationless shock and better clinical outcomes Based on the datafrom the ALVEOLI trial a ldquoproinflammatoryrdquo endotypewas associated with higher mortality and better response tohigher levels of positive end-expiratory pressure [176]

(2) Anti-Inflammatory Cytokines The inflammatory responseis also strongly influenced by anti-inflammatory systemsincluding nonspecific (eg 2-macroglobulin IL-10) andspecific (eg IL-1 receptor antagonist (IL-1RA) antagonistssoluble IL-1 receptor II (sIL-1RII) soluble TNF receptorI (sTNF-RI) and soluble TNF receptor II (sTNF-RII)) ofproinflammatory cytokines

(a) IL-1RA Circulating IL-1RA levels are increased but donot predict the development of ARDS in at-risk patients[56] Studies of gene expression in alveolar macrophagesand circulating leukocytes from healthy control subjects andpatients with ARDS revealed that sIL-1RII may be valuable asa biomarker because of increased levels in both the lung andcirculation during ARDS [57]

(b) sTNF-RIsTNF-RII Soluble TNF-120572 receptors (sTNF-R)I and II can bind TNF and compete with its binding tothe cellular receptor thus reducing its bioavailability SolubleTNF-RI and TNF-II are associated with morbidity andmortality in patients with ARDS [54] and a strategy of lowtidal volume ventilation is associated with decreased sTNF-RI levels [54] Trauma-associated ARDS differs clinically andbiologically from ARDS due to other clinical disorders withlower levels of sTNF-RI patients with trauma as a primarycause of ARDS [6 58]

(c) IL-10 Interleukin-10 (IL-10) is an anti-inflammatorycytokine that is produced by several cells including B lym-phocytes monocytes and alveolar macrophages [60] Asidefrom inhibiting the production of IL-1 and TNF-120572 IL-10

Disease Markers 9

upregulates TNF receptors [177] and stimulates the produc-tion of the naturally occurring IL-1RAand the release of sTNFreceptors [178] IL-10 inhibits the production of proinflam-matory mediators by alveolar macrophages involved duringARDS [179] ARDS patients have lower plasma and BALlevels of IL-10 than at-risk patients who did not develop thesyndrome [61] Higher baseline IL-10 levels were associatedwith higher morbidity and mortality [59]

(3) Additional Markers Other markers with potential clinicalimportance in ARDS-associated inflammation have beenidentified as putative biomarkers during ARDS

High mobility group box nuclear protein 1 (HMGB1) is aDNAnuclear binding protein that is secreted by immune cellsincluding monocytes and macrophages HMGB1 increasesearly after severe trauma and correlates with systemic inflam-matory response and development of ARDS [62] Alveolarand plasma levels of HMGB1 (as measured in the arterial orcentral venous blood) are elevated in patients with ARDS andassociated with outcome [109] In 20 patients with ARDSplasma levels of HMGB1 were also higher in nonsurvivorsand correlated with levels of sRAGE [63]

Lipopolysaccharide binding protein (LBP) is an acutephase protein that is correlated with lung inflammationduring ARDS [64] More recently it has also been demon-strated that serum levels of LBPwere strongly associated withincreasedmortality and the development of ARDS in patientswith severe sepsis [65]

Nitric oxide (NO) is a marker of oxidative stress thathas also been investigated as a marker of ARDS In patientswith persistent ARDS higher levels of nitric oxide andof its end-products (eg nitrotyrosine) are associated withmortality [66] In contrast higher urine NO levels werestrongly associated with better clinical outcomes includingmortality and ventilator-free days in patients enrolled in theARDSNet low tidal volume trial [46] Extracellular citrullinethe effective precursor of NO is lower in the plasma frompatients with severe sepsis and lower plasma citrulline isassociated with the presence of ARDS [67] Mechanismsinvolved in the regulation of lung injury by NO-dependentpathways remain unknown

Although C-reactive protein (CRP) is widely consideredas a marker of systemic inflammation higher levels of CRPare associated with better outcome among patients withARDS [68] Nevertheless a recent study found that albuminlevels rather than CRP may help to predict and monitor theseverity and course of ARDS in febrile critically ill patientswith ARDS or at risk for the syndrome [69] In the samestudy levels of lactate dehydrogenase (LDH) predicted 28-day mortality but were not correlated with severity [69]

313 Coagulation and Fibrinolysis During early ARDS acti-vation of the inflammatory cascades results in the activationof the coagulation system which in turn can influenceinflammatory responses by affecting the expression of variouscytokines such as IL-1 IL-6 and IL-8 Activation of coagula-tion pathways induces migration of inflammatory cells intoalveoli through the endothelial and epithelial barriers and

generates thrombin formation In addition proinflammatoryevents may also inhibit fibrinolysis and induce platelet acti-vation [17]

Extravascular fibrin deposition when localized predomi-nantly in the alveolar compartment is found in several acuteinflammatory lung diseases and enhanced alveolar procoag-ulant activity is reported inARDS patients [180] Fibrin depo-sition may be beneficial for gas exchange by sealing leakagesites when lung capillary endothelial and epithelial barriersare disrupted Nevertheless fibrin alveolar deposition maybe harmful since it can lead to activation of neutrophilsand fibroblasts endothelial injury loss of surfactant activityfavoring alveolar collapse impaired alveolar fluid clearanceand thrombotic obstruction of the microcirculation [180]

(1) PAI-1 The balance between activation of coagulationand activation of fibrinolysis is an important determinantof the amount and duration of fibrin deposition duringlung injury Plasminogen activator (PA) and plasminogenactivator inhibitor-1 (PAI-1) regulate fibrinolysis through theconversion of plasminogen to plasmin a fibrinolytic enzymePA-1 is amajor endogenous inhibitor of PA Both PA and PA-1are secreted by various cells including macrophages fibrob-lasts and lung endothelial and epithelial cells [71] DuringARDS alveolar epithelial cells and activated macrophagesoverexpress PAI-1 thus contributing to decreased alveolarfibrinolytic activity Nevertheless the value of PAI-1 asa biomarker in ARDS remains controversial PAI-1 levelswere higher in patients with ARDS than in patients withhydrostatic lung edema [72] and higher PAI-1 levels areassociated withmortality and higher durations ofmechanicalventilation in patients with ARDS [72 169] In a large Finnishstudy PAI-1 levels were not correlated with mortality ordevelopment of ARDS in critically ill patients undermechan-ical ventilation but low baseline plasma levels of the solubleurokinase plasminogen activator receptor (suPAR) were pre-dictive of survival [181] In a secondary analysis of two largerandomized controlled trials PAI-1 was associated with lunginjury (as defined as decreased oxygenation index) but notwithmortality [28] Nevertheless in another study of patientsfrom the ARDSNet ARMA study higher levels of PAI-1were independently associated with higher mortality andclinical outcomes including organ failure [182] Howeverthis association between PAI-1 levels and the development ofmultiorgan failure was not confirmed in a recent study of 100ARDS patients [32]

(2) Protein C Protein C system is an important endogenousregulator of coagulation and fibrinolysis Protein C is synthe-sized by the liver and circulates as an inactive compoundIt is transformed to its active form on cell surface by thethrombomodulin- (TM-) thrombin complex [75 76] Theendothelial cell protein C receptor (EPCR) is another cellsurface protein that can further enhance protein activationby binding the TM-thrombin complex [183] In additionto suppressing thrombin formation activated protein C hasanti-inflammatory properties such as decreasing the levelsof proinflammatory cytokines [184] Protein C can improveendothelial permeability and exert antiapoptotic effects via

10 Disease Markers

p53 pathways [185] Activated protein C can also inactivatePAI-1 thus promoting fibrinolysis [186] Plasma protein Cwas significantly lower in patients with ARDS as comparedto controls and it was associated with worse clinical out-comes including higher hospital mortality shorter durationof unassisted ventilation and increased risk ofmultiple organfailure [73] In a larger cohort of patients with early ARDSlow plasma levels of protein C were again associated withmortality and adverse clinical outcomes [182] Decreasedlevels of protein C during ARDS suggest a link betweenhypercoagulability and mortality

(3) Thrombomodulin Thrombomodulin (TM) is a mul-tidomain transmembrane-bound glycoprotein found on thesurface of endothelial cell Its main role is to neutralize theprocoagulant effects of thrombin and accelerate activationof protein C In addition to its membrane-bound form TMalso exists as a circulating soluble isoform in the plasmaIn patients with ARDS levels of soluble thrombomodulin(sTM) are higher in the pulmonary edema fluid than inplasma [73] suggesting an alveolar source but no correlationwas found between plasma sTM and the development ofARDS yet higher levels of sTM were observed in patientsat high risk for ARDS In patients with established ARDShigher plasma and alveolar levels of sTM were correlatedwith severity of illness and multiple organ failure [73] Ina larger analysis of 449 patients elevated levels of plasmasTM were associated with increased mortality thus possiblyreflecting an increased degree of inflammation and both lungand systemic endothelial damage [74]

(4) Tissue Factor (TF) Tissue factor (TF) is a 47 kDa trans-membrane glycoprotein that is the most potent stimulator ofthe extrinsic coagulation cascade TF initiates the coagulationcascade by binding and allosterically activating coagulationfactor VIIa The resulting TF-VIIa complex binds the sub-strate coagulation factor X via multiple interactions alongan extended interface to produce the TF-VIIa-X complexThis complex leads eventually to thrombin formation andfibrin deposition [77] Levels of TF in lung edema fluid arehigher than plasma levels in patients with ARDS supportinga lung origin for TF in this setting and both plasma andalveolar levels of TF are higher in ARDS patients as comparedto patients with hydrostatic edema [187] Notably patientswith sepsis-induced ARDS may have higher levels of TF ascompared to patients without ARDS [78]

(5) Cell-Free Hb Levels of cell-free hemoglobin (Hb) arehigher in the air space of ARDS patients as comparedto critically ill patients with hydrostatic lung edema [79]Instillation of red blood cells or cell-free hemoglobin causeslung injury in rats [188] and intra-alveolar hemorrhage isassociated with high levels of intra-alveolar cell-free Hbmore severe lung injury and increased lipid peroxidationin the lung from mice with tissue factor deficiency [79]Precise cellular and molecular mechanisms by which cell-free hemoglobin in the air space could mediate or potenti-ate ARDS are currently under investigation [189] Cell-freeHb could activate chemokine release within the lung and

decompartmentalization of hemoglobin is likely to provide asignificant proinflammatory stimulus in the setting of diffusealveolar damage and hemorrhage during ARDS [80]

314 EFPL Protein Ratio The pathophysiology of ARDSincludes disruption of several physical barriers includingendothelial and epithelial cell layers the basement mem-brane and the extracellularmatrix resulting in increased pul-monary microvascular permeability The pulmonary edemafluid-to-plasma protein (EFPL) ratio is a rapid safe andnoninvasive measure of alveolar-capillary membrane per-meability The EFPL ratio was first proposed as a tool todetermine the etiology of acute pulmonary edema [81] Morerecently in a large study of 390 critically ill patientsWare et aldemonstrated that the EFPL ratio had an excellent discrimi-native value in distinguishing ARDS from hydrostatic edemaand was strongly associated with clinical outcomes Using acutoff of 065 the EFPL ratio had a sensitivity of 81 and aspecificity of 81 for the diagnosis of ARDS [82]

32 Fibroproliferative Phase of ARDS In some patientsimportant and persistent accumulation of macrophagesfibrocytes fibroblasts and myofibroblasts in the alveolarcompartment leads to excessive deposition of ECM com-ponents including fibronectin and collagen types I and IIIamong other proteins An imbalance between profibrotic andantifibrotic mediators may subsequently drive this fibropro-liferative response [190] Growth factors play a major rolein the resolution of ARDS [17] Lung endothelial repair ispromoted by vascular endothelial growth factor (VEGF)A variety of growth factors promote repair of the alveo-lar epithelium including keratinocyte growth factor (KGF)hepatocyte growth factor (HGF) fibroblast growth factor(FGF) and transforming growth factor-120572 (TGF-120572) [17] Twomajor pathways with opposite effects involve growth factorsduring ARDS tyrosine kinase receptor mediation (eg KGFHGF FGF and VEGF) and serine-threonine kinase receptorssuch as TGF-1205731 which tend to have opposed effect on theupregulation that occurs when the tyrosine kinase receptorpathway is involved [85 191 192]

321 Endothelial Proliferation Novel evidence points to apotential role of VEGF in promoting repair of the alveolar-capillarymembrane during recovery fromARDS and under-standing the role of VEGF in this disease process couldbe crucial for developing new therapeutic strategies [85193] In the lung VEGF is produced primarily by epithelialcells it increases microvascular permeability [83] but has animportant role also during the repair phase by stimulatingendothelial cell proliferation and survival [86 149] Thelevels of VEGF are increased in plasma from patients withARDS but are decreased in BAL fluid compared to healthycontrols subsequently BAL levels of VEGF increase duringthe resolution of lung injury [39 84 149]

322 Epithelial Proliferation and Apoptosis KGF also knownas FGF-7 is a potent mitogenic factor for alveolar epithelialcells that is primarily produced by fibroblasts and other

Disease Markers 11

cells such as T lymphocytes KGF regulates transepithelialtransport of sodium by stimulating the epithelial channelNa+-K+-ATPase in alveolar epithelial cells [87]

HGF is a nonspecific mitogen secreted by fibroblastsalveolar macrophages endothelial cells and epithelial cellsSeveral animal and human studies suggest that KGF andHGFcould protect the alveolar space against injury and couldfacilitate the repair of alveolar structures after injury [88 194195] KGF levels could be measured in the BAL from patientswith ARDS but not in the BAL from those without ARDS inaddition BALKGFwas associated with poor prognosis [196]Elevated HGF levels were also associated with outcome [196]In 36 patients with ARDS and 11 patients with hydrostaticlung edema HGF and KGF were proven biologically activein the edema fluid of patients with ARDS and higher levelsof HGFwere associated withmortality in these patients [197]

Apoptosis of alveolar epithelial cells is a major phe-nomenon in the initiation and perpetuation of lung injury[89] The FasFasL system plays an important role in theregulation of cell life and death through its ability to initiateapoptosis [198] This system combines the cell membranesurface receptor Fas (CD95) and its natural ligand FasL(CD95L) Membrane-bound FasL mediates lymphocyte-dependent cytotoxicity clonal deletion of alloreactive T cellsand activation-induced suicide of T cells [199] Its solubleform (sFasL) results from cleavage of membrane FasL byMMPs and induces apoptosis in susceptible cells [200]Apoptosis is inducedwhenmembrane-bound or soluble FasLbinds to Fas-bearing cells By contrast apoptosis is inhibitedwhen soluble Fas binds to either membrane-bound FasL orsFasL thus preventing FasL from interacting withmembrane-bound Fas receptors [201] In patients with ARDS sFasL wasdetectable in the lung before and after the onset of clinicallydefined ARDS and nonsurvivors had significantly higherBAL levels of sFasL on day 1 as compared with survivors[200] Both soluble Fas and soluble FasL were associated withoutcome and higher in the lung edema fluid from patientswith ARDS compared to control patients with hydrostaticpulmonary edema [202] Nevertheless recent findings sug-gested limited role for FasFasL system and apoptosis inairway epithelial cell death during ARDS [90]

323 Fibroblast Proliferation Pulmonary fibroblasts pro-duce procollagen III peptide (PCP-III) that is a precursorof collagen The NT part of procollagen III resulting fromthe enzymatic cleavage of procollagen by specific proteases inthe extracellular space is considered as a marker of collagensynthesis Alveolar levels of N-PCP-III are higher in ARDSpatient as compared with controls [203] The elevation ofN-PCP-III in pulmonary edema fluid begins within the first24 h of ARDS that is during the acute phase of increasedendothelial and epithelial permeability to protein suggestingthat fibrosing alveolitis could begin very early in the course ofclinical ARDS [203] In another study high levels of N-PCP-III were early predictors of poor outcome [204 205] Morerecently Forel et al measured alveolar N-PCP-III in patientswith nonresolving ARDS thus identifying patients who haddeveloped lung fibroproliferation [206] Unfortunately it

is still unknown whether N-PCP-III measurements couldbe useful in selecting patients who would benefit fromglucocorticoid therapy among others to reduce the ARDS-associated lung fibrosis [207]

4 Perspectives

41 Combining Biomarkers Despite advances in the identi-fication of biomarker candidate and better understanding ofARDS pathogenesis no single clinical or biological markerreliably predicts clinical outcomes inARDSThe combinationof clinical and biological marker is attractive in order toimprove the sensitivity andor the specificity of the testespecially through a recent approach aimed at measuring8 biological markers that reflect endothelial and epithelialinjury inflammation and coagulation vWF SP-D TNF-R1IL-6 IL-8 ICAM-1 protein C and PAI-1 in 549 patientsenrolled in the the ARDSNet trial of low versus high positiveend-expiratory pressure [208] Clinical predictors predictedmortality with an area under the ROC curve (AUC) of082 whereas a combination of these 8 biomarkers and theclinical predictors had an AUC of 085 The best performingbiomarkers were the neutrophil chemotactic factor IL-8 andSP-D a product of AT2 cells [208] supporting the conceptthat acute inflammation and alveolar epithelial injury areimportant pathogenetic pathways in human ARDS Morerecently a panel of biomarkers of lung epithelial injuryand inflammation (SP-D sRAGE IL-8 CC16 and IL-6)provided excellent discrimination for diagnosis of ARDSin patients with severe sepsis [20] Therefore and beyondtheir better diagnostic and prognostic values the use of suchbiomarker panels may be useful for selecting patients forclinical trials that are designed to reduce lung epithelial injury[113] Nevertheless whether a therapeutic strategy based onbiomarker measurements would benefit patient outcome hasnever been investigated

42 Lung Imaging as an ARDS Biomarker Studies of lungimaging during ARDS have revealed that adequate ventilatorsettings may vary among patients with the same syndromeIn a large study gas and tissue distribution in the lungs ofARDS patients were assessed using computed tomography(CT) and compared to those of healthy volunteers [11] Lungmorphology in ARDS is characterized by marked excess oflung tissue associated with a major decrease in aerated lungregions and in functional residual capacity Some patientswith ARDS exhibit preserved aeration of the upper lobesdespite the presence of an overall excess of lung tissue (ldquofocalrdquoARDS) as opposed to other patients with more diffuse lossof aeration and excessive lung tissue (ldquodiffuserdquo or ldquononfocalrdquoARDS) [209]

Lung morphology may influence the response to pos-itive end-expiratory pressure (PEEP) recruitment maneu-vers (RM) prone position and patient outcome [12 210]In a prospective study of nineteen patients with ARDSConstantin et al found that lung morphology at zero end-expiratory pressure could predict the response to a RM withcontinuous positive airway pressure of 40 cm H

2O for 40

12 Disease Markers

seconds Nonfocal morphology was associated with higherlung recruitability and PaO

2FiO2was significantly increased

by the RM [12 211] In contrast patients with focal lungmorphology were at risk of significant hyperinflation duringthe RM with no improvement of arterial oxygenation

It has also been hypothesized that the effects of PEEPmay depend on lung morphology Puybasset et al assessedthe responses to PEEP among patients with focal or nonfocalARDS [210] The regional distribution of intrapulmonarygas and lung tissue influences the effects of PEEP in ARDSpatients maximal alveolar recruitment without evidenceof overdistension was observed in patients with nonfocalARDS Nevertheless PEEP induced mild alveolar recruit-ment in patients with focal ARDS along with overdistensionof previously aerated lung regions

Interestingly phenotyping patients with ARDS basedon their lung morphology might be possible by measuringplasma sRAGEwith commercially available kits even thoughthese findings need further validation [100 112] HoweverRAGE pathway is a promising candidate for subphenotypingpatients with ARDS as it is believed to play a major rolein the mechanisms leading to AFC and their regulation[110] Recent findings that support a relationship betweenimpaired AFC and lung morphology may therefore fill a gapin the full recognition of an ARDS phenotype based on lungmorphology that could be linked to an endotype of impairedAFC and activated RAGE pathway [12 100 101 112 113 212]

43 Biomarkers in ARDS Can They Improve Patient CareBiomarkers are broadly used in critically ill patientsespecially during inflammatory andor infectious diseasesBiomarkers have been commonly defined as characteristicsthat are objectively measured and evaluated as indicatorsof normal biological processes pathogenic processes orpharmacologic responses to therapeutic interventions [213214] Biomarkers provide a powerful approach to understanda disease with multiple applications in observational andanalytic epidemiology randomized clinical trials screeningand diagnosis or prognosis [215]

Nevertheless there are important technical attributes fora relevant biomarker First the marker must be present inperipheral body tissue andor fluid (eg blood urine salivabreath or cerebrospinal fluid) second it must be easy todetect or quantify in assays that are both affordable androbust and third its regulation should be associated asspecifically as possible with damage of a particular tissuepreferably in a quantifiable manner Prior to the widespreaduse of a marker of interest it is essential that validation andconfirmation of candidate biomarkers by robust statisticalmethods are performed during biomarker discovery [215]Sensitivity and specificity are common quality parametersfor biomarkers Sensitivity describes the probability of apositive test in cases and specificity describes probability ofnegative test in controls An association between sensitivityand specificity is represented in the ROC curve by graphingsensitivity versus 100 minus specificity Area under the ROC curve(AUROC) is therefore a measure of performance of a markerThere is no absolute cutoff value of AUROC for robustness of

a marker but aminimum of 07 is required and values greaterthan 08 are good particularly in a heterogeneous critically illpatient population [216 217]

To summarize an ideal biomarker should indicate aclear relationship with the pathophysiologic event needsto be reliable reproducible disease specific and sensitiveand should be sampled by simple methods and relativelyinexpensive with little or no diurnal variation DuringARDS no single marker has been validated with all thesecriteria to date yet we believe that sRAGE may fulfill allprerequisites of a biomarker of ARDS First plasma sRAGEhas good diagnostic and prognostic values [96 99 100109 112] Second it is very well correlated with lung injuryseverity and specific pathophysiologic features of ARDS forexample alveolar fluid clearance and lung morphology [9699ndash101 109 112] Previous studies of the predictive value ofearly levels of sRAGE for the development of ARDS in ageneral population of patients admitted to the emergencydepartment were negative [130] but current research focuseson both the kinetics of sRAGE and esRAGE and RAGE genepolymorphisms as predictors of the development of ARDSin at-risk critically ill patients [114] Finally there is someevidence suggesting that monitoring sRAGE could informat least partially on therapeutic responses in patients with orwithout ARDS [24 99 113] If these data are confirmed byfuture studies such findingswould definitely help to reinforcesRAGE a real biomarker of ARDS

5 Conclusion

Biomarker research provides an important translational linkto our understanding of lung pathobiology Through theidentification and testing of candidate biomarkers we havegained insight into the pathogenic importance of endothelialand epithelial injury and have started to unravel the complexpathways that contribute to endothelial and epithelial celldysfunction inflammation fibrosis and apoptosis in ARDSIn addition biomarker studies may help us to explore thecellular and molecular mechanisms of various therapeuticstrategies for ARDS and to better understand the potentialproinflammatory effects of mechanical ventilation Giventhe clinical heterogeneity of patients with ARDS and thecomplexity of the underlying pathobiology it is unlikely thata single biomarker will emerge for ARDS as cardiac-specifictroponin did for myocardial infarction but the develop-ment of small biomarker panels reflecting each importantlung injury pathway would provide valuable predictive andprognostic information for both clinicians and investigatorsWhile biomarkers are currently not recommended for usein clinical practice in ARDS biomarker discovery mayhold significant promise in order to develop and applytargeted therapies and to identify candidates for enrollmentin patient-tailored clinical trials of novel therapies for ARDS

Disclosure

The funders had no influence on the study design conductand analysis or on the preparation of this paper

Disease Markers 13

Conflict of Interests

No conflict of interests other sources of financial supportcorporate involvement patent holdings and so forth are tobe declared for all authors

Authorsrsquo Contribution

Raiko Blondonnet was involved in the conception and designof the review in writing the paper and in its revision priorto submission Jean-Michel Constantin was involved in theconception and design of the review in writing the paperand in its revision prior to submission Vincent Sapin wasinvolved in the conception and design of the review inwriting the paper and in its revision prior to submissionMatthieu Jabaudon takes responsibility for the content ofthe paper and was involved in the conception and design ofthe review in writing the paper and in its revision prior tosubmission

Acknowledgments

This work was supported by grants from the AuvergneRegional Council (ldquoProgramme Nouveau Chercheur de laRegion Auvergnerdquo 2013) the french Agence Nationale de laRecherche and the Direction Generale de lrsquoOffre de Soins(ldquoProgramme de Recherche Translationnelle en Santerdquo ANR-13-PRTS-0010)

References

[1] VM Ranieri G D Rubenfeld P TThompson et al ldquoAcute res-piratory distress syndrome the Berlin definitionrdquo The Journalof the American Medical Association vol 307 no 23 pp 2526ndash2533 2012

[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000

[3] C Brun-Buisson C Minelli G Bertolini et al ldquoEpidemiologyand outcome of acute lung injury in European intensive careunitsrdquo Intensive Care Medicine vol 30 no 1 pp 51ndash61 2004

[4] G D Rubenfeld E Caldwell E Peabody et al ldquoIncidence andoutcomes of acute lung injuryrdquo The New England Journal ofMedicine vol 353 no 16 pp 1685ndash1693 2005

[5] D W Dowdy M P Eid C R Dennison et al ldquoQuality oflife after acute respiratory distress syndrome a meta-analysisrdquoIntensive Care Medicine vol 32 no 8 pp 1115ndash1124 2006

[6] C S Calfee M D Eisner L B Ware et al ldquoTrauma-associatedlung injury differs clinically and biologically from acute lunginjury due to other clinical disordersrdquo Critical Care Medicinevol 35 no 10 pp 2243ndash2250 2007

[7] C S Calfee D R Janz G R Bernard et al ldquoDistinct molecularphenotypes of direct versus indirect ARDS in single and multi-center studiesrdquo Chest vol 147 no 6 pp 1539ndash1548 2015

[8] P Tejera N J Meyer F Chen et al ldquoDistinct and replicablegenetic risk factors for acute respiratory distress syndromeof pulmonary or extrapulmonary originrdquo Journal of MedicalGenetics vol 49 no 11 pp 671ndash680 2012

[9] M A Matthay G A Zimmerman C Esmon et al ldquoFutureresearch directions in acute lung injury summary of a National

Heart Lung and Blood Institute Working Grouprdquo AmericanJournal of Respiratory and Critical Care Medicine vol 167 no7 pp 1027ndash1035 2003

[10] J P Reilly S Bellamy M G S Shashaty et al ldquoHeterogeneousphenotypes of acute respiratory distress syndrome after majortraumardquo Annals of the American Thoracic Society vol 11 no 5pp 728ndash736 2014

[11] L Puybasset P Cluzel N Chao et al ldquoA computed tomographyscan assessment of regional lung volume in acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol158 no 5 pp 1644ndash1655 1998

[12] J-M Constantin S Grasso G Chanques et al ldquoLungmorphol-ogy predicts response to recruitment maneuver in patients withacute respiratory distress syndromerdquo Critical Care Medicinevol 38 no 4 pp 1108ndash1117 2010

[13] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoSubphenotypes in acute respiratorydistress syndrome latent class analysis of data from tworandomised controlled trialsrdquoThe Lancet Respiratory Medicinevol 2 no 8 pp 611ndash620 2014

[14] R Marshall G Bellingan and G Laurent ldquoThe acute respira-tory distress syndrome fibrosis in the fast lanerdquoThorax vol 53no 10 pp 815ndash817 1998

[15] R B Henderson J A R Hobbs M Mathies and N HoggldquoRapid recruitment of inflammatory monocytes is independentof neutrophil migrationrdquo Blood vol 102 no 1 pp 328ndash3352003

[16] HMMarriott andDH Dockrell ldquoThe role of themacrophagein lung disease mediated by bacteriardquo Experimental LungResearch vol 33 no 10 pp 493ndash505 2007

[17] L J M Cross and M A Matthay ldquoBiomarkers in acute lunginjury insights into the pathogenesis of acute lung injuryrdquoCritical Care Clinics vol 27 no 2 pp 355ndash377 2011

[18] H K Gaggin and J L Januzzi ldquoBiomarkers and diagnostics inheart failurerdquo Biochimica et Biophysica Acta (BBA)mdashMolecularBasis of Disease vol 1832 no 12 pp 2442ndash2450 2013

[19] E Christenson and R H Christenson ldquoThe role of cardiacbiomarkers in the diagnosis and management of patientspresenting with suspected acute coronary syndromerdquo Annals ofLaboratory Medicine vol 33 no 5 pp 309ndash318 2013

[20] L B Ware T Koyama Z Zhao et al ldquoBiomarkers of lungepithelial injury and inflammation distinguish severe sepsispatientswith acute respiratory distress syndromerdquoCritical Carevol 17 no 5 article R253 2013

[21] M A Matthay L B Ware and G A Zimmerman ldquoTheacute respiratory distress syndromerdquo The Journal of ClinicalInvestigation vol 122 no 8 pp 2731ndash2740 2012

[22] M Shirasawa N Fujiwara S Hirabayashi et al ldquoReceptor foradvanced glycation end-products is a marker of type I lungalveolar cellsrdquo Genes to Cells vol 9 no 2 pp 165ndash174 2004

[23] M Neeper A M Schmidt J Brett et al ldquoCloning andexpression of a cell surface receptor for advanced glycosylationend products of proteinsrdquo The Journal of Biological Chemistryvol 267 no 21 pp 14998ndash15004 1992

[24] M Jabaudon E Futier L Roszyk V Sapin B Pereira andJ Constantin ldquoAssociation between intraoperative ventilatorsettings and plasma levels of soluble receptor for advancedglycation end-products in patients without pre-existing lunginjuryrdquo Respirology vol 20 no 7 pp 1131ndash1138 2015

[25] L G Dobbs R F Gonzalez L Allen and D K Froh ldquoHTI56an integral membrane protein specific to human alveolar type

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

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Disease Markers

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4 Disease Markers

Table 1 Biomarkers of acute respiratory distress syndrome organized by phases and pathways of lung injury

Pathophysiologic feature of ARDS Biomarker ReferencesExudative phase

Epithelium damage

(i) Alveolar type 1 cells RAGE [22ndash24]HTI56

[25 26]

(ii) Alveolar type 2 cells Surfactant [27 28]KL-6 [29 30]

(iii) Clara cells CC16 [31 32]Endothelium damage

Ang-1 Ang-2 [33 34]ICAM-1 [35 138ndash140]Selectins [36 37]VEGF [38 39]vWF [40ndash42]

Lung matrix alterationLaminin [43 44]

Elastindesmosine [45 46]MMPs [47ndash49]

Inflammatory cascade

(i) Proinflammatory

IL-1120573TNF-120572 [17 161ndash164 167]IL-18 [50 51]IL-6 [52ndash55]IL-8 [169ndash171]

(ii) Anti-inflammatoryIL-1RA [56 57]

sTNF-RIsTNF-RII [6 54 58]IL-10 [59ndash61]

(iii) Additional markers

HMGB1 [62 63]LBP [64 65]NO [46 66 67]CRP [68]

Albumin [69]LDH [69]

Coagulation and fibrinolysisPA-1 [32 53 70ndash72]

Protein C [75 76 182]Thrombomodulin [73 74]

Tissue factor [75ndash78]Cell-free hemoglobin [75 76 79 80]

Pulmonary vascular permeabilityEFPL ratio [81 82]

Fibroproliferative phaseEndothelial proliferation

VEGF [39 83ndash86]Epithelial proliferation

KGF [87]HGF [88 194 195 197]

Epithelial apoptosisFasFasL [25 88ndash91]

Fibroblast proliferationN-PCP-III [88 194 195 203 207]

Disease Markers 5

HTI56 Human type I cell-specificmembrane protein (HTI56)

is a 56-kDa glycosylated lung protein specific to the apicalmembrane of human AT1 cells HTI

56has biochemical char-

acteristics of an integral membrane protein [25] Althoughthe precise functions of HTI

56remain unknown HTI

56is

an analog to RTI40 a 40ndash42 kDa integral membrane protein

specific to the apical membrane of rat AT1 cells [26] Patientswith ARDS had higher levels of HTI

56in both lung edema

fluid and plasma as compared to patients with hydrostaticlung edema [94] but no study assessing the associationbetween HTI

56levels and other endpoints in patients with

ARDS (eg prognosis) has been published to date

(b) Alveolar Type 2 Cells AT2 cells have important homeo-static functions in the lung including AFC and productionof alveolar surfactant (involved in lung compliance keepingthe alveolus open) AT2 cells are also known as keymediatorsof the epithelial repair process [115]

Surfactant Proteins Surfactant has a vital role in maintainingthe integrity of the alveolar-capillary interface Its essentialfunction is to decrease surface tension into the alveoli thusstabilizing lung volume at low transpulmonary pressuresSurfactant is composed of approximately 80 phospholipids8 other lipids (cholesterol triacylglycerol and free fattyacids) and 12 proteins Four surfactant-associated proteins(SP) designated SP-A SP-B SP-C and SP-D representapproximately half of proteins composing surfactant SP-Aand SP-D easily dissociate from lipids and are hydrosolubleThey belong to the lung innate immune system therebyenhancing phagocytosis of bacteria and virus They alsoexert regulatory effects on AT2 cells SP-B and SP-C aresmall extremely hydrophobic proteins that are important inthe formation of the surfactant monolayer in the terminalairspaces and in the reduction of surface tension thuspreventing end-expiratory alveolar collapse [116]

Early observations in ARDS revealed a loss in surfacetension suggesting a functional loss of the surfactant proteins[117] In a first case report of three patients the ratioof plasma SP-BSP-A was inversely associated with bothblood oxygenation and static respiratory system compliancesuggesting that SP-B breaches the alveolocapillary barriermore readily than SP-A and may therefore provide a moresensitive marker of lung injury [118] Plasma levels of SP-Aand SP-B are increased in patients with ARDS [70] and in at-risk patients [119 120] whereas lower SP-A and SP-B levelswere found in the BAL fluid of patients at risk for ARDSprior to the onset of the clinical syndrome SP-A and SP-Blevels remained low for as long as 14 days in patients withsustained ARDS Interestingly this decrease in BAL SP-A andSP-B does not result simply from dilution of alveolar fluids byplasma entering the alveolar spaces as SP-D levels remainedstable in parallel [119] In a cohort of 38 patients reducedpulmonary edema fluid SP-D and elevated plasma SP-A atthe onset of ARDS were associated with poor prognosis [27]Nevertheless in a study of 259 patients from the ARDSNettrial of low versus high end-expiratory pressure in ARDS(ALVEOLI) as well as in 75 patients enrolled in a randomized

trial of activated protein C for ARDS plasma SP-D was notassociated with 28-day mortality or ventilator-free days [28]

KL-6 Krebs von den Lungen-6 (KL-6) is a human MUC1mucin that belongs to the high-molecular-weight glyco-protein family After the cleavage of S-S bond KL-6 canspread into the pulmonary epithelial lining fluid In thenormal lung this glycoprotein can be predominantly foundin AT2 cells and its expression is enhanced during AT2proliferation regeneration or injury thus representing anattractive biomarker in ARDS Plasma KL-6 is elevated inARDS patients and correlates with lung injury and mortality[29 121ndash123] Plasma levels of SP-D and KL-6 increase overtime in patients with ARDS and may represent biologicalmarkers of ventilator-associated lung injury because theirincrease is attenuated by lung-protective ventilation [30]

(c) CC16 Clara cell protein (CC16) is a 158 kDa homod-imeric protein that is abundantly secreted in airways by thenonciliated bronchiolar Clara cells Clara cells are devotedto the protection of the respiratory tract against toxicinhaled agents the repair of damaged epithelium xenobioticsdetoxification and the secretion of proteins with importantbiological activities CC16 is highly expressed in the epitheliallining fluid with antioxidantinflammatory roles notably bymodulating the production andor activity of phospholipase-A2 interferon-120574 and tumor necrosis factor-120572 [31] Availablestudies found contradictory inconclusive findings duringARDS Although higher levels of CC16 are associated withlung injury and inflammation in some experimental andclinical studies patients with ARDS had lower plasma andpulmonary edema fluid levels of CC16 than patients withacute cardiogenic pulmonary edema and no correlation wasfound between CC16 and prognosis So many conflictingfindings do not currently support the association of CC16with the diagnosis or prognosis of ARDS

(2) Vascular Endothelium Vascular endothelial injury ischaracterized by the disruption of cell components leadingto increased microvascular permeability and alveolar edemaEndothelial injury is mainly driven by the activation ofinflammation and coagulation cascades The activation ofendothelial cells by circulating mediators leads to increasedexpression of cell surface molecules that are importantmediators of leukocyte adhesion and contribute to leuko-cyte accumulation and transmigration [124] Activated lym-phocytes can also release mediators in microvessels thatincrease vascular permeability Along with these leukocytesignals inflammatory mediators such as tumor necrosis fac-tor (TNF) thrombin and vascular endothelial growth factor(VEGF) disrupt endothelial-cadherin bonds and contributeto the vascular leak underlying edema formation in ARDSPlatelets also contribute to endothelial injury through therelease of cytokines and through fibrin clotting [92]

(a) Angiopoietin Angiogenic agents along with VEGF andangiopoietin-1 (Ang-1) play key roles in vascular develop-ment VEGF stimulates the generation of new immature

6 Disease Markers

and leaky blood vessels whereas Ang-1 enhances angiogene-sis inducing vascularmaturation anddecreases vascular per-meability [33] The most encouraging data result from recentstudies of angiopoietin-2 (Ang-2) an endothelial protein thathas been studied extensively during sepsis [125] Ang-2 has animportant role as it increases endothelial junction instabilityenhances vascular leak naturally antagonizes Ang-1 and inthe absence of other angiogenic stimuli induces vascularregression and endothelial cell apoptosis Both Ang-1 andAng-2 are ligands for the tyrosine kinase receptor Tie-2 [126] and a link between Ang-2 and inflammation hasbeen reported [127] Therefore such vascular growth factorshave been proposed as biomarkers for ARDS [128] Firsttwo single-nucleotide polymorphisms within the Ang-2 gene(rs1868554 and rs2442598) were associated with the riskof developing ARDS in trauma patients [129] In additionAgrawal et al found in a prospective study of 230 patientsadmitted to the intensive care unit (ICU) without ARDSthat higher levels of Ang-2 were significantly associatedwith increased development of ARDS [130] In surgical ICUpatients levels of Ang-2 were higher in patients with ARDSthan in those without the syndrome [131] A higher Ang-2Ang-1 ratio was also an independent predictor of mortalityin ARDS patients [131 132] and patients with infection-related ARDS whose Ang-2 levels increased between day 0and day 3 doubled their odds of death suggesting that Ang-2kinetics may be particularly valuable by reflecting evolvinglung injury [34] Finally in a large study of 931 patientsenrolled in the ARDSNet fluid and catheter treatment trialbaseline plasma levels of Ang-2 were associated with 90-daymortality in patients with noninfectious ARDS whereas thisassociation was not found in patients with infection as theirprimary ARDS risk factor Based on a secondary analysisof two large studies Calfee et al further demonstrated thatindirect lung injury is characterized by a molecular pheno-type consistent with more severe lung endothelial injury asassessed by plasma Ang-2 and less severe epithelial injury[7]

(b) ICAM-1 The soluble intercellular adhesion molecule-1 (sICAM-1) is an inducible glycoprotein expressed onthe surface of vascular endothelial cells and other cells(eg hematopoietic cells AT1 cells) [35] Under physiologicconditions sICAM-1 is not constitutively expressed or isexpressed at low levels in most tissues During inflammationand in response to stimuli such as interferon-120574 (IFN-120574) orinterleukin-1 (IL-1) levels of sICAM-1 are upregulated [133]Elevated levels have also been found in both plasma andlung edema fluid from patients with ARDS as compared topatients with hydrostatic lung edema [134] In a multicenterstudy the increase of sICAM-1 from baseline to day 3was associated with poor clinical outcome [135] and in aprospective cohort of 65 patients with ARDS baseline plasmalevels of sICAM-1 were also associated with mortality [136]In pediatric patients with ARDS early elevated plasma levelsof sICAM-1 were associated with increased risks of death andof prolongedmechanical ventilation [137] In traumapatientshigher plasma levels of sICAM-1 at baseline were correlated

with future development of multiple organ dysfunction syn-drome (MODS) but not with the development of ARDS [138ndash140]

(c) Selectins Selectins are membrane-associated glycopro-teins that mediate the adhesion of leukocytes and plateletsto vascular surface L-selectin is mainly expressed by leuko-cytes P-selectin is rapidly redistributed from membranoussecretory granules to the surface of activated platelets andendothelial cells [36] E-selectin is expressed by cytokine-activated endothelial cells It has been shown that plasmalevels of such soluble adhesion molecules were markedlyhigher in nonsurvivors among critically ill patients and thatthey were negatively correlated with lung function (egPaO2FiO2ratio) [141] Other studies found that plasma P-

selectin was elevated in patients with ARDS especially inthose who subsequently died as compared with patients withother pulmonary diseases or sepsis but without ARDS [142]Interestingly patients with ARDS with chronic alcohol con-sumption had elevated levels of soluble E-selectin in both theplasma and epithelial fluid consistent with altered endothe-lial and alveolar-capillary function [143] More recently E-selectin was measured in the plasma levels from 50 individ-uals admitted to the emergency department and who wereat-risk for developing ARDS with higher E-selectin levelsbeing associated with both ARDS development and 28-daymortality [144] Circulating soluble E-selectin levels wereelevated in pneumonia patientswithARDS and plasma levelsdecreased along with the treatment of pneumonia [37]

(d) VEGF One of the most extensively studied endothelialmarkers in ARDS is VEGF albeit its value as a biomarkerremains unclear Vascular endothelial growth factors belongto the platelet-derived growth factor supergene family Theyplay central roles in the regulation of angiogenesis andlymphangiogenesis [38] Alternative splicing of the VEGFgene (6p213) transcript leads to the generation of severalsplice variants or isoforms with various sizes [145] VEGF-Ais a 34ndash46 kDa glycoprotein acting as the major factor impli-cated in angiogenesis It binds to two tyrosine kinase (TK)receptors named VEGFR-1 (Flt-1) and VEGFR-2 (KDRFlk-1) and regulates endothelial cell proliferationmigration vas-cular permeability secretion and other endothelial functions[146] The expression of VEGF in ARDS varies dependingon the degree of epithelial and endothelial damage Manylung cells release VEGF for example AT2 cells neutrophilsalveolar macrophages and activated T cells Thus VEGFis potentially capable of having an effect on both alveolarepithelial and endothelial barriers Interestingly overexpres-sion of VEGF induces pulmonary edema in animal models[147] In a single center study plasma levels of VEGF wereincreased in subjects with ARDS compared to controls andelevated plasma VEGF as measured on day 4 was associatedwith mortality in patients with ARDS [83] Neverthelessseveral studies suggest that plasma and alveolar VEGF mayhelp to predict the development of ARDS and its recoveryWhereas plasma VEGF is increased in ARDS patients VEGFlevels were decreased in the BAL fluid from ARDS patients

Disease Markers 7

as compared to controls [84 148 149] In order to betterunderstand such differences between plasma and alveolarexpression of VEGF Ware et al conducted a study with theaim to determine whether changes in alveolar levels of VEGFwere specific to ARDS or not [39] the authors found thatalveolar levels of VEGF were decreased in both patients withARDS and those with hydrostatic edema The mechanismsimplicated in this alveolar decrease in VEGF during ARDSmight not depend on the degree of lung injury but rather onthe degree of alveolar flooding [39]

(e) vWF Early studies of endothelial markers focused on vonWillebrand Factor (vWF) a macromolecular antigen that isproduced predominantly by endothelial cells and to a lesserextent by platelets In the setting of endothelial activationor injury vWF is released from preformed stocks into thecirculation [40 41] VWFhas been investigated as a biologicalmarker of endothelial injury in patients both at-risk forARDSand with established ARDS [40 150] In a prospective studyof 45 ICU patients with sepsis patients with nonpulmonarysepsis had higher levels of plasma vWF with good predictiveand prognostic values for ARDS Indeed elevated plasmalevels of vWF had a sensitivity of 87 and a specificity of77 for the prediction of ARDS development in the settingof nonpulmonary sepsis [151] However subsequent studiesin patients at-risk for ARDS did not confirm these findings[42 152 153] In another study of 559 patients with ARDSenrolled in the National Heart Lung and Blood InstituteARDS Network trial of lower tidal volume nonsurvivorshad higher plasma levels of vWF compared to survivors[40] Higher vWF levels were significantly associated withfewer organ failure-free days suggesting that the degree ofendothelial activation and injury is strongly associated withoutcomes in ARDS nevertheless ventilator settings had noimpact on vWF levels in this study [40]

(f) Lung ExtracellularMatrixThe extracellularmatrix (ECM)forms the region of the lung situated between the alveo-lar epithelium and the vascular endothelium ECM playsa mechanical role as it supports and maintains tissularstructures ECM also represents a complex and dynamicmeshwork influencing many biological cell functions such asdevelopment proliferation and migration [154] Collagensare the main component of ECM along with glycoproteinsand proteoglycans including hyaluronic acid

Laminin Laminins (LM) are ECM proteins with high molec-ular weights that deposit in basal membranes Lamininsare involved in cell processes such as cellular adhesiongrowth and differentiation [43] Laminin-5 (LM-5) plays animportant role in cell migration and in the remodeling ofepithelial tissue LM-5 is activated through its cleavage bymatrix metalloproteinases (MMPs) thus releasing a solubleLN 1205742 NH2-terminal fragment (G2F) that does not depositin the ECM and can therefore be detected in the peripheralblood In a small single center study lamininwasmeasured inthe plasma and lung edema fluid from 17 patients with ARDSwith higher levels found in patients with ARDS as comparedto healthy volunteers [44] Interestingly nonsurvivors had

higher plasma levels of laminin as measured 5 days afterARDS onset than survivors and survivors had decreasinglevels of the marker over time suggesting that its secretionis suppressed during ARDS recovery

ElastinDesmosine Elastin is another critical protein of theECM that gives the lung its elastic recoil ability In adultselastin which is expressed by lungs and other tissues isusually excreted in the urine During lung epithelial andendothelial injury elastin can be broken down by proteasessuch as neutrophil elastase [45] Elastin breakdown results insmaller fragments containing desmosine and isodesmosine[155] In a large study of 579 patients with ARDS thoseventilated with lower tidal volumes had lower urine desmo-sine levels a finding that may reflect reduced extracellularmatrix breakdown however no correlation with mortalitywas found in patients with ARDS [46]

MMPs Matrix metalloproteinases (MMPs) are zinc-depend-ent endopeptidases that are able to degrade almost allextracellular matrix components MMP-8 a member of theleukocyte-derived MMPs contributes to the degradationturnover and remodeling of the extracellular matrix digest-ing type I collagen [47 48] MMPs are major actors inalmost all phases of the inflammatory response and theirfunction is highly regulated At the tissue level most impor-tant inhibitors are the tissue inhibitors of metalloproteinases(TIMPs) In fulminant inflammation the inhibitory capacityof TIMPs may be overwhelmed leading to excessive tissuedamage and adverse outcome [47] Previous studies suggestthat MMPs may have an important role in ARDS althoughthis role may be either harmful or beneficial [156 157] In arecent study despiteMMP-8 levels did not predict outcome inARDS patients higher levels of TIMP-1 were independentlyassociated with increased 90-day mortality in a large groupof critically ill mechanically ventilated patients [47] Thesefindings are in contradiction to those from a study inpediatric ARDS patients in which higher MMP-8 and activeMMP-9 levels as measured 48 hours after disease onset wereassociated with longer durations of mechanical ventilationand fewer ventilator-free days [158] ElevatedMMP-2 MMP-8 and MMP-9 in the BAL fluid from ARDS patients wereassociated with patterns of acute inflammation but with pooroutcome [157] Interestingly MMP-3 and MMP-13 may beprotective against lung injury by cleaving transmembranereceptor RAGE into sRAGE thus regulating RAGE activationby its ligands [48 49]

312 Inflammatory Cascades During ARDS inflammatoryresponses can either be related to an ongoing primaryinfectious stimulus such as pneumonia or to systemic inflam-mation such as in sepsis or in pancreatitis [2] The inflam-matory cascade involves inflammatory cells and the releaseof inflammatory mediators as driven by a complex networkof cytokines A comparison between blood and alveolarcytokines suggests that most inflammatory mediators orig-inate from the lung [17] Alarmins or damage-associatedmolecular patterns (DAMPs) are released by dead cells orlocal inflammatory cells (eg alveolar macrophages) They

8 Disease Markers

activate and recruit immune cells via binding to differentreceptors such as TLR IL-1 receptor (IL-1R) or RAGEthereby initiating and perpetuating multiple proinflamma-tory pathways [21 159]

Regulation of the inflammatory response is a complexprocess that requires interplay between several immunemediators [160] Both pro- and anti-inflammatory biomark-ers have been studied in ARDS

(1) Proinflammatory Cytokines

(a) IL-1120573 and TNF-120572 IL-1120573 and TNF-120572 are the most biolog-ically potent cytokines secreted by activated macrophages inthe early phase of ARDS They cause the release of a varietyof proinflammatory chemokines such as monocyte chemo-tactic protein-1 (MCP-1) macrophage inflammatory protein-1120572 (MIP-1120572) IL-6 and IL-8 with subsequent recruitmentof inflammatory cells into the air spaces alteration of theendothelial-epithelial barrier permeability and impairmentof fluid transport leading to alveolar edema [17] TNF-120572 alsopromotes lung edema indirectly through the production ofreactive oxygen species (ROS) and a decreased expressionof epithelial sodium (ENaC) and Na+-K+-ATPase channels[161] Finally TNF-120572 a potent chemoattractant for fibrob-lasts is a promoter of lung fibrosis in experimental studies[162 163] Interestingly the ratio of BAL to serum levelsof both TNF-120572 and IL-1120573 is typically high suggesting thatsuch cytokines may originate from the lung in the settingof ARDS [164] Persistent elevation of plasma and BAL IL-1120573 is associated with worse outcome [165 166] Both TNF-120572 and IL-1120573 are elevated in the plasma and BAL fluid frompatients at risk of and with ARDS [164 167] and associatedwith mortality [166]

(b) IL-18 Inflammasomes are intracellular macromolecularcomplexes that serve as platforms for the activation of theproinflammatory enzyme caspase-1 which in turn cleavespro-IL-1120573 and pro-IL-18 into IL-1120573 and IL-18 [50] Theseinflammasome-activated cytokines play central roles in thepropagation of the acute inflammatory response IL-18 andcaspase-1 play critical roles in the development of lunginjury and higher levels of IL-18 are correlated with diseaseseverity and mortality in patients with ARDS [168] Among38 patients with acute respiratory failure those with ARDShad significantly higher serum levels of IL-18 and serum IL-18 was significantly higher in nonsurvivors [51]

(c) IL-6 IL-6 is produced by a wide range of cells includingmonocytesmacrophages endothelial cells fibroblasts andsmoothmuscle cells in response to stimulation by endotoxinIL-1120573 and TNF-120572 [52] IL-6 is one of the most importantmediators of fever and is critical for B-cell differentiation andmaturation with secretion of immunoglobulins cytotoxic Tcell differentiation macrophage and monocyte function andproduction of acute phase proteins Although IL-6 activatesboth proinflammatory and anti-inflammatory mechanismsIL-6 primarily correlates with a proinflammatory profileduring the early phase of ARDS Plasma IL-6 increases earlyin patients at risk of developing ARDS [53] IL-6 is elevated in

both plasma and BAL fluid during ARDS [59] and correlateswith mortality [54 55]

(d) IL-8 IL-8 is a proinflammatory cytokine with a role inneutrophilmonocyte chemotaxis and neutrophil apoptosisinhibitionHighplasma andBAL levels of IL-8 are found earlyduring ARDS and predict outcome [169] However previousstudies did not support such findings [170 171] In a recentmonocenter study of 100 patients only baseline IL-8 (among6 other biomarkers) was associated with the development ofmultiorgan failure even after adjustment for other relevantvariables [32] Also several studies have evaluated the roleof the anti-IL-8 autoantibodyIL-8 immune complexes inARDS a pathway that could lead to the identification of novelbiomarkers and therapeutic targets [17 172ndash175]

In a recent study Calfee et al used latent class analysisto integrate both clinical and biological data to identifytwo ARDS endotypes in an analysis of 1022 patients fromtwo ARDSNet trials (ARMA and ALVEOLI) [13] A firstendotype was categorized by more severe inflammation asassessed by both IL-6 and IL-8 levels and worse clinicaloutcomes whereas a second endotype had less inflammationless shock and better clinical outcomes Based on the datafrom the ALVEOLI trial a ldquoproinflammatoryrdquo endotypewas associated with higher mortality and better response tohigher levels of positive end-expiratory pressure [176]

(2) Anti-Inflammatory Cytokines The inflammatory responseis also strongly influenced by anti-inflammatory systemsincluding nonspecific (eg 2-macroglobulin IL-10) andspecific (eg IL-1 receptor antagonist (IL-1RA) antagonistssoluble IL-1 receptor II (sIL-1RII) soluble TNF receptorI (sTNF-RI) and soluble TNF receptor II (sTNF-RII)) ofproinflammatory cytokines

(a) IL-1RA Circulating IL-1RA levels are increased but donot predict the development of ARDS in at-risk patients[56] Studies of gene expression in alveolar macrophagesand circulating leukocytes from healthy control subjects andpatients with ARDS revealed that sIL-1RII may be valuable asa biomarker because of increased levels in both the lung andcirculation during ARDS [57]

(b) sTNF-RIsTNF-RII Soluble TNF-120572 receptors (sTNF-R)I and II can bind TNF and compete with its binding tothe cellular receptor thus reducing its bioavailability SolubleTNF-RI and TNF-II are associated with morbidity andmortality in patients with ARDS [54] and a strategy of lowtidal volume ventilation is associated with decreased sTNF-RI levels [54] Trauma-associated ARDS differs clinically andbiologically from ARDS due to other clinical disorders withlower levels of sTNF-RI patients with trauma as a primarycause of ARDS [6 58]

(c) IL-10 Interleukin-10 (IL-10) is an anti-inflammatorycytokine that is produced by several cells including B lym-phocytes monocytes and alveolar macrophages [60] Asidefrom inhibiting the production of IL-1 and TNF-120572 IL-10

Disease Markers 9

upregulates TNF receptors [177] and stimulates the produc-tion of the naturally occurring IL-1RAand the release of sTNFreceptors [178] IL-10 inhibits the production of proinflam-matory mediators by alveolar macrophages involved duringARDS [179] ARDS patients have lower plasma and BALlevels of IL-10 than at-risk patients who did not develop thesyndrome [61] Higher baseline IL-10 levels were associatedwith higher morbidity and mortality [59]

(3) Additional Markers Other markers with potential clinicalimportance in ARDS-associated inflammation have beenidentified as putative biomarkers during ARDS

High mobility group box nuclear protein 1 (HMGB1) is aDNAnuclear binding protein that is secreted by immune cellsincluding monocytes and macrophages HMGB1 increasesearly after severe trauma and correlates with systemic inflam-matory response and development of ARDS [62] Alveolarand plasma levels of HMGB1 (as measured in the arterial orcentral venous blood) are elevated in patients with ARDS andassociated with outcome [109] In 20 patients with ARDSplasma levels of HMGB1 were also higher in nonsurvivorsand correlated with levels of sRAGE [63]

Lipopolysaccharide binding protein (LBP) is an acutephase protein that is correlated with lung inflammationduring ARDS [64] More recently it has also been demon-strated that serum levels of LBPwere strongly associated withincreasedmortality and the development of ARDS in patientswith severe sepsis [65]

Nitric oxide (NO) is a marker of oxidative stress thathas also been investigated as a marker of ARDS In patientswith persistent ARDS higher levels of nitric oxide andof its end-products (eg nitrotyrosine) are associated withmortality [66] In contrast higher urine NO levels werestrongly associated with better clinical outcomes includingmortality and ventilator-free days in patients enrolled in theARDSNet low tidal volume trial [46] Extracellular citrullinethe effective precursor of NO is lower in the plasma frompatients with severe sepsis and lower plasma citrulline isassociated with the presence of ARDS [67] Mechanismsinvolved in the regulation of lung injury by NO-dependentpathways remain unknown

Although C-reactive protein (CRP) is widely consideredas a marker of systemic inflammation higher levels of CRPare associated with better outcome among patients withARDS [68] Nevertheless a recent study found that albuminlevels rather than CRP may help to predict and monitor theseverity and course of ARDS in febrile critically ill patientswith ARDS or at risk for the syndrome [69] In the samestudy levels of lactate dehydrogenase (LDH) predicted 28-day mortality but were not correlated with severity [69]

313 Coagulation and Fibrinolysis During early ARDS acti-vation of the inflammatory cascades results in the activationof the coagulation system which in turn can influenceinflammatory responses by affecting the expression of variouscytokines such as IL-1 IL-6 and IL-8 Activation of coagula-tion pathways induces migration of inflammatory cells intoalveoli through the endothelial and epithelial barriers and

generates thrombin formation In addition proinflammatoryevents may also inhibit fibrinolysis and induce platelet acti-vation [17]

Extravascular fibrin deposition when localized predomi-nantly in the alveolar compartment is found in several acuteinflammatory lung diseases and enhanced alveolar procoag-ulant activity is reported inARDS patients [180] Fibrin depo-sition may be beneficial for gas exchange by sealing leakagesites when lung capillary endothelial and epithelial barriersare disrupted Nevertheless fibrin alveolar deposition maybe harmful since it can lead to activation of neutrophilsand fibroblasts endothelial injury loss of surfactant activityfavoring alveolar collapse impaired alveolar fluid clearanceand thrombotic obstruction of the microcirculation [180]

(1) PAI-1 The balance between activation of coagulationand activation of fibrinolysis is an important determinantof the amount and duration of fibrin deposition duringlung injury Plasminogen activator (PA) and plasminogenactivator inhibitor-1 (PAI-1) regulate fibrinolysis through theconversion of plasminogen to plasmin a fibrinolytic enzymePA-1 is amajor endogenous inhibitor of PA Both PA and PA-1are secreted by various cells including macrophages fibrob-lasts and lung endothelial and epithelial cells [71] DuringARDS alveolar epithelial cells and activated macrophagesoverexpress PAI-1 thus contributing to decreased alveolarfibrinolytic activity Nevertheless the value of PAI-1 asa biomarker in ARDS remains controversial PAI-1 levelswere higher in patients with ARDS than in patients withhydrostatic lung edema [72] and higher PAI-1 levels areassociated withmortality and higher durations ofmechanicalventilation in patients with ARDS [72 169] In a large Finnishstudy PAI-1 levels were not correlated with mortality ordevelopment of ARDS in critically ill patients undermechan-ical ventilation but low baseline plasma levels of the solubleurokinase plasminogen activator receptor (suPAR) were pre-dictive of survival [181] In a secondary analysis of two largerandomized controlled trials PAI-1 was associated with lunginjury (as defined as decreased oxygenation index) but notwithmortality [28] Nevertheless in another study of patientsfrom the ARDSNet ARMA study higher levels of PAI-1were independently associated with higher mortality andclinical outcomes including organ failure [182] Howeverthis association between PAI-1 levels and the development ofmultiorgan failure was not confirmed in a recent study of 100ARDS patients [32]

(2) Protein C Protein C system is an important endogenousregulator of coagulation and fibrinolysis Protein C is synthe-sized by the liver and circulates as an inactive compoundIt is transformed to its active form on cell surface by thethrombomodulin- (TM-) thrombin complex [75 76] Theendothelial cell protein C receptor (EPCR) is another cellsurface protein that can further enhance protein activationby binding the TM-thrombin complex [183] In additionto suppressing thrombin formation activated protein C hasanti-inflammatory properties such as decreasing the levelsof proinflammatory cytokines [184] Protein C can improveendothelial permeability and exert antiapoptotic effects via

10 Disease Markers

p53 pathways [185] Activated protein C can also inactivatePAI-1 thus promoting fibrinolysis [186] Plasma protein Cwas significantly lower in patients with ARDS as comparedto controls and it was associated with worse clinical out-comes including higher hospital mortality shorter durationof unassisted ventilation and increased risk ofmultiple organfailure [73] In a larger cohort of patients with early ARDSlow plasma levels of protein C were again associated withmortality and adverse clinical outcomes [182] Decreasedlevels of protein C during ARDS suggest a link betweenhypercoagulability and mortality

(3) Thrombomodulin Thrombomodulin (TM) is a mul-tidomain transmembrane-bound glycoprotein found on thesurface of endothelial cell Its main role is to neutralize theprocoagulant effects of thrombin and accelerate activationof protein C In addition to its membrane-bound form TMalso exists as a circulating soluble isoform in the plasmaIn patients with ARDS levels of soluble thrombomodulin(sTM) are higher in the pulmonary edema fluid than inplasma [73] suggesting an alveolar source but no correlationwas found between plasma sTM and the development ofARDS yet higher levels of sTM were observed in patientsat high risk for ARDS In patients with established ARDShigher plasma and alveolar levels of sTM were correlatedwith severity of illness and multiple organ failure [73] Ina larger analysis of 449 patients elevated levels of plasmasTM were associated with increased mortality thus possiblyreflecting an increased degree of inflammation and both lungand systemic endothelial damage [74]

(4) Tissue Factor (TF) Tissue factor (TF) is a 47 kDa trans-membrane glycoprotein that is the most potent stimulator ofthe extrinsic coagulation cascade TF initiates the coagulationcascade by binding and allosterically activating coagulationfactor VIIa The resulting TF-VIIa complex binds the sub-strate coagulation factor X via multiple interactions alongan extended interface to produce the TF-VIIa-X complexThis complex leads eventually to thrombin formation andfibrin deposition [77] Levels of TF in lung edema fluid arehigher than plasma levels in patients with ARDS supportinga lung origin for TF in this setting and both plasma andalveolar levels of TF are higher in ARDS patients as comparedto patients with hydrostatic edema [187] Notably patientswith sepsis-induced ARDS may have higher levels of TF ascompared to patients without ARDS [78]

(5) Cell-Free Hb Levels of cell-free hemoglobin (Hb) arehigher in the air space of ARDS patients as comparedto critically ill patients with hydrostatic lung edema [79]Instillation of red blood cells or cell-free hemoglobin causeslung injury in rats [188] and intra-alveolar hemorrhage isassociated with high levels of intra-alveolar cell-free Hbmore severe lung injury and increased lipid peroxidationin the lung from mice with tissue factor deficiency [79]Precise cellular and molecular mechanisms by which cell-free hemoglobin in the air space could mediate or potenti-ate ARDS are currently under investigation [189] Cell-freeHb could activate chemokine release within the lung and

decompartmentalization of hemoglobin is likely to provide asignificant proinflammatory stimulus in the setting of diffusealveolar damage and hemorrhage during ARDS [80]

314 EFPL Protein Ratio The pathophysiology of ARDSincludes disruption of several physical barriers includingendothelial and epithelial cell layers the basement mem-brane and the extracellularmatrix resulting in increased pul-monary microvascular permeability The pulmonary edemafluid-to-plasma protein (EFPL) ratio is a rapid safe andnoninvasive measure of alveolar-capillary membrane per-meability The EFPL ratio was first proposed as a tool todetermine the etiology of acute pulmonary edema [81] Morerecently in a large study of 390 critically ill patientsWare et aldemonstrated that the EFPL ratio had an excellent discrimi-native value in distinguishing ARDS from hydrostatic edemaand was strongly associated with clinical outcomes Using acutoff of 065 the EFPL ratio had a sensitivity of 81 and aspecificity of 81 for the diagnosis of ARDS [82]

32 Fibroproliferative Phase of ARDS In some patientsimportant and persistent accumulation of macrophagesfibrocytes fibroblasts and myofibroblasts in the alveolarcompartment leads to excessive deposition of ECM com-ponents including fibronectin and collagen types I and IIIamong other proteins An imbalance between profibrotic andantifibrotic mediators may subsequently drive this fibropro-liferative response [190] Growth factors play a major rolein the resolution of ARDS [17] Lung endothelial repair ispromoted by vascular endothelial growth factor (VEGF)A variety of growth factors promote repair of the alveo-lar epithelium including keratinocyte growth factor (KGF)hepatocyte growth factor (HGF) fibroblast growth factor(FGF) and transforming growth factor-120572 (TGF-120572) [17] Twomajor pathways with opposite effects involve growth factorsduring ARDS tyrosine kinase receptor mediation (eg KGFHGF FGF and VEGF) and serine-threonine kinase receptorssuch as TGF-1205731 which tend to have opposed effect on theupregulation that occurs when the tyrosine kinase receptorpathway is involved [85 191 192]

321 Endothelial Proliferation Novel evidence points to apotential role of VEGF in promoting repair of the alveolar-capillarymembrane during recovery fromARDS and under-standing the role of VEGF in this disease process couldbe crucial for developing new therapeutic strategies [85193] In the lung VEGF is produced primarily by epithelialcells it increases microvascular permeability [83] but has animportant role also during the repair phase by stimulatingendothelial cell proliferation and survival [86 149] Thelevels of VEGF are increased in plasma from patients withARDS but are decreased in BAL fluid compared to healthycontrols subsequently BAL levels of VEGF increase duringthe resolution of lung injury [39 84 149]

322 Epithelial Proliferation and Apoptosis KGF also knownas FGF-7 is a potent mitogenic factor for alveolar epithelialcells that is primarily produced by fibroblasts and other

Disease Markers 11

cells such as T lymphocytes KGF regulates transepithelialtransport of sodium by stimulating the epithelial channelNa+-K+-ATPase in alveolar epithelial cells [87]

HGF is a nonspecific mitogen secreted by fibroblastsalveolar macrophages endothelial cells and epithelial cellsSeveral animal and human studies suggest that KGF andHGFcould protect the alveolar space against injury and couldfacilitate the repair of alveolar structures after injury [88 194195] KGF levels could be measured in the BAL from patientswith ARDS but not in the BAL from those without ARDS inaddition BALKGFwas associated with poor prognosis [196]Elevated HGF levels were also associated with outcome [196]In 36 patients with ARDS and 11 patients with hydrostaticlung edema HGF and KGF were proven biologically activein the edema fluid of patients with ARDS and higher levelsof HGFwere associated withmortality in these patients [197]

Apoptosis of alveolar epithelial cells is a major phe-nomenon in the initiation and perpetuation of lung injury[89] The FasFasL system plays an important role in theregulation of cell life and death through its ability to initiateapoptosis [198] This system combines the cell membranesurface receptor Fas (CD95) and its natural ligand FasL(CD95L) Membrane-bound FasL mediates lymphocyte-dependent cytotoxicity clonal deletion of alloreactive T cellsand activation-induced suicide of T cells [199] Its solubleform (sFasL) results from cleavage of membrane FasL byMMPs and induces apoptosis in susceptible cells [200]Apoptosis is inducedwhenmembrane-bound or soluble FasLbinds to Fas-bearing cells By contrast apoptosis is inhibitedwhen soluble Fas binds to either membrane-bound FasL orsFasL thus preventing FasL from interacting withmembrane-bound Fas receptors [201] In patients with ARDS sFasL wasdetectable in the lung before and after the onset of clinicallydefined ARDS and nonsurvivors had significantly higherBAL levels of sFasL on day 1 as compared with survivors[200] Both soluble Fas and soluble FasL were associated withoutcome and higher in the lung edema fluid from patientswith ARDS compared to control patients with hydrostaticpulmonary edema [202] Nevertheless recent findings sug-gested limited role for FasFasL system and apoptosis inairway epithelial cell death during ARDS [90]

323 Fibroblast Proliferation Pulmonary fibroblasts pro-duce procollagen III peptide (PCP-III) that is a precursorof collagen The NT part of procollagen III resulting fromthe enzymatic cleavage of procollagen by specific proteases inthe extracellular space is considered as a marker of collagensynthesis Alveolar levels of N-PCP-III are higher in ARDSpatient as compared with controls [203] The elevation ofN-PCP-III in pulmonary edema fluid begins within the first24 h of ARDS that is during the acute phase of increasedendothelial and epithelial permeability to protein suggestingthat fibrosing alveolitis could begin very early in the course ofclinical ARDS [203] In another study high levels of N-PCP-III were early predictors of poor outcome [204 205] Morerecently Forel et al measured alveolar N-PCP-III in patientswith nonresolving ARDS thus identifying patients who haddeveloped lung fibroproliferation [206] Unfortunately it

is still unknown whether N-PCP-III measurements couldbe useful in selecting patients who would benefit fromglucocorticoid therapy among others to reduce the ARDS-associated lung fibrosis [207]

4 Perspectives

41 Combining Biomarkers Despite advances in the identi-fication of biomarker candidate and better understanding ofARDS pathogenesis no single clinical or biological markerreliably predicts clinical outcomes inARDSThe combinationof clinical and biological marker is attractive in order toimprove the sensitivity andor the specificity of the testespecially through a recent approach aimed at measuring8 biological markers that reflect endothelial and epithelialinjury inflammation and coagulation vWF SP-D TNF-R1IL-6 IL-8 ICAM-1 protein C and PAI-1 in 549 patientsenrolled in the the ARDSNet trial of low versus high positiveend-expiratory pressure [208] Clinical predictors predictedmortality with an area under the ROC curve (AUC) of082 whereas a combination of these 8 biomarkers and theclinical predictors had an AUC of 085 The best performingbiomarkers were the neutrophil chemotactic factor IL-8 andSP-D a product of AT2 cells [208] supporting the conceptthat acute inflammation and alveolar epithelial injury areimportant pathogenetic pathways in human ARDS Morerecently a panel of biomarkers of lung epithelial injuryand inflammation (SP-D sRAGE IL-8 CC16 and IL-6)provided excellent discrimination for diagnosis of ARDSin patients with severe sepsis [20] Therefore and beyondtheir better diagnostic and prognostic values the use of suchbiomarker panels may be useful for selecting patients forclinical trials that are designed to reduce lung epithelial injury[113] Nevertheless whether a therapeutic strategy based onbiomarker measurements would benefit patient outcome hasnever been investigated

42 Lung Imaging as an ARDS Biomarker Studies of lungimaging during ARDS have revealed that adequate ventilatorsettings may vary among patients with the same syndromeIn a large study gas and tissue distribution in the lungs ofARDS patients were assessed using computed tomography(CT) and compared to those of healthy volunteers [11] Lungmorphology in ARDS is characterized by marked excess oflung tissue associated with a major decrease in aerated lungregions and in functional residual capacity Some patientswith ARDS exhibit preserved aeration of the upper lobesdespite the presence of an overall excess of lung tissue (ldquofocalrdquoARDS) as opposed to other patients with more diffuse lossof aeration and excessive lung tissue (ldquodiffuserdquo or ldquononfocalrdquoARDS) [209]

Lung morphology may influence the response to pos-itive end-expiratory pressure (PEEP) recruitment maneu-vers (RM) prone position and patient outcome [12 210]In a prospective study of nineteen patients with ARDSConstantin et al found that lung morphology at zero end-expiratory pressure could predict the response to a RM withcontinuous positive airway pressure of 40 cm H

2O for 40

12 Disease Markers

seconds Nonfocal morphology was associated with higherlung recruitability and PaO

2FiO2was significantly increased

by the RM [12 211] In contrast patients with focal lungmorphology were at risk of significant hyperinflation duringthe RM with no improvement of arterial oxygenation

It has also been hypothesized that the effects of PEEPmay depend on lung morphology Puybasset et al assessedthe responses to PEEP among patients with focal or nonfocalARDS [210] The regional distribution of intrapulmonarygas and lung tissue influences the effects of PEEP in ARDSpatients maximal alveolar recruitment without evidenceof overdistension was observed in patients with nonfocalARDS Nevertheless PEEP induced mild alveolar recruit-ment in patients with focal ARDS along with overdistensionof previously aerated lung regions

Interestingly phenotyping patients with ARDS basedon their lung morphology might be possible by measuringplasma sRAGEwith commercially available kits even thoughthese findings need further validation [100 112] HoweverRAGE pathway is a promising candidate for subphenotypingpatients with ARDS as it is believed to play a major rolein the mechanisms leading to AFC and their regulation[110] Recent findings that support a relationship betweenimpaired AFC and lung morphology may therefore fill a gapin the full recognition of an ARDS phenotype based on lungmorphology that could be linked to an endotype of impairedAFC and activated RAGE pathway [12 100 101 112 113 212]

43 Biomarkers in ARDS Can They Improve Patient CareBiomarkers are broadly used in critically ill patientsespecially during inflammatory andor infectious diseasesBiomarkers have been commonly defined as characteristicsthat are objectively measured and evaluated as indicatorsof normal biological processes pathogenic processes orpharmacologic responses to therapeutic interventions [213214] Biomarkers provide a powerful approach to understanda disease with multiple applications in observational andanalytic epidemiology randomized clinical trials screeningand diagnosis or prognosis [215]

Nevertheless there are important technical attributes fora relevant biomarker First the marker must be present inperipheral body tissue andor fluid (eg blood urine salivabreath or cerebrospinal fluid) second it must be easy todetect or quantify in assays that are both affordable androbust and third its regulation should be associated asspecifically as possible with damage of a particular tissuepreferably in a quantifiable manner Prior to the widespreaduse of a marker of interest it is essential that validation andconfirmation of candidate biomarkers by robust statisticalmethods are performed during biomarker discovery [215]Sensitivity and specificity are common quality parametersfor biomarkers Sensitivity describes the probability of apositive test in cases and specificity describes probability ofnegative test in controls An association between sensitivityand specificity is represented in the ROC curve by graphingsensitivity versus 100 minus specificity Area under the ROC curve(AUROC) is therefore a measure of performance of a markerThere is no absolute cutoff value of AUROC for robustness of

a marker but aminimum of 07 is required and values greaterthan 08 are good particularly in a heterogeneous critically illpatient population [216 217]

To summarize an ideal biomarker should indicate aclear relationship with the pathophysiologic event needsto be reliable reproducible disease specific and sensitiveand should be sampled by simple methods and relativelyinexpensive with little or no diurnal variation DuringARDS no single marker has been validated with all thesecriteria to date yet we believe that sRAGE may fulfill allprerequisites of a biomarker of ARDS First plasma sRAGEhas good diagnostic and prognostic values [96 99 100109 112] Second it is very well correlated with lung injuryseverity and specific pathophysiologic features of ARDS forexample alveolar fluid clearance and lung morphology [9699ndash101 109 112] Previous studies of the predictive value ofearly levels of sRAGE for the development of ARDS in ageneral population of patients admitted to the emergencydepartment were negative [130] but current research focuseson both the kinetics of sRAGE and esRAGE and RAGE genepolymorphisms as predictors of the development of ARDSin at-risk critically ill patients [114] Finally there is someevidence suggesting that monitoring sRAGE could informat least partially on therapeutic responses in patients with orwithout ARDS [24 99 113] If these data are confirmed byfuture studies such findingswould definitely help to reinforcesRAGE a real biomarker of ARDS

5 Conclusion

Biomarker research provides an important translational linkto our understanding of lung pathobiology Through theidentification and testing of candidate biomarkers we havegained insight into the pathogenic importance of endothelialand epithelial injury and have started to unravel the complexpathways that contribute to endothelial and epithelial celldysfunction inflammation fibrosis and apoptosis in ARDSIn addition biomarker studies may help us to explore thecellular and molecular mechanisms of various therapeuticstrategies for ARDS and to better understand the potentialproinflammatory effects of mechanical ventilation Giventhe clinical heterogeneity of patients with ARDS and thecomplexity of the underlying pathobiology it is unlikely thata single biomarker will emerge for ARDS as cardiac-specifictroponin did for myocardial infarction but the develop-ment of small biomarker panels reflecting each importantlung injury pathway would provide valuable predictive andprognostic information for both clinicians and investigatorsWhile biomarkers are currently not recommended for usein clinical practice in ARDS biomarker discovery mayhold significant promise in order to develop and applytargeted therapies and to identify candidates for enrollmentin patient-tailored clinical trials of novel therapies for ARDS

Disclosure

The funders had no influence on the study design conductand analysis or on the preparation of this paper

Disease Markers 13

Conflict of Interests

No conflict of interests other sources of financial supportcorporate involvement patent holdings and so forth are tobe declared for all authors

Authorsrsquo Contribution

Raiko Blondonnet was involved in the conception and designof the review in writing the paper and in its revision priorto submission Jean-Michel Constantin was involved in theconception and design of the review in writing the paperand in its revision prior to submission Vincent Sapin wasinvolved in the conception and design of the review inwriting the paper and in its revision prior to submissionMatthieu Jabaudon takes responsibility for the content ofthe paper and was involved in the conception and design ofthe review in writing the paper and in its revision prior tosubmission

Acknowledgments

This work was supported by grants from the AuvergneRegional Council (ldquoProgramme Nouveau Chercheur de laRegion Auvergnerdquo 2013) the french Agence Nationale de laRecherche and the Direction Generale de lrsquoOffre de Soins(ldquoProgramme de Recherche Translationnelle en Santerdquo ANR-13-PRTS-0010)

References

[1] VM Ranieri G D Rubenfeld P TThompson et al ldquoAcute res-piratory distress syndrome the Berlin definitionrdquo The Journalof the American Medical Association vol 307 no 23 pp 2526ndash2533 2012

[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000

[3] C Brun-Buisson C Minelli G Bertolini et al ldquoEpidemiologyand outcome of acute lung injury in European intensive careunitsrdquo Intensive Care Medicine vol 30 no 1 pp 51ndash61 2004

[4] G D Rubenfeld E Caldwell E Peabody et al ldquoIncidence andoutcomes of acute lung injuryrdquo The New England Journal ofMedicine vol 353 no 16 pp 1685ndash1693 2005

[5] D W Dowdy M P Eid C R Dennison et al ldquoQuality oflife after acute respiratory distress syndrome a meta-analysisrdquoIntensive Care Medicine vol 32 no 8 pp 1115ndash1124 2006

[6] C S Calfee M D Eisner L B Ware et al ldquoTrauma-associatedlung injury differs clinically and biologically from acute lunginjury due to other clinical disordersrdquo Critical Care Medicinevol 35 no 10 pp 2243ndash2250 2007

[7] C S Calfee D R Janz G R Bernard et al ldquoDistinct molecularphenotypes of direct versus indirect ARDS in single and multi-center studiesrdquo Chest vol 147 no 6 pp 1539ndash1548 2015

[8] P Tejera N J Meyer F Chen et al ldquoDistinct and replicablegenetic risk factors for acute respiratory distress syndromeof pulmonary or extrapulmonary originrdquo Journal of MedicalGenetics vol 49 no 11 pp 671ndash680 2012

[9] M A Matthay G A Zimmerman C Esmon et al ldquoFutureresearch directions in acute lung injury summary of a National

Heart Lung and Blood Institute Working Grouprdquo AmericanJournal of Respiratory and Critical Care Medicine vol 167 no7 pp 1027ndash1035 2003

[10] J P Reilly S Bellamy M G S Shashaty et al ldquoHeterogeneousphenotypes of acute respiratory distress syndrome after majortraumardquo Annals of the American Thoracic Society vol 11 no 5pp 728ndash736 2014

[11] L Puybasset P Cluzel N Chao et al ldquoA computed tomographyscan assessment of regional lung volume in acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol158 no 5 pp 1644ndash1655 1998

[12] J-M Constantin S Grasso G Chanques et al ldquoLungmorphol-ogy predicts response to recruitment maneuver in patients withacute respiratory distress syndromerdquo Critical Care Medicinevol 38 no 4 pp 1108ndash1117 2010

[13] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoSubphenotypes in acute respiratorydistress syndrome latent class analysis of data from tworandomised controlled trialsrdquoThe Lancet Respiratory Medicinevol 2 no 8 pp 611ndash620 2014

[14] R Marshall G Bellingan and G Laurent ldquoThe acute respira-tory distress syndrome fibrosis in the fast lanerdquoThorax vol 53no 10 pp 815ndash817 1998

[15] R B Henderson J A R Hobbs M Mathies and N HoggldquoRapid recruitment of inflammatory monocytes is independentof neutrophil migrationrdquo Blood vol 102 no 1 pp 328ndash3352003

[16] HMMarriott andDH Dockrell ldquoThe role of themacrophagein lung disease mediated by bacteriardquo Experimental LungResearch vol 33 no 10 pp 493ndash505 2007

[17] L J M Cross and M A Matthay ldquoBiomarkers in acute lunginjury insights into the pathogenesis of acute lung injuryrdquoCritical Care Clinics vol 27 no 2 pp 355ndash377 2011

[18] H K Gaggin and J L Januzzi ldquoBiomarkers and diagnostics inheart failurerdquo Biochimica et Biophysica Acta (BBA)mdashMolecularBasis of Disease vol 1832 no 12 pp 2442ndash2450 2013

[19] E Christenson and R H Christenson ldquoThe role of cardiacbiomarkers in the diagnosis and management of patientspresenting with suspected acute coronary syndromerdquo Annals ofLaboratory Medicine vol 33 no 5 pp 309ndash318 2013

[20] L B Ware T Koyama Z Zhao et al ldquoBiomarkers of lungepithelial injury and inflammation distinguish severe sepsispatientswith acute respiratory distress syndromerdquoCritical Carevol 17 no 5 article R253 2013

[21] M A Matthay L B Ware and G A Zimmerman ldquoTheacute respiratory distress syndromerdquo The Journal of ClinicalInvestigation vol 122 no 8 pp 2731ndash2740 2012

[22] M Shirasawa N Fujiwara S Hirabayashi et al ldquoReceptor foradvanced glycation end-products is a marker of type I lungalveolar cellsrdquo Genes to Cells vol 9 no 2 pp 165ndash174 2004

[23] M Neeper A M Schmidt J Brett et al ldquoCloning andexpression of a cell surface receptor for advanced glycosylationend products of proteinsrdquo The Journal of Biological Chemistryvol 267 no 21 pp 14998ndash15004 1992

[24] M Jabaudon E Futier L Roszyk V Sapin B Pereira andJ Constantin ldquoAssociation between intraoperative ventilatorsettings and plasma levels of soluble receptor for advancedglycation end-products in patients without pre-existing lunginjuryrdquo Respirology vol 20 no 7 pp 1131ndash1138 2015

[25] L G Dobbs R F Gonzalez L Allen and D K Froh ldquoHTI56an integral membrane protein specific to human alveolar type

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

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BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Disease Markers 5

HTI56 Human type I cell-specificmembrane protein (HTI56)

is a 56-kDa glycosylated lung protein specific to the apicalmembrane of human AT1 cells HTI

56has biochemical char-

acteristics of an integral membrane protein [25] Althoughthe precise functions of HTI

56remain unknown HTI

56is

an analog to RTI40 a 40ndash42 kDa integral membrane protein

specific to the apical membrane of rat AT1 cells [26] Patientswith ARDS had higher levels of HTI

56in both lung edema

fluid and plasma as compared to patients with hydrostaticlung edema [94] but no study assessing the associationbetween HTI

56levels and other endpoints in patients with

ARDS (eg prognosis) has been published to date

(b) Alveolar Type 2 Cells AT2 cells have important homeo-static functions in the lung including AFC and productionof alveolar surfactant (involved in lung compliance keepingthe alveolus open) AT2 cells are also known as keymediatorsof the epithelial repair process [115]

Surfactant Proteins Surfactant has a vital role in maintainingthe integrity of the alveolar-capillary interface Its essentialfunction is to decrease surface tension into the alveoli thusstabilizing lung volume at low transpulmonary pressuresSurfactant is composed of approximately 80 phospholipids8 other lipids (cholesterol triacylglycerol and free fattyacids) and 12 proteins Four surfactant-associated proteins(SP) designated SP-A SP-B SP-C and SP-D representapproximately half of proteins composing surfactant SP-Aand SP-D easily dissociate from lipids and are hydrosolubleThey belong to the lung innate immune system therebyenhancing phagocytosis of bacteria and virus They alsoexert regulatory effects on AT2 cells SP-B and SP-C aresmall extremely hydrophobic proteins that are important inthe formation of the surfactant monolayer in the terminalairspaces and in the reduction of surface tension thuspreventing end-expiratory alveolar collapse [116]

Early observations in ARDS revealed a loss in surfacetension suggesting a functional loss of the surfactant proteins[117] In a first case report of three patients the ratioof plasma SP-BSP-A was inversely associated with bothblood oxygenation and static respiratory system compliancesuggesting that SP-B breaches the alveolocapillary barriermore readily than SP-A and may therefore provide a moresensitive marker of lung injury [118] Plasma levels of SP-Aand SP-B are increased in patients with ARDS [70] and in at-risk patients [119 120] whereas lower SP-A and SP-B levelswere found in the BAL fluid of patients at risk for ARDSprior to the onset of the clinical syndrome SP-A and SP-Blevels remained low for as long as 14 days in patients withsustained ARDS Interestingly this decrease in BAL SP-A andSP-B does not result simply from dilution of alveolar fluids byplasma entering the alveolar spaces as SP-D levels remainedstable in parallel [119] In a cohort of 38 patients reducedpulmonary edema fluid SP-D and elevated plasma SP-A atthe onset of ARDS were associated with poor prognosis [27]Nevertheless in a study of 259 patients from the ARDSNettrial of low versus high end-expiratory pressure in ARDS(ALVEOLI) as well as in 75 patients enrolled in a randomized

trial of activated protein C for ARDS plasma SP-D was notassociated with 28-day mortality or ventilator-free days [28]

KL-6 Krebs von den Lungen-6 (KL-6) is a human MUC1mucin that belongs to the high-molecular-weight glyco-protein family After the cleavage of S-S bond KL-6 canspread into the pulmonary epithelial lining fluid In thenormal lung this glycoprotein can be predominantly foundin AT2 cells and its expression is enhanced during AT2proliferation regeneration or injury thus representing anattractive biomarker in ARDS Plasma KL-6 is elevated inARDS patients and correlates with lung injury and mortality[29 121ndash123] Plasma levels of SP-D and KL-6 increase overtime in patients with ARDS and may represent biologicalmarkers of ventilator-associated lung injury because theirincrease is attenuated by lung-protective ventilation [30]

(c) CC16 Clara cell protein (CC16) is a 158 kDa homod-imeric protein that is abundantly secreted in airways by thenonciliated bronchiolar Clara cells Clara cells are devotedto the protection of the respiratory tract against toxicinhaled agents the repair of damaged epithelium xenobioticsdetoxification and the secretion of proteins with importantbiological activities CC16 is highly expressed in the epitheliallining fluid with antioxidantinflammatory roles notably bymodulating the production andor activity of phospholipase-A2 interferon-120574 and tumor necrosis factor-120572 [31] Availablestudies found contradictory inconclusive findings duringARDS Although higher levels of CC16 are associated withlung injury and inflammation in some experimental andclinical studies patients with ARDS had lower plasma andpulmonary edema fluid levels of CC16 than patients withacute cardiogenic pulmonary edema and no correlation wasfound between CC16 and prognosis So many conflictingfindings do not currently support the association of CC16with the diagnosis or prognosis of ARDS

(2) Vascular Endothelium Vascular endothelial injury ischaracterized by the disruption of cell components leadingto increased microvascular permeability and alveolar edemaEndothelial injury is mainly driven by the activation ofinflammation and coagulation cascades The activation ofendothelial cells by circulating mediators leads to increasedexpression of cell surface molecules that are importantmediators of leukocyte adhesion and contribute to leuko-cyte accumulation and transmigration [124] Activated lym-phocytes can also release mediators in microvessels thatincrease vascular permeability Along with these leukocytesignals inflammatory mediators such as tumor necrosis fac-tor (TNF) thrombin and vascular endothelial growth factor(VEGF) disrupt endothelial-cadherin bonds and contributeto the vascular leak underlying edema formation in ARDSPlatelets also contribute to endothelial injury through therelease of cytokines and through fibrin clotting [92]

(a) Angiopoietin Angiogenic agents along with VEGF andangiopoietin-1 (Ang-1) play key roles in vascular develop-ment VEGF stimulates the generation of new immature

6 Disease Markers

and leaky blood vessels whereas Ang-1 enhances angiogene-sis inducing vascularmaturation anddecreases vascular per-meability [33] The most encouraging data result from recentstudies of angiopoietin-2 (Ang-2) an endothelial protein thathas been studied extensively during sepsis [125] Ang-2 has animportant role as it increases endothelial junction instabilityenhances vascular leak naturally antagonizes Ang-1 and inthe absence of other angiogenic stimuli induces vascularregression and endothelial cell apoptosis Both Ang-1 andAng-2 are ligands for the tyrosine kinase receptor Tie-2 [126] and a link between Ang-2 and inflammation hasbeen reported [127] Therefore such vascular growth factorshave been proposed as biomarkers for ARDS [128] Firsttwo single-nucleotide polymorphisms within the Ang-2 gene(rs1868554 and rs2442598) were associated with the riskof developing ARDS in trauma patients [129] In additionAgrawal et al found in a prospective study of 230 patientsadmitted to the intensive care unit (ICU) without ARDSthat higher levels of Ang-2 were significantly associatedwith increased development of ARDS [130] In surgical ICUpatients levels of Ang-2 were higher in patients with ARDSthan in those without the syndrome [131] A higher Ang-2Ang-1 ratio was also an independent predictor of mortalityin ARDS patients [131 132] and patients with infection-related ARDS whose Ang-2 levels increased between day 0and day 3 doubled their odds of death suggesting that Ang-2kinetics may be particularly valuable by reflecting evolvinglung injury [34] Finally in a large study of 931 patientsenrolled in the ARDSNet fluid and catheter treatment trialbaseline plasma levels of Ang-2 were associated with 90-daymortality in patients with noninfectious ARDS whereas thisassociation was not found in patients with infection as theirprimary ARDS risk factor Based on a secondary analysisof two large studies Calfee et al further demonstrated thatindirect lung injury is characterized by a molecular pheno-type consistent with more severe lung endothelial injury asassessed by plasma Ang-2 and less severe epithelial injury[7]

(b) ICAM-1 The soluble intercellular adhesion molecule-1 (sICAM-1) is an inducible glycoprotein expressed onthe surface of vascular endothelial cells and other cells(eg hematopoietic cells AT1 cells) [35] Under physiologicconditions sICAM-1 is not constitutively expressed or isexpressed at low levels in most tissues During inflammationand in response to stimuli such as interferon-120574 (IFN-120574) orinterleukin-1 (IL-1) levels of sICAM-1 are upregulated [133]Elevated levels have also been found in both plasma andlung edema fluid from patients with ARDS as compared topatients with hydrostatic lung edema [134] In a multicenterstudy the increase of sICAM-1 from baseline to day 3was associated with poor clinical outcome [135] and in aprospective cohort of 65 patients with ARDS baseline plasmalevels of sICAM-1 were also associated with mortality [136]In pediatric patients with ARDS early elevated plasma levelsof sICAM-1 were associated with increased risks of death andof prolongedmechanical ventilation [137] In traumapatientshigher plasma levels of sICAM-1 at baseline were correlated

with future development of multiple organ dysfunction syn-drome (MODS) but not with the development of ARDS [138ndash140]

(c) Selectins Selectins are membrane-associated glycopro-teins that mediate the adhesion of leukocytes and plateletsto vascular surface L-selectin is mainly expressed by leuko-cytes P-selectin is rapidly redistributed from membranoussecretory granules to the surface of activated platelets andendothelial cells [36] E-selectin is expressed by cytokine-activated endothelial cells It has been shown that plasmalevels of such soluble adhesion molecules were markedlyhigher in nonsurvivors among critically ill patients and thatthey were negatively correlated with lung function (egPaO2FiO2ratio) [141] Other studies found that plasma P-

selectin was elevated in patients with ARDS especially inthose who subsequently died as compared with patients withother pulmonary diseases or sepsis but without ARDS [142]Interestingly patients with ARDS with chronic alcohol con-sumption had elevated levels of soluble E-selectin in both theplasma and epithelial fluid consistent with altered endothe-lial and alveolar-capillary function [143] More recently E-selectin was measured in the plasma levels from 50 individ-uals admitted to the emergency department and who wereat-risk for developing ARDS with higher E-selectin levelsbeing associated with both ARDS development and 28-daymortality [144] Circulating soluble E-selectin levels wereelevated in pneumonia patientswithARDS and plasma levelsdecreased along with the treatment of pneumonia [37]

(d) VEGF One of the most extensively studied endothelialmarkers in ARDS is VEGF albeit its value as a biomarkerremains unclear Vascular endothelial growth factors belongto the platelet-derived growth factor supergene family Theyplay central roles in the regulation of angiogenesis andlymphangiogenesis [38] Alternative splicing of the VEGFgene (6p213) transcript leads to the generation of severalsplice variants or isoforms with various sizes [145] VEGF-Ais a 34ndash46 kDa glycoprotein acting as the major factor impli-cated in angiogenesis It binds to two tyrosine kinase (TK)receptors named VEGFR-1 (Flt-1) and VEGFR-2 (KDRFlk-1) and regulates endothelial cell proliferationmigration vas-cular permeability secretion and other endothelial functions[146] The expression of VEGF in ARDS varies dependingon the degree of epithelial and endothelial damage Manylung cells release VEGF for example AT2 cells neutrophilsalveolar macrophages and activated T cells Thus VEGFis potentially capable of having an effect on both alveolarepithelial and endothelial barriers Interestingly overexpres-sion of VEGF induces pulmonary edema in animal models[147] In a single center study plasma levels of VEGF wereincreased in subjects with ARDS compared to controls andelevated plasma VEGF as measured on day 4 was associatedwith mortality in patients with ARDS [83] Neverthelessseveral studies suggest that plasma and alveolar VEGF mayhelp to predict the development of ARDS and its recoveryWhereas plasma VEGF is increased in ARDS patients VEGFlevels were decreased in the BAL fluid from ARDS patients

Disease Markers 7

as compared to controls [84 148 149] In order to betterunderstand such differences between plasma and alveolarexpression of VEGF Ware et al conducted a study with theaim to determine whether changes in alveolar levels of VEGFwere specific to ARDS or not [39] the authors found thatalveolar levels of VEGF were decreased in both patients withARDS and those with hydrostatic edema The mechanismsimplicated in this alveolar decrease in VEGF during ARDSmight not depend on the degree of lung injury but rather onthe degree of alveolar flooding [39]

(e) vWF Early studies of endothelial markers focused on vonWillebrand Factor (vWF) a macromolecular antigen that isproduced predominantly by endothelial cells and to a lesserextent by platelets In the setting of endothelial activationor injury vWF is released from preformed stocks into thecirculation [40 41] VWFhas been investigated as a biologicalmarker of endothelial injury in patients both at-risk forARDSand with established ARDS [40 150] In a prospective studyof 45 ICU patients with sepsis patients with nonpulmonarysepsis had higher levels of plasma vWF with good predictiveand prognostic values for ARDS Indeed elevated plasmalevels of vWF had a sensitivity of 87 and a specificity of77 for the prediction of ARDS development in the settingof nonpulmonary sepsis [151] However subsequent studiesin patients at-risk for ARDS did not confirm these findings[42 152 153] In another study of 559 patients with ARDSenrolled in the National Heart Lung and Blood InstituteARDS Network trial of lower tidal volume nonsurvivorshad higher plasma levels of vWF compared to survivors[40] Higher vWF levels were significantly associated withfewer organ failure-free days suggesting that the degree ofendothelial activation and injury is strongly associated withoutcomes in ARDS nevertheless ventilator settings had noimpact on vWF levels in this study [40]

(f) Lung ExtracellularMatrixThe extracellularmatrix (ECM)forms the region of the lung situated between the alveo-lar epithelium and the vascular endothelium ECM playsa mechanical role as it supports and maintains tissularstructures ECM also represents a complex and dynamicmeshwork influencing many biological cell functions such asdevelopment proliferation and migration [154] Collagensare the main component of ECM along with glycoproteinsand proteoglycans including hyaluronic acid

Laminin Laminins (LM) are ECM proteins with high molec-ular weights that deposit in basal membranes Lamininsare involved in cell processes such as cellular adhesiongrowth and differentiation [43] Laminin-5 (LM-5) plays animportant role in cell migration and in the remodeling ofepithelial tissue LM-5 is activated through its cleavage bymatrix metalloproteinases (MMPs) thus releasing a solubleLN 1205742 NH2-terminal fragment (G2F) that does not depositin the ECM and can therefore be detected in the peripheralblood In a small single center study lamininwasmeasured inthe plasma and lung edema fluid from 17 patients with ARDSwith higher levels found in patients with ARDS as comparedto healthy volunteers [44] Interestingly nonsurvivors had

higher plasma levels of laminin as measured 5 days afterARDS onset than survivors and survivors had decreasinglevels of the marker over time suggesting that its secretionis suppressed during ARDS recovery

ElastinDesmosine Elastin is another critical protein of theECM that gives the lung its elastic recoil ability In adultselastin which is expressed by lungs and other tissues isusually excreted in the urine During lung epithelial andendothelial injury elastin can be broken down by proteasessuch as neutrophil elastase [45] Elastin breakdown results insmaller fragments containing desmosine and isodesmosine[155] In a large study of 579 patients with ARDS thoseventilated with lower tidal volumes had lower urine desmo-sine levels a finding that may reflect reduced extracellularmatrix breakdown however no correlation with mortalitywas found in patients with ARDS [46]

MMPs Matrix metalloproteinases (MMPs) are zinc-depend-ent endopeptidases that are able to degrade almost allextracellular matrix components MMP-8 a member of theleukocyte-derived MMPs contributes to the degradationturnover and remodeling of the extracellular matrix digest-ing type I collagen [47 48] MMPs are major actors inalmost all phases of the inflammatory response and theirfunction is highly regulated At the tissue level most impor-tant inhibitors are the tissue inhibitors of metalloproteinases(TIMPs) In fulminant inflammation the inhibitory capacityof TIMPs may be overwhelmed leading to excessive tissuedamage and adverse outcome [47] Previous studies suggestthat MMPs may have an important role in ARDS althoughthis role may be either harmful or beneficial [156 157] In arecent study despiteMMP-8 levels did not predict outcome inARDS patients higher levels of TIMP-1 were independentlyassociated with increased 90-day mortality in a large groupof critically ill mechanically ventilated patients [47] Thesefindings are in contradiction to those from a study inpediatric ARDS patients in which higher MMP-8 and activeMMP-9 levels as measured 48 hours after disease onset wereassociated with longer durations of mechanical ventilationand fewer ventilator-free days [158] ElevatedMMP-2 MMP-8 and MMP-9 in the BAL fluid from ARDS patients wereassociated with patterns of acute inflammation but with pooroutcome [157] Interestingly MMP-3 and MMP-13 may beprotective against lung injury by cleaving transmembranereceptor RAGE into sRAGE thus regulating RAGE activationby its ligands [48 49]

312 Inflammatory Cascades During ARDS inflammatoryresponses can either be related to an ongoing primaryinfectious stimulus such as pneumonia or to systemic inflam-mation such as in sepsis or in pancreatitis [2] The inflam-matory cascade involves inflammatory cells and the releaseof inflammatory mediators as driven by a complex networkof cytokines A comparison between blood and alveolarcytokines suggests that most inflammatory mediators orig-inate from the lung [17] Alarmins or damage-associatedmolecular patterns (DAMPs) are released by dead cells orlocal inflammatory cells (eg alveolar macrophages) They

8 Disease Markers

activate and recruit immune cells via binding to differentreceptors such as TLR IL-1 receptor (IL-1R) or RAGEthereby initiating and perpetuating multiple proinflamma-tory pathways [21 159]

Regulation of the inflammatory response is a complexprocess that requires interplay between several immunemediators [160] Both pro- and anti-inflammatory biomark-ers have been studied in ARDS

(1) Proinflammatory Cytokines

(a) IL-1120573 and TNF-120572 IL-1120573 and TNF-120572 are the most biolog-ically potent cytokines secreted by activated macrophages inthe early phase of ARDS They cause the release of a varietyof proinflammatory chemokines such as monocyte chemo-tactic protein-1 (MCP-1) macrophage inflammatory protein-1120572 (MIP-1120572) IL-6 and IL-8 with subsequent recruitmentof inflammatory cells into the air spaces alteration of theendothelial-epithelial barrier permeability and impairmentof fluid transport leading to alveolar edema [17] TNF-120572 alsopromotes lung edema indirectly through the production ofreactive oxygen species (ROS) and a decreased expressionof epithelial sodium (ENaC) and Na+-K+-ATPase channels[161] Finally TNF-120572 a potent chemoattractant for fibrob-lasts is a promoter of lung fibrosis in experimental studies[162 163] Interestingly the ratio of BAL to serum levelsof both TNF-120572 and IL-1120573 is typically high suggesting thatsuch cytokines may originate from the lung in the settingof ARDS [164] Persistent elevation of plasma and BAL IL-1120573 is associated with worse outcome [165 166] Both TNF-120572 and IL-1120573 are elevated in the plasma and BAL fluid frompatients at risk of and with ARDS [164 167] and associatedwith mortality [166]

(b) IL-18 Inflammasomes are intracellular macromolecularcomplexes that serve as platforms for the activation of theproinflammatory enzyme caspase-1 which in turn cleavespro-IL-1120573 and pro-IL-18 into IL-1120573 and IL-18 [50] Theseinflammasome-activated cytokines play central roles in thepropagation of the acute inflammatory response IL-18 andcaspase-1 play critical roles in the development of lunginjury and higher levels of IL-18 are correlated with diseaseseverity and mortality in patients with ARDS [168] Among38 patients with acute respiratory failure those with ARDShad significantly higher serum levels of IL-18 and serum IL-18 was significantly higher in nonsurvivors [51]

(c) IL-6 IL-6 is produced by a wide range of cells includingmonocytesmacrophages endothelial cells fibroblasts andsmoothmuscle cells in response to stimulation by endotoxinIL-1120573 and TNF-120572 [52] IL-6 is one of the most importantmediators of fever and is critical for B-cell differentiation andmaturation with secretion of immunoglobulins cytotoxic Tcell differentiation macrophage and monocyte function andproduction of acute phase proteins Although IL-6 activatesboth proinflammatory and anti-inflammatory mechanismsIL-6 primarily correlates with a proinflammatory profileduring the early phase of ARDS Plasma IL-6 increases earlyin patients at risk of developing ARDS [53] IL-6 is elevated in

both plasma and BAL fluid during ARDS [59] and correlateswith mortality [54 55]

(d) IL-8 IL-8 is a proinflammatory cytokine with a role inneutrophilmonocyte chemotaxis and neutrophil apoptosisinhibitionHighplasma andBAL levels of IL-8 are found earlyduring ARDS and predict outcome [169] However previousstudies did not support such findings [170 171] In a recentmonocenter study of 100 patients only baseline IL-8 (among6 other biomarkers) was associated with the development ofmultiorgan failure even after adjustment for other relevantvariables [32] Also several studies have evaluated the roleof the anti-IL-8 autoantibodyIL-8 immune complexes inARDS a pathway that could lead to the identification of novelbiomarkers and therapeutic targets [17 172ndash175]

In a recent study Calfee et al used latent class analysisto integrate both clinical and biological data to identifytwo ARDS endotypes in an analysis of 1022 patients fromtwo ARDSNet trials (ARMA and ALVEOLI) [13] A firstendotype was categorized by more severe inflammation asassessed by both IL-6 and IL-8 levels and worse clinicaloutcomes whereas a second endotype had less inflammationless shock and better clinical outcomes Based on the datafrom the ALVEOLI trial a ldquoproinflammatoryrdquo endotypewas associated with higher mortality and better response tohigher levels of positive end-expiratory pressure [176]

(2) Anti-Inflammatory Cytokines The inflammatory responseis also strongly influenced by anti-inflammatory systemsincluding nonspecific (eg 2-macroglobulin IL-10) andspecific (eg IL-1 receptor antagonist (IL-1RA) antagonistssoluble IL-1 receptor II (sIL-1RII) soluble TNF receptorI (sTNF-RI) and soluble TNF receptor II (sTNF-RII)) ofproinflammatory cytokines

(a) IL-1RA Circulating IL-1RA levels are increased but donot predict the development of ARDS in at-risk patients[56] Studies of gene expression in alveolar macrophagesand circulating leukocytes from healthy control subjects andpatients with ARDS revealed that sIL-1RII may be valuable asa biomarker because of increased levels in both the lung andcirculation during ARDS [57]

(b) sTNF-RIsTNF-RII Soluble TNF-120572 receptors (sTNF-R)I and II can bind TNF and compete with its binding tothe cellular receptor thus reducing its bioavailability SolubleTNF-RI and TNF-II are associated with morbidity andmortality in patients with ARDS [54] and a strategy of lowtidal volume ventilation is associated with decreased sTNF-RI levels [54] Trauma-associated ARDS differs clinically andbiologically from ARDS due to other clinical disorders withlower levels of sTNF-RI patients with trauma as a primarycause of ARDS [6 58]

(c) IL-10 Interleukin-10 (IL-10) is an anti-inflammatorycytokine that is produced by several cells including B lym-phocytes monocytes and alveolar macrophages [60] Asidefrom inhibiting the production of IL-1 and TNF-120572 IL-10

Disease Markers 9

upregulates TNF receptors [177] and stimulates the produc-tion of the naturally occurring IL-1RAand the release of sTNFreceptors [178] IL-10 inhibits the production of proinflam-matory mediators by alveolar macrophages involved duringARDS [179] ARDS patients have lower plasma and BALlevels of IL-10 than at-risk patients who did not develop thesyndrome [61] Higher baseline IL-10 levels were associatedwith higher morbidity and mortality [59]

(3) Additional Markers Other markers with potential clinicalimportance in ARDS-associated inflammation have beenidentified as putative biomarkers during ARDS

High mobility group box nuclear protein 1 (HMGB1) is aDNAnuclear binding protein that is secreted by immune cellsincluding monocytes and macrophages HMGB1 increasesearly after severe trauma and correlates with systemic inflam-matory response and development of ARDS [62] Alveolarand plasma levels of HMGB1 (as measured in the arterial orcentral venous blood) are elevated in patients with ARDS andassociated with outcome [109] In 20 patients with ARDSplasma levels of HMGB1 were also higher in nonsurvivorsand correlated with levels of sRAGE [63]

Lipopolysaccharide binding protein (LBP) is an acutephase protein that is correlated with lung inflammationduring ARDS [64] More recently it has also been demon-strated that serum levels of LBPwere strongly associated withincreasedmortality and the development of ARDS in patientswith severe sepsis [65]

Nitric oxide (NO) is a marker of oxidative stress thathas also been investigated as a marker of ARDS In patientswith persistent ARDS higher levels of nitric oxide andof its end-products (eg nitrotyrosine) are associated withmortality [66] In contrast higher urine NO levels werestrongly associated with better clinical outcomes includingmortality and ventilator-free days in patients enrolled in theARDSNet low tidal volume trial [46] Extracellular citrullinethe effective precursor of NO is lower in the plasma frompatients with severe sepsis and lower plasma citrulline isassociated with the presence of ARDS [67] Mechanismsinvolved in the regulation of lung injury by NO-dependentpathways remain unknown

Although C-reactive protein (CRP) is widely consideredas a marker of systemic inflammation higher levels of CRPare associated with better outcome among patients withARDS [68] Nevertheless a recent study found that albuminlevels rather than CRP may help to predict and monitor theseverity and course of ARDS in febrile critically ill patientswith ARDS or at risk for the syndrome [69] In the samestudy levels of lactate dehydrogenase (LDH) predicted 28-day mortality but were not correlated with severity [69]

313 Coagulation and Fibrinolysis During early ARDS acti-vation of the inflammatory cascades results in the activationof the coagulation system which in turn can influenceinflammatory responses by affecting the expression of variouscytokines such as IL-1 IL-6 and IL-8 Activation of coagula-tion pathways induces migration of inflammatory cells intoalveoli through the endothelial and epithelial barriers and

generates thrombin formation In addition proinflammatoryevents may also inhibit fibrinolysis and induce platelet acti-vation [17]

Extravascular fibrin deposition when localized predomi-nantly in the alveolar compartment is found in several acuteinflammatory lung diseases and enhanced alveolar procoag-ulant activity is reported inARDS patients [180] Fibrin depo-sition may be beneficial for gas exchange by sealing leakagesites when lung capillary endothelial and epithelial barriersare disrupted Nevertheless fibrin alveolar deposition maybe harmful since it can lead to activation of neutrophilsand fibroblasts endothelial injury loss of surfactant activityfavoring alveolar collapse impaired alveolar fluid clearanceand thrombotic obstruction of the microcirculation [180]

(1) PAI-1 The balance between activation of coagulationand activation of fibrinolysis is an important determinantof the amount and duration of fibrin deposition duringlung injury Plasminogen activator (PA) and plasminogenactivator inhibitor-1 (PAI-1) regulate fibrinolysis through theconversion of plasminogen to plasmin a fibrinolytic enzymePA-1 is amajor endogenous inhibitor of PA Both PA and PA-1are secreted by various cells including macrophages fibrob-lasts and lung endothelial and epithelial cells [71] DuringARDS alveolar epithelial cells and activated macrophagesoverexpress PAI-1 thus contributing to decreased alveolarfibrinolytic activity Nevertheless the value of PAI-1 asa biomarker in ARDS remains controversial PAI-1 levelswere higher in patients with ARDS than in patients withhydrostatic lung edema [72] and higher PAI-1 levels areassociated withmortality and higher durations ofmechanicalventilation in patients with ARDS [72 169] In a large Finnishstudy PAI-1 levels were not correlated with mortality ordevelopment of ARDS in critically ill patients undermechan-ical ventilation but low baseline plasma levels of the solubleurokinase plasminogen activator receptor (suPAR) were pre-dictive of survival [181] In a secondary analysis of two largerandomized controlled trials PAI-1 was associated with lunginjury (as defined as decreased oxygenation index) but notwithmortality [28] Nevertheless in another study of patientsfrom the ARDSNet ARMA study higher levels of PAI-1were independently associated with higher mortality andclinical outcomes including organ failure [182] Howeverthis association between PAI-1 levels and the development ofmultiorgan failure was not confirmed in a recent study of 100ARDS patients [32]

(2) Protein C Protein C system is an important endogenousregulator of coagulation and fibrinolysis Protein C is synthe-sized by the liver and circulates as an inactive compoundIt is transformed to its active form on cell surface by thethrombomodulin- (TM-) thrombin complex [75 76] Theendothelial cell protein C receptor (EPCR) is another cellsurface protein that can further enhance protein activationby binding the TM-thrombin complex [183] In additionto suppressing thrombin formation activated protein C hasanti-inflammatory properties such as decreasing the levelsof proinflammatory cytokines [184] Protein C can improveendothelial permeability and exert antiapoptotic effects via

10 Disease Markers

p53 pathways [185] Activated protein C can also inactivatePAI-1 thus promoting fibrinolysis [186] Plasma protein Cwas significantly lower in patients with ARDS as comparedto controls and it was associated with worse clinical out-comes including higher hospital mortality shorter durationof unassisted ventilation and increased risk ofmultiple organfailure [73] In a larger cohort of patients with early ARDSlow plasma levels of protein C were again associated withmortality and adverse clinical outcomes [182] Decreasedlevels of protein C during ARDS suggest a link betweenhypercoagulability and mortality

(3) Thrombomodulin Thrombomodulin (TM) is a mul-tidomain transmembrane-bound glycoprotein found on thesurface of endothelial cell Its main role is to neutralize theprocoagulant effects of thrombin and accelerate activationof protein C In addition to its membrane-bound form TMalso exists as a circulating soluble isoform in the plasmaIn patients with ARDS levels of soluble thrombomodulin(sTM) are higher in the pulmonary edema fluid than inplasma [73] suggesting an alveolar source but no correlationwas found between plasma sTM and the development ofARDS yet higher levels of sTM were observed in patientsat high risk for ARDS In patients with established ARDShigher plasma and alveolar levels of sTM were correlatedwith severity of illness and multiple organ failure [73] Ina larger analysis of 449 patients elevated levels of plasmasTM were associated with increased mortality thus possiblyreflecting an increased degree of inflammation and both lungand systemic endothelial damage [74]

(4) Tissue Factor (TF) Tissue factor (TF) is a 47 kDa trans-membrane glycoprotein that is the most potent stimulator ofthe extrinsic coagulation cascade TF initiates the coagulationcascade by binding and allosterically activating coagulationfactor VIIa The resulting TF-VIIa complex binds the sub-strate coagulation factor X via multiple interactions alongan extended interface to produce the TF-VIIa-X complexThis complex leads eventually to thrombin formation andfibrin deposition [77] Levels of TF in lung edema fluid arehigher than plasma levels in patients with ARDS supportinga lung origin for TF in this setting and both plasma andalveolar levels of TF are higher in ARDS patients as comparedto patients with hydrostatic edema [187] Notably patientswith sepsis-induced ARDS may have higher levels of TF ascompared to patients without ARDS [78]

(5) Cell-Free Hb Levels of cell-free hemoglobin (Hb) arehigher in the air space of ARDS patients as comparedto critically ill patients with hydrostatic lung edema [79]Instillation of red blood cells or cell-free hemoglobin causeslung injury in rats [188] and intra-alveolar hemorrhage isassociated with high levels of intra-alveolar cell-free Hbmore severe lung injury and increased lipid peroxidationin the lung from mice with tissue factor deficiency [79]Precise cellular and molecular mechanisms by which cell-free hemoglobin in the air space could mediate or potenti-ate ARDS are currently under investigation [189] Cell-freeHb could activate chemokine release within the lung and

decompartmentalization of hemoglobin is likely to provide asignificant proinflammatory stimulus in the setting of diffusealveolar damage and hemorrhage during ARDS [80]

314 EFPL Protein Ratio The pathophysiology of ARDSincludes disruption of several physical barriers includingendothelial and epithelial cell layers the basement mem-brane and the extracellularmatrix resulting in increased pul-monary microvascular permeability The pulmonary edemafluid-to-plasma protein (EFPL) ratio is a rapid safe andnoninvasive measure of alveolar-capillary membrane per-meability The EFPL ratio was first proposed as a tool todetermine the etiology of acute pulmonary edema [81] Morerecently in a large study of 390 critically ill patientsWare et aldemonstrated that the EFPL ratio had an excellent discrimi-native value in distinguishing ARDS from hydrostatic edemaand was strongly associated with clinical outcomes Using acutoff of 065 the EFPL ratio had a sensitivity of 81 and aspecificity of 81 for the diagnosis of ARDS [82]

32 Fibroproliferative Phase of ARDS In some patientsimportant and persistent accumulation of macrophagesfibrocytes fibroblasts and myofibroblasts in the alveolarcompartment leads to excessive deposition of ECM com-ponents including fibronectin and collagen types I and IIIamong other proteins An imbalance between profibrotic andantifibrotic mediators may subsequently drive this fibropro-liferative response [190] Growth factors play a major rolein the resolution of ARDS [17] Lung endothelial repair ispromoted by vascular endothelial growth factor (VEGF)A variety of growth factors promote repair of the alveo-lar epithelium including keratinocyte growth factor (KGF)hepatocyte growth factor (HGF) fibroblast growth factor(FGF) and transforming growth factor-120572 (TGF-120572) [17] Twomajor pathways with opposite effects involve growth factorsduring ARDS tyrosine kinase receptor mediation (eg KGFHGF FGF and VEGF) and serine-threonine kinase receptorssuch as TGF-1205731 which tend to have opposed effect on theupregulation that occurs when the tyrosine kinase receptorpathway is involved [85 191 192]

321 Endothelial Proliferation Novel evidence points to apotential role of VEGF in promoting repair of the alveolar-capillarymembrane during recovery fromARDS and under-standing the role of VEGF in this disease process couldbe crucial for developing new therapeutic strategies [85193] In the lung VEGF is produced primarily by epithelialcells it increases microvascular permeability [83] but has animportant role also during the repair phase by stimulatingendothelial cell proliferation and survival [86 149] Thelevels of VEGF are increased in plasma from patients withARDS but are decreased in BAL fluid compared to healthycontrols subsequently BAL levels of VEGF increase duringthe resolution of lung injury [39 84 149]

322 Epithelial Proliferation and Apoptosis KGF also knownas FGF-7 is a potent mitogenic factor for alveolar epithelialcells that is primarily produced by fibroblasts and other

Disease Markers 11

cells such as T lymphocytes KGF regulates transepithelialtransport of sodium by stimulating the epithelial channelNa+-K+-ATPase in alveolar epithelial cells [87]

HGF is a nonspecific mitogen secreted by fibroblastsalveolar macrophages endothelial cells and epithelial cellsSeveral animal and human studies suggest that KGF andHGFcould protect the alveolar space against injury and couldfacilitate the repair of alveolar structures after injury [88 194195] KGF levels could be measured in the BAL from patientswith ARDS but not in the BAL from those without ARDS inaddition BALKGFwas associated with poor prognosis [196]Elevated HGF levels were also associated with outcome [196]In 36 patients with ARDS and 11 patients with hydrostaticlung edema HGF and KGF were proven biologically activein the edema fluid of patients with ARDS and higher levelsof HGFwere associated withmortality in these patients [197]

Apoptosis of alveolar epithelial cells is a major phe-nomenon in the initiation and perpetuation of lung injury[89] The FasFasL system plays an important role in theregulation of cell life and death through its ability to initiateapoptosis [198] This system combines the cell membranesurface receptor Fas (CD95) and its natural ligand FasL(CD95L) Membrane-bound FasL mediates lymphocyte-dependent cytotoxicity clonal deletion of alloreactive T cellsand activation-induced suicide of T cells [199] Its solubleform (sFasL) results from cleavage of membrane FasL byMMPs and induces apoptosis in susceptible cells [200]Apoptosis is inducedwhenmembrane-bound or soluble FasLbinds to Fas-bearing cells By contrast apoptosis is inhibitedwhen soluble Fas binds to either membrane-bound FasL orsFasL thus preventing FasL from interacting withmembrane-bound Fas receptors [201] In patients with ARDS sFasL wasdetectable in the lung before and after the onset of clinicallydefined ARDS and nonsurvivors had significantly higherBAL levels of sFasL on day 1 as compared with survivors[200] Both soluble Fas and soluble FasL were associated withoutcome and higher in the lung edema fluid from patientswith ARDS compared to control patients with hydrostaticpulmonary edema [202] Nevertheless recent findings sug-gested limited role for FasFasL system and apoptosis inairway epithelial cell death during ARDS [90]

323 Fibroblast Proliferation Pulmonary fibroblasts pro-duce procollagen III peptide (PCP-III) that is a precursorof collagen The NT part of procollagen III resulting fromthe enzymatic cleavage of procollagen by specific proteases inthe extracellular space is considered as a marker of collagensynthesis Alveolar levels of N-PCP-III are higher in ARDSpatient as compared with controls [203] The elevation ofN-PCP-III in pulmonary edema fluid begins within the first24 h of ARDS that is during the acute phase of increasedendothelial and epithelial permeability to protein suggestingthat fibrosing alveolitis could begin very early in the course ofclinical ARDS [203] In another study high levels of N-PCP-III were early predictors of poor outcome [204 205] Morerecently Forel et al measured alveolar N-PCP-III in patientswith nonresolving ARDS thus identifying patients who haddeveloped lung fibroproliferation [206] Unfortunately it

is still unknown whether N-PCP-III measurements couldbe useful in selecting patients who would benefit fromglucocorticoid therapy among others to reduce the ARDS-associated lung fibrosis [207]

4 Perspectives

41 Combining Biomarkers Despite advances in the identi-fication of biomarker candidate and better understanding ofARDS pathogenesis no single clinical or biological markerreliably predicts clinical outcomes inARDSThe combinationof clinical and biological marker is attractive in order toimprove the sensitivity andor the specificity of the testespecially through a recent approach aimed at measuring8 biological markers that reflect endothelial and epithelialinjury inflammation and coagulation vWF SP-D TNF-R1IL-6 IL-8 ICAM-1 protein C and PAI-1 in 549 patientsenrolled in the the ARDSNet trial of low versus high positiveend-expiratory pressure [208] Clinical predictors predictedmortality with an area under the ROC curve (AUC) of082 whereas a combination of these 8 biomarkers and theclinical predictors had an AUC of 085 The best performingbiomarkers were the neutrophil chemotactic factor IL-8 andSP-D a product of AT2 cells [208] supporting the conceptthat acute inflammation and alveolar epithelial injury areimportant pathogenetic pathways in human ARDS Morerecently a panel of biomarkers of lung epithelial injuryand inflammation (SP-D sRAGE IL-8 CC16 and IL-6)provided excellent discrimination for diagnosis of ARDSin patients with severe sepsis [20] Therefore and beyondtheir better diagnostic and prognostic values the use of suchbiomarker panels may be useful for selecting patients forclinical trials that are designed to reduce lung epithelial injury[113] Nevertheless whether a therapeutic strategy based onbiomarker measurements would benefit patient outcome hasnever been investigated

42 Lung Imaging as an ARDS Biomarker Studies of lungimaging during ARDS have revealed that adequate ventilatorsettings may vary among patients with the same syndromeIn a large study gas and tissue distribution in the lungs ofARDS patients were assessed using computed tomography(CT) and compared to those of healthy volunteers [11] Lungmorphology in ARDS is characterized by marked excess oflung tissue associated with a major decrease in aerated lungregions and in functional residual capacity Some patientswith ARDS exhibit preserved aeration of the upper lobesdespite the presence of an overall excess of lung tissue (ldquofocalrdquoARDS) as opposed to other patients with more diffuse lossof aeration and excessive lung tissue (ldquodiffuserdquo or ldquononfocalrdquoARDS) [209]

Lung morphology may influence the response to pos-itive end-expiratory pressure (PEEP) recruitment maneu-vers (RM) prone position and patient outcome [12 210]In a prospective study of nineteen patients with ARDSConstantin et al found that lung morphology at zero end-expiratory pressure could predict the response to a RM withcontinuous positive airway pressure of 40 cm H

2O for 40

12 Disease Markers

seconds Nonfocal morphology was associated with higherlung recruitability and PaO

2FiO2was significantly increased

by the RM [12 211] In contrast patients with focal lungmorphology were at risk of significant hyperinflation duringthe RM with no improvement of arterial oxygenation

It has also been hypothesized that the effects of PEEPmay depend on lung morphology Puybasset et al assessedthe responses to PEEP among patients with focal or nonfocalARDS [210] The regional distribution of intrapulmonarygas and lung tissue influences the effects of PEEP in ARDSpatients maximal alveolar recruitment without evidenceof overdistension was observed in patients with nonfocalARDS Nevertheless PEEP induced mild alveolar recruit-ment in patients with focal ARDS along with overdistensionof previously aerated lung regions

Interestingly phenotyping patients with ARDS basedon their lung morphology might be possible by measuringplasma sRAGEwith commercially available kits even thoughthese findings need further validation [100 112] HoweverRAGE pathway is a promising candidate for subphenotypingpatients with ARDS as it is believed to play a major rolein the mechanisms leading to AFC and their regulation[110] Recent findings that support a relationship betweenimpaired AFC and lung morphology may therefore fill a gapin the full recognition of an ARDS phenotype based on lungmorphology that could be linked to an endotype of impairedAFC and activated RAGE pathway [12 100 101 112 113 212]

43 Biomarkers in ARDS Can They Improve Patient CareBiomarkers are broadly used in critically ill patientsespecially during inflammatory andor infectious diseasesBiomarkers have been commonly defined as characteristicsthat are objectively measured and evaluated as indicatorsof normal biological processes pathogenic processes orpharmacologic responses to therapeutic interventions [213214] Biomarkers provide a powerful approach to understanda disease with multiple applications in observational andanalytic epidemiology randomized clinical trials screeningand diagnosis or prognosis [215]

Nevertheless there are important technical attributes fora relevant biomarker First the marker must be present inperipheral body tissue andor fluid (eg blood urine salivabreath or cerebrospinal fluid) second it must be easy todetect or quantify in assays that are both affordable androbust and third its regulation should be associated asspecifically as possible with damage of a particular tissuepreferably in a quantifiable manner Prior to the widespreaduse of a marker of interest it is essential that validation andconfirmation of candidate biomarkers by robust statisticalmethods are performed during biomarker discovery [215]Sensitivity and specificity are common quality parametersfor biomarkers Sensitivity describes the probability of apositive test in cases and specificity describes probability ofnegative test in controls An association between sensitivityand specificity is represented in the ROC curve by graphingsensitivity versus 100 minus specificity Area under the ROC curve(AUROC) is therefore a measure of performance of a markerThere is no absolute cutoff value of AUROC for robustness of

a marker but aminimum of 07 is required and values greaterthan 08 are good particularly in a heterogeneous critically illpatient population [216 217]

To summarize an ideal biomarker should indicate aclear relationship with the pathophysiologic event needsto be reliable reproducible disease specific and sensitiveand should be sampled by simple methods and relativelyinexpensive with little or no diurnal variation DuringARDS no single marker has been validated with all thesecriteria to date yet we believe that sRAGE may fulfill allprerequisites of a biomarker of ARDS First plasma sRAGEhas good diagnostic and prognostic values [96 99 100109 112] Second it is very well correlated with lung injuryseverity and specific pathophysiologic features of ARDS forexample alveolar fluid clearance and lung morphology [9699ndash101 109 112] Previous studies of the predictive value ofearly levels of sRAGE for the development of ARDS in ageneral population of patients admitted to the emergencydepartment were negative [130] but current research focuseson both the kinetics of sRAGE and esRAGE and RAGE genepolymorphisms as predictors of the development of ARDSin at-risk critically ill patients [114] Finally there is someevidence suggesting that monitoring sRAGE could informat least partially on therapeutic responses in patients with orwithout ARDS [24 99 113] If these data are confirmed byfuture studies such findingswould definitely help to reinforcesRAGE a real biomarker of ARDS

5 Conclusion

Biomarker research provides an important translational linkto our understanding of lung pathobiology Through theidentification and testing of candidate biomarkers we havegained insight into the pathogenic importance of endothelialand epithelial injury and have started to unravel the complexpathways that contribute to endothelial and epithelial celldysfunction inflammation fibrosis and apoptosis in ARDSIn addition biomarker studies may help us to explore thecellular and molecular mechanisms of various therapeuticstrategies for ARDS and to better understand the potentialproinflammatory effects of mechanical ventilation Giventhe clinical heterogeneity of patients with ARDS and thecomplexity of the underlying pathobiology it is unlikely thata single biomarker will emerge for ARDS as cardiac-specifictroponin did for myocardial infarction but the develop-ment of small biomarker panels reflecting each importantlung injury pathway would provide valuable predictive andprognostic information for both clinicians and investigatorsWhile biomarkers are currently not recommended for usein clinical practice in ARDS biomarker discovery mayhold significant promise in order to develop and applytargeted therapies and to identify candidates for enrollmentin patient-tailored clinical trials of novel therapies for ARDS

Disclosure

The funders had no influence on the study design conductand analysis or on the preparation of this paper

Disease Markers 13

Conflict of Interests

No conflict of interests other sources of financial supportcorporate involvement patent holdings and so forth are tobe declared for all authors

Authorsrsquo Contribution

Raiko Blondonnet was involved in the conception and designof the review in writing the paper and in its revision priorto submission Jean-Michel Constantin was involved in theconception and design of the review in writing the paperand in its revision prior to submission Vincent Sapin wasinvolved in the conception and design of the review inwriting the paper and in its revision prior to submissionMatthieu Jabaudon takes responsibility for the content ofthe paper and was involved in the conception and design ofthe review in writing the paper and in its revision prior tosubmission

Acknowledgments

This work was supported by grants from the AuvergneRegional Council (ldquoProgramme Nouveau Chercheur de laRegion Auvergnerdquo 2013) the french Agence Nationale de laRecherche and the Direction Generale de lrsquoOffre de Soins(ldquoProgramme de Recherche Translationnelle en Santerdquo ANR-13-PRTS-0010)

References

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[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000

[3] C Brun-Buisson C Minelli G Bertolini et al ldquoEpidemiologyand outcome of acute lung injury in European intensive careunitsrdquo Intensive Care Medicine vol 30 no 1 pp 51ndash61 2004

[4] G D Rubenfeld E Caldwell E Peabody et al ldquoIncidence andoutcomes of acute lung injuryrdquo The New England Journal ofMedicine vol 353 no 16 pp 1685ndash1693 2005

[5] D W Dowdy M P Eid C R Dennison et al ldquoQuality oflife after acute respiratory distress syndrome a meta-analysisrdquoIntensive Care Medicine vol 32 no 8 pp 1115ndash1124 2006

[6] C S Calfee M D Eisner L B Ware et al ldquoTrauma-associatedlung injury differs clinically and biologically from acute lunginjury due to other clinical disordersrdquo Critical Care Medicinevol 35 no 10 pp 2243ndash2250 2007

[7] C S Calfee D R Janz G R Bernard et al ldquoDistinct molecularphenotypes of direct versus indirect ARDS in single and multi-center studiesrdquo Chest vol 147 no 6 pp 1539ndash1548 2015

[8] P Tejera N J Meyer F Chen et al ldquoDistinct and replicablegenetic risk factors for acute respiratory distress syndromeof pulmonary or extrapulmonary originrdquo Journal of MedicalGenetics vol 49 no 11 pp 671ndash680 2012

[9] M A Matthay G A Zimmerman C Esmon et al ldquoFutureresearch directions in acute lung injury summary of a National

Heart Lung and Blood Institute Working Grouprdquo AmericanJournal of Respiratory and Critical Care Medicine vol 167 no7 pp 1027ndash1035 2003

[10] J P Reilly S Bellamy M G S Shashaty et al ldquoHeterogeneousphenotypes of acute respiratory distress syndrome after majortraumardquo Annals of the American Thoracic Society vol 11 no 5pp 728ndash736 2014

[11] L Puybasset P Cluzel N Chao et al ldquoA computed tomographyscan assessment of regional lung volume in acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol158 no 5 pp 1644ndash1655 1998

[12] J-M Constantin S Grasso G Chanques et al ldquoLungmorphol-ogy predicts response to recruitment maneuver in patients withacute respiratory distress syndromerdquo Critical Care Medicinevol 38 no 4 pp 1108ndash1117 2010

[13] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoSubphenotypes in acute respiratorydistress syndrome latent class analysis of data from tworandomised controlled trialsrdquoThe Lancet Respiratory Medicinevol 2 no 8 pp 611ndash620 2014

[14] R Marshall G Bellingan and G Laurent ldquoThe acute respira-tory distress syndrome fibrosis in the fast lanerdquoThorax vol 53no 10 pp 815ndash817 1998

[15] R B Henderson J A R Hobbs M Mathies and N HoggldquoRapid recruitment of inflammatory monocytes is independentof neutrophil migrationrdquo Blood vol 102 no 1 pp 328ndash3352003

[16] HMMarriott andDH Dockrell ldquoThe role of themacrophagein lung disease mediated by bacteriardquo Experimental LungResearch vol 33 no 10 pp 493ndash505 2007

[17] L J M Cross and M A Matthay ldquoBiomarkers in acute lunginjury insights into the pathogenesis of acute lung injuryrdquoCritical Care Clinics vol 27 no 2 pp 355ndash377 2011

[18] H K Gaggin and J L Januzzi ldquoBiomarkers and diagnostics inheart failurerdquo Biochimica et Biophysica Acta (BBA)mdashMolecularBasis of Disease vol 1832 no 12 pp 2442ndash2450 2013

[19] E Christenson and R H Christenson ldquoThe role of cardiacbiomarkers in the diagnosis and management of patientspresenting with suspected acute coronary syndromerdquo Annals ofLaboratory Medicine vol 33 no 5 pp 309ndash318 2013

[20] L B Ware T Koyama Z Zhao et al ldquoBiomarkers of lungepithelial injury and inflammation distinguish severe sepsispatientswith acute respiratory distress syndromerdquoCritical Carevol 17 no 5 article R253 2013

[21] M A Matthay L B Ware and G A Zimmerman ldquoTheacute respiratory distress syndromerdquo The Journal of ClinicalInvestigation vol 122 no 8 pp 2731ndash2740 2012

[22] M Shirasawa N Fujiwara S Hirabayashi et al ldquoReceptor foradvanced glycation end-products is a marker of type I lungalveolar cellsrdquo Genes to Cells vol 9 no 2 pp 165ndash174 2004

[23] M Neeper A M Schmidt J Brett et al ldquoCloning andexpression of a cell surface receptor for advanced glycosylationend products of proteinsrdquo The Journal of Biological Chemistryvol 267 no 21 pp 14998ndash15004 1992

[24] M Jabaudon E Futier L Roszyk V Sapin B Pereira andJ Constantin ldquoAssociation between intraoperative ventilatorsettings and plasma levels of soluble receptor for advancedglycation end-products in patients without pre-existing lunginjuryrdquo Respirology vol 20 no 7 pp 1131ndash1138 2015

[25] L G Dobbs R F Gonzalez L Allen and D K Froh ldquoHTI56an integral membrane protein specific to human alveolar type

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

6 Disease Markers

and leaky blood vessels whereas Ang-1 enhances angiogene-sis inducing vascularmaturation anddecreases vascular per-meability [33] The most encouraging data result from recentstudies of angiopoietin-2 (Ang-2) an endothelial protein thathas been studied extensively during sepsis [125] Ang-2 has animportant role as it increases endothelial junction instabilityenhances vascular leak naturally antagonizes Ang-1 and inthe absence of other angiogenic stimuli induces vascularregression and endothelial cell apoptosis Both Ang-1 andAng-2 are ligands for the tyrosine kinase receptor Tie-2 [126] and a link between Ang-2 and inflammation hasbeen reported [127] Therefore such vascular growth factorshave been proposed as biomarkers for ARDS [128] Firsttwo single-nucleotide polymorphisms within the Ang-2 gene(rs1868554 and rs2442598) were associated with the riskof developing ARDS in trauma patients [129] In additionAgrawal et al found in a prospective study of 230 patientsadmitted to the intensive care unit (ICU) without ARDSthat higher levels of Ang-2 were significantly associatedwith increased development of ARDS [130] In surgical ICUpatients levels of Ang-2 were higher in patients with ARDSthan in those without the syndrome [131] A higher Ang-2Ang-1 ratio was also an independent predictor of mortalityin ARDS patients [131 132] and patients with infection-related ARDS whose Ang-2 levels increased between day 0and day 3 doubled their odds of death suggesting that Ang-2kinetics may be particularly valuable by reflecting evolvinglung injury [34] Finally in a large study of 931 patientsenrolled in the ARDSNet fluid and catheter treatment trialbaseline plasma levels of Ang-2 were associated with 90-daymortality in patients with noninfectious ARDS whereas thisassociation was not found in patients with infection as theirprimary ARDS risk factor Based on a secondary analysisof two large studies Calfee et al further demonstrated thatindirect lung injury is characterized by a molecular pheno-type consistent with more severe lung endothelial injury asassessed by plasma Ang-2 and less severe epithelial injury[7]

(b) ICAM-1 The soluble intercellular adhesion molecule-1 (sICAM-1) is an inducible glycoprotein expressed onthe surface of vascular endothelial cells and other cells(eg hematopoietic cells AT1 cells) [35] Under physiologicconditions sICAM-1 is not constitutively expressed or isexpressed at low levels in most tissues During inflammationand in response to stimuli such as interferon-120574 (IFN-120574) orinterleukin-1 (IL-1) levels of sICAM-1 are upregulated [133]Elevated levels have also been found in both plasma andlung edema fluid from patients with ARDS as compared topatients with hydrostatic lung edema [134] In a multicenterstudy the increase of sICAM-1 from baseline to day 3was associated with poor clinical outcome [135] and in aprospective cohort of 65 patients with ARDS baseline plasmalevels of sICAM-1 were also associated with mortality [136]In pediatric patients with ARDS early elevated plasma levelsof sICAM-1 were associated with increased risks of death andof prolongedmechanical ventilation [137] In traumapatientshigher plasma levels of sICAM-1 at baseline were correlated

with future development of multiple organ dysfunction syn-drome (MODS) but not with the development of ARDS [138ndash140]

(c) Selectins Selectins are membrane-associated glycopro-teins that mediate the adhesion of leukocytes and plateletsto vascular surface L-selectin is mainly expressed by leuko-cytes P-selectin is rapidly redistributed from membranoussecretory granules to the surface of activated platelets andendothelial cells [36] E-selectin is expressed by cytokine-activated endothelial cells It has been shown that plasmalevels of such soluble adhesion molecules were markedlyhigher in nonsurvivors among critically ill patients and thatthey were negatively correlated with lung function (egPaO2FiO2ratio) [141] Other studies found that plasma P-

selectin was elevated in patients with ARDS especially inthose who subsequently died as compared with patients withother pulmonary diseases or sepsis but without ARDS [142]Interestingly patients with ARDS with chronic alcohol con-sumption had elevated levels of soluble E-selectin in both theplasma and epithelial fluid consistent with altered endothe-lial and alveolar-capillary function [143] More recently E-selectin was measured in the plasma levels from 50 individ-uals admitted to the emergency department and who wereat-risk for developing ARDS with higher E-selectin levelsbeing associated with both ARDS development and 28-daymortality [144] Circulating soluble E-selectin levels wereelevated in pneumonia patientswithARDS and plasma levelsdecreased along with the treatment of pneumonia [37]

(d) VEGF One of the most extensively studied endothelialmarkers in ARDS is VEGF albeit its value as a biomarkerremains unclear Vascular endothelial growth factors belongto the platelet-derived growth factor supergene family Theyplay central roles in the regulation of angiogenesis andlymphangiogenesis [38] Alternative splicing of the VEGFgene (6p213) transcript leads to the generation of severalsplice variants or isoforms with various sizes [145] VEGF-Ais a 34ndash46 kDa glycoprotein acting as the major factor impli-cated in angiogenesis It binds to two tyrosine kinase (TK)receptors named VEGFR-1 (Flt-1) and VEGFR-2 (KDRFlk-1) and regulates endothelial cell proliferationmigration vas-cular permeability secretion and other endothelial functions[146] The expression of VEGF in ARDS varies dependingon the degree of epithelial and endothelial damage Manylung cells release VEGF for example AT2 cells neutrophilsalveolar macrophages and activated T cells Thus VEGFis potentially capable of having an effect on both alveolarepithelial and endothelial barriers Interestingly overexpres-sion of VEGF induces pulmonary edema in animal models[147] In a single center study plasma levels of VEGF wereincreased in subjects with ARDS compared to controls andelevated plasma VEGF as measured on day 4 was associatedwith mortality in patients with ARDS [83] Neverthelessseveral studies suggest that plasma and alveolar VEGF mayhelp to predict the development of ARDS and its recoveryWhereas plasma VEGF is increased in ARDS patients VEGFlevels were decreased in the BAL fluid from ARDS patients

Disease Markers 7

as compared to controls [84 148 149] In order to betterunderstand such differences between plasma and alveolarexpression of VEGF Ware et al conducted a study with theaim to determine whether changes in alveolar levels of VEGFwere specific to ARDS or not [39] the authors found thatalveolar levels of VEGF were decreased in both patients withARDS and those with hydrostatic edema The mechanismsimplicated in this alveolar decrease in VEGF during ARDSmight not depend on the degree of lung injury but rather onthe degree of alveolar flooding [39]

(e) vWF Early studies of endothelial markers focused on vonWillebrand Factor (vWF) a macromolecular antigen that isproduced predominantly by endothelial cells and to a lesserextent by platelets In the setting of endothelial activationor injury vWF is released from preformed stocks into thecirculation [40 41] VWFhas been investigated as a biologicalmarker of endothelial injury in patients both at-risk forARDSand with established ARDS [40 150] In a prospective studyof 45 ICU patients with sepsis patients with nonpulmonarysepsis had higher levels of plasma vWF with good predictiveand prognostic values for ARDS Indeed elevated plasmalevels of vWF had a sensitivity of 87 and a specificity of77 for the prediction of ARDS development in the settingof nonpulmonary sepsis [151] However subsequent studiesin patients at-risk for ARDS did not confirm these findings[42 152 153] In another study of 559 patients with ARDSenrolled in the National Heart Lung and Blood InstituteARDS Network trial of lower tidal volume nonsurvivorshad higher plasma levels of vWF compared to survivors[40] Higher vWF levels were significantly associated withfewer organ failure-free days suggesting that the degree ofendothelial activation and injury is strongly associated withoutcomes in ARDS nevertheless ventilator settings had noimpact on vWF levels in this study [40]

(f) Lung ExtracellularMatrixThe extracellularmatrix (ECM)forms the region of the lung situated between the alveo-lar epithelium and the vascular endothelium ECM playsa mechanical role as it supports and maintains tissularstructures ECM also represents a complex and dynamicmeshwork influencing many biological cell functions such asdevelopment proliferation and migration [154] Collagensare the main component of ECM along with glycoproteinsand proteoglycans including hyaluronic acid

Laminin Laminins (LM) are ECM proteins with high molec-ular weights that deposit in basal membranes Lamininsare involved in cell processes such as cellular adhesiongrowth and differentiation [43] Laminin-5 (LM-5) plays animportant role in cell migration and in the remodeling ofepithelial tissue LM-5 is activated through its cleavage bymatrix metalloproteinases (MMPs) thus releasing a solubleLN 1205742 NH2-terminal fragment (G2F) that does not depositin the ECM and can therefore be detected in the peripheralblood In a small single center study lamininwasmeasured inthe plasma and lung edema fluid from 17 patients with ARDSwith higher levels found in patients with ARDS as comparedto healthy volunteers [44] Interestingly nonsurvivors had

higher plasma levels of laminin as measured 5 days afterARDS onset than survivors and survivors had decreasinglevels of the marker over time suggesting that its secretionis suppressed during ARDS recovery

ElastinDesmosine Elastin is another critical protein of theECM that gives the lung its elastic recoil ability In adultselastin which is expressed by lungs and other tissues isusually excreted in the urine During lung epithelial andendothelial injury elastin can be broken down by proteasessuch as neutrophil elastase [45] Elastin breakdown results insmaller fragments containing desmosine and isodesmosine[155] In a large study of 579 patients with ARDS thoseventilated with lower tidal volumes had lower urine desmo-sine levels a finding that may reflect reduced extracellularmatrix breakdown however no correlation with mortalitywas found in patients with ARDS [46]

MMPs Matrix metalloproteinases (MMPs) are zinc-depend-ent endopeptidases that are able to degrade almost allextracellular matrix components MMP-8 a member of theleukocyte-derived MMPs contributes to the degradationturnover and remodeling of the extracellular matrix digest-ing type I collagen [47 48] MMPs are major actors inalmost all phases of the inflammatory response and theirfunction is highly regulated At the tissue level most impor-tant inhibitors are the tissue inhibitors of metalloproteinases(TIMPs) In fulminant inflammation the inhibitory capacityof TIMPs may be overwhelmed leading to excessive tissuedamage and adverse outcome [47] Previous studies suggestthat MMPs may have an important role in ARDS althoughthis role may be either harmful or beneficial [156 157] In arecent study despiteMMP-8 levels did not predict outcome inARDS patients higher levels of TIMP-1 were independentlyassociated with increased 90-day mortality in a large groupof critically ill mechanically ventilated patients [47] Thesefindings are in contradiction to those from a study inpediatric ARDS patients in which higher MMP-8 and activeMMP-9 levels as measured 48 hours after disease onset wereassociated with longer durations of mechanical ventilationand fewer ventilator-free days [158] ElevatedMMP-2 MMP-8 and MMP-9 in the BAL fluid from ARDS patients wereassociated with patterns of acute inflammation but with pooroutcome [157] Interestingly MMP-3 and MMP-13 may beprotective against lung injury by cleaving transmembranereceptor RAGE into sRAGE thus regulating RAGE activationby its ligands [48 49]

312 Inflammatory Cascades During ARDS inflammatoryresponses can either be related to an ongoing primaryinfectious stimulus such as pneumonia or to systemic inflam-mation such as in sepsis or in pancreatitis [2] The inflam-matory cascade involves inflammatory cells and the releaseof inflammatory mediators as driven by a complex networkof cytokines A comparison between blood and alveolarcytokines suggests that most inflammatory mediators orig-inate from the lung [17] Alarmins or damage-associatedmolecular patterns (DAMPs) are released by dead cells orlocal inflammatory cells (eg alveolar macrophages) They

8 Disease Markers

activate and recruit immune cells via binding to differentreceptors such as TLR IL-1 receptor (IL-1R) or RAGEthereby initiating and perpetuating multiple proinflamma-tory pathways [21 159]

Regulation of the inflammatory response is a complexprocess that requires interplay between several immunemediators [160] Both pro- and anti-inflammatory biomark-ers have been studied in ARDS

(1) Proinflammatory Cytokines

(a) IL-1120573 and TNF-120572 IL-1120573 and TNF-120572 are the most biolog-ically potent cytokines secreted by activated macrophages inthe early phase of ARDS They cause the release of a varietyof proinflammatory chemokines such as monocyte chemo-tactic protein-1 (MCP-1) macrophage inflammatory protein-1120572 (MIP-1120572) IL-6 and IL-8 with subsequent recruitmentof inflammatory cells into the air spaces alteration of theendothelial-epithelial barrier permeability and impairmentof fluid transport leading to alveolar edema [17] TNF-120572 alsopromotes lung edema indirectly through the production ofreactive oxygen species (ROS) and a decreased expressionof epithelial sodium (ENaC) and Na+-K+-ATPase channels[161] Finally TNF-120572 a potent chemoattractant for fibrob-lasts is a promoter of lung fibrosis in experimental studies[162 163] Interestingly the ratio of BAL to serum levelsof both TNF-120572 and IL-1120573 is typically high suggesting thatsuch cytokines may originate from the lung in the settingof ARDS [164] Persistent elevation of plasma and BAL IL-1120573 is associated with worse outcome [165 166] Both TNF-120572 and IL-1120573 are elevated in the plasma and BAL fluid frompatients at risk of and with ARDS [164 167] and associatedwith mortality [166]

(b) IL-18 Inflammasomes are intracellular macromolecularcomplexes that serve as platforms for the activation of theproinflammatory enzyme caspase-1 which in turn cleavespro-IL-1120573 and pro-IL-18 into IL-1120573 and IL-18 [50] Theseinflammasome-activated cytokines play central roles in thepropagation of the acute inflammatory response IL-18 andcaspase-1 play critical roles in the development of lunginjury and higher levels of IL-18 are correlated with diseaseseverity and mortality in patients with ARDS [168] Among38 patients with acute respiratory failure those with ARDShad significantly higher serum levels of IL-18 and serum IL-18 was significantly higher in nonsurvivors [51]

(c) IL-6 IL-6 is produced by a wide range of cells includingmonocytesmacrophages endothelial cells fibroblasts andsmoothmuscle cells in response to stimulation by endotoxinIL-1120573 and TNF-120572 [52] IL-6 is one of the most importantmediators of fever and is critical for B-cell differentiation andmaturation with secretion of immunoglobulins cytotoxic Tcell differentiation macrophage and monocyte function andproduction of acute phase proteins Although IL-6 activatesboth proinflammatory and anti-inflammatory mechanismsIL-6 primarily correlates with a proinflammatory profileduring the early phase of ARDS Plasma IL-6 increases earlyin patients at risk of developing ARDS [53] IL-6 is elevated in

both plasma and BAL fluid during ARDS [59] and correlateswith mortality [54 55]

(d) IL-8 IL-8 is a proinflammatory cytokine with a role inneutrophilmonocyte chemotaxis and neutrophil apoptosisinhibitionHighplasma andBAL levels of IL-8 are found earlyduring ARDS and predict outcome [169] However previousstudies did not support such findings [170 171] In a recentmonocenter study of 100 patients only baseline IL-8 (among6 other biomarkers) was associated with the development ofmultiorgan failure even after adjustment for other relevantvariables [32] Also several studies have evaluated the roleof the anti-IL-8 autoantibodyIL-8 immune complexes inARDS a pathway that could lead to the identification of novelbiomarkers and therapeutic targets [17 172ndash175]

In a recent study Calfee et al used latent class analysisto integrate both clinical and biological data to identifytwo ARDS endotypes in an analysis of 1022 patients fromtwo ARDSNet trials (ARMA and ALVEOLI) [13] A firstendotype was categorized by more severe inflammation asassessed by both IL-6 and IL-8 levels and worse clinicaloutcomes whereas a second endotype had less inflammationless shock and better clinical outcomes Based on the datafrom the ALVEOLI trial a ldquoproinflammatoryrdquo endotypewas associated with higher mortality and better response tohigher levels of positive end-expiratory pressure [176]

(2) Anti-Inflammatory Cytokines The inflammatory responseis also strongly influenced by anti-inflammatory systemsincluding nonspecific (eg 2-macroglobulin IL-10) andspecific (eg IL-1 receptor antagonist (IL-1RA) antagonistssoluble IL-1 receptor II (sIL-1RII) soluble TNF receptorI (sTNF-RI) and soluble TNF receptor II (sTNF-RII)) ofproinflammatory cytokines

(a) IL-1RA Circulating IL-1RA levels are increased but donot predict the development of ARDS in at-risk patients[56] Studies of gene expression in alveolar macrophagesand circulating leukocytes from healthy control subjects andpatients with ARDS revealed that sIL-1RII may be valuable asa biomarker because of increased levels in both the lung andcirculation during ARDS [57]

(b) sTNF-RIsTNF-RII Soluble TNF-120572 receptors (sTNF-R)I and II can bind TNF and compete with its binding tothe cellular receptor thus reducing its bioavailability SolubleTNF-RI and TNF-II are associated with morbidity andmortality in patients with ARDS [54] and a strategy of lowtidal volume ventilation is associated with decreased sTNF-RI levels [54] Trauma-associated ARDS differs clinically andbiologically from ARDS due to other clinical disorders withlower levels of sTNF-RI patients with trauma as a primarycause of ARDS [6 58]

(c) IL-10 Interleukin-10 (IL-10) is an anti-inflammatorycytokine that is produced by several cells including B lym-phocytes monocytes and alveolar macrophages [60] Asidefrom inhibiting the production of IL-1 and TNF-120572 IL-10

Disease Markers 9

upregulates TNF receptors [177] and stimulates the produc-tion of the naturally occurring IL-1RAand the release of sTNFreceptors [178] IL-10 inhibits the production of proinflam-matory mediators by alveolar macrophages involved duringARDS [179] ARDS patients have lower plasma and BALlevels of IL-10 than at-risk patients who did not develop thesyndrome [61] Higher baseline IL-10 levels were associatedwith higher morbidity and mortality [59]

(3) Additional Markers Other markers with potential clinicalimportance in ARDS-associated inflammation have beenidentified as putative biomarkers during ARDS

High mobility group box nuclear protein 1 (HMGB1) is aDNAnuclear binding protein that is secreted by immune cellsincluding monocytes and macrophages HMGB1 increasesearly after severe trauma and correlates with systemic inflam-matory response and development of ARDS [62] Alveolarand plasma levels of HMGB1 (as measured in the arterial orcentral venous blood) are elevated in patients with ARDS andassociated with outcome [109] In 20 patients with ARDSplasma levels of HMGB1 were also higher in nonsurvivorsand correlated with levels of sRAGE [63]

Lipopolysaccharide binding protein (LBP) is an acutephase protein that is correlated with lung inflammationduring ARDS [64] More recently it has also been demon-strated that serum levels of LBPwere strongly associated withincreasedmortality and the development of ARDS in patientswith severe sepsis [65]

Nitric oxide (NO) is a marker of oxidative stress thathas also been investigated as a marker of ARDS In patientswith persistent ARDS higher levels of nitric oxide andof its end-products (eg nitrotyrosine) are associated withmortality [66] In contrast higher urine NO levels werestrongly associated with better clinical outcomes includingmortality and ventilator-free days in patients enrolled in theARDSNet low tidal volume trial [46] Extracellular citrullinethe effective precursor of NO is lower in the plasma frompatients with severe sepsis and lower plasma citrulline isassociated with the presence of ARDS [67] Mechanismsinvolved in the regulation of lung injury by NO-dependentpathways remain unknown

Although C-reactive protein (CRP) is widely consideredas a marker of systemic inflammation higher levels of CRPare associated with better outcome among patients withARDS [68] Nevertheless a recent study found that albuminlevels rather than CRP may help to predict and monitor theseverity and course of ARDS in febrile critically ill patientswith ARDS or at risk for the syndrome [69] In the samestudy levels of lactate dehydrogenase (LDH) predicted 28-day mortality but were not correlated with severity [69]

313 Coagulation and Fibrinolysis During early ARDS acti-vation of the inflammatory cascades results in the activationof the coagulation system which in turn can influenceinflammatory responses by affecting the expression of variouscytokines such as IL-1 IL-6 and IL-8 Activation of coagula-tion pathways induces migration of inflammatory cells intoalveoli through the endothelial and epithelial barriers and

generates thrombin formation In addition proinflammatoryevents may also inhibit fibrinolysis and induce platelet acti-vation [17]

Extravascular fibrin deposition when localized predomi-nantly in the alveolar compartment is found in several acuteinflammatory lung diseases and enhanced alveolar procoag-ulant activity is reported inARDS patients [180] Fibrin depo-sition may be beneficial for gas exchange by sealing leakagesites when lung capillary endothelial and epithelial barriersare disrupted Nevertheless fibrin alveolar deposition maybe harmful since it can lead to activation of neutrophilsand fibroblasts endothelial injury loss of surfactant activityfavoring alveolar collapse impaired alveolar fluid clearanceand thrombotic obstruction of the microcirculation [180]

(1) PAI-1 The balance between activation of coagulationand activation of fibrinolysis is an important determinantof the amount and duration of fibrin deposition duringlung injury Plasminogen activator (PA) and plasminogenactivator inhibitor-1 (PAI-1) regulate fibrinolysis through theconversion of plasminogen to plasmin a fibrinolytic enzymePA-1 is amajor endogenous inhibitor of PA Both PA and PA-1are secreted by various cells including macrophages fibrob-lasts and lung endothelial and epithelial cells [71] DuringARDS alveolar epithelial cells and activated macrophagesoverexpress PAI-1 thus contributing to decreased alveolarfibrinolytic activity Nevertheless the value of PAI-1 asa biomarker in ARDS remains controversial PAI-1 levelswere higher in patients with ARDS than in patients withhydrostatic lung edema [72] and higher PAI-1 levels areassociated withmortality and higher durations ofmechanicalventilation in patients with ARDS [72 169] In a large Finnishstudy PAI-1 levels were not correlated with mortality ordevelopment of ARDS in critically ill patients undermechan-ical ventilation but low baseline plasma levels of the solubleurokinase plasminogen activator receptor (suPAR) were pre-dictive of survival [181] In a secondary analysis of two largerandomized controlled trials PAI-1 was associated with lunginjury (as defined as decreased oxygenation index) but notwithmortality [28] Nevertheless in another study of patientsfrom the ARDSNet ARMA study higher levels of PAI-1were independently associated with higher mortality andclinical outcomes including organ failure [182] Howeverthis association between PAI-1 levels and the development ofmultiorgan failure was not confirmed in a recent study of 100ARDS patients [32]

(2) Protein C Protein C system is an important endogenousregulator of coagulation and fibrinolysis Protein C is synthe-sized by the liver and circulates as an inactive compoundIt is transformed to its active form on cell surface by thethrombomodulin- (TM-) thrombin complex [75 76] Theendothelial cell protein C receptor (EPCR) is another cellsurface protein that can further enhance protein activationby binding the TM-thrombin complex [183] In additionto suppressing thrombin formation activated protein C hasanti-inflammatory properties such as decreasing the levelsof proinflammatory cytokines [184] Protein C can improveendothelial permeability and exert antiapoptotic effects via

10 Disease Markers

p53 pathways [185] Activated protein C can also inactivatePAI-1 thus promoting fibrinolysis [186] Plasma protein Cwas significantly lower in patients with ARDS as comparedto controls and it was associated with worse clinical out-comes including higher hospital mortality shorter durationof unassisted ventilation and increased risk ofmultiple organfailure [73] In a larger cohort of patients with early ARDSlow plasma levels of protein C were again associated withmortality and adverse clinical outcomes [182] Decreasedlevels of protein C during ARDS suggest a link betweenhypercoagulability and mortality

(3) Thrombomodulin Thrombomodulin (TM) is a mul-tidomain transmembrane-bound glycoprotein found on thesurface of endothelial cell Its main role is to neutralize theprocoagulant effects of thrombin and accelerate activationof protein C In addition to its membrane-bound form TMalso exists as a circulating soluble isoform in the plasmaIn patients with ARDS levels of soluble thrombomodulin(sTM) are higher in the pulmonary edema fluid than inplasma [73] suggesting an alveolar source but no correlationwas found between plasma sTM and the development ofARDS yet higher levels of sTM were observed in patientsat high risk for ARDS In patients with established ARDShigher plasma and alveolar levels of sTM were correlatedwith severity of illness and multiple organ failure [73] Ina larger analysis of 449 patients elevated levels of plasmasTM were associated with increased mortality thus possiblyreflecting an increased degree of inflammation and both lungand systemic endothelial damage [74]

(4) Tissue Factor (TF) Tissue factor (TF) is a 47 kDa trans-membrane glycoprotein that is the most potent stimulator ofthe extrinsic coagulation cascade TF initiates the coagulationcascade by binding and allosterically activating coagulationfactor VIIa The resulting TF-VIIa complex binds the sub-strate coagulation factor X via multiple interactions alongan extended interface to produce the TF-VIIa-X complexThis complex leads eventually to thrombin formation andfibrin deposition [77] Levels of TF in lung edema fluid arehigher than plasma levels in patients with ARDS supportinga lung origin for TF in this setting and both plasma andalveolar levels of TF are higher in ARDS patients as comparedto patients with hydrostatic edema [187] Notably patientswith sepsis-induced ARDS may have higher levels of TF ascompared to patients without ARDS [78]

(5) Cell-Free Hb Levels of cell-free hemoglobin (Hb) arehigher in the air space of ARDS patients as comparedto critically ill patients with hydrostatic lung edema [79]Instillation of red blood cells or cell-free hemoglobin causeslung injury in rats [188] and intra-alveolar hemorrhage isassociated with high levels of intra-alveolar cell-free Hbmore severe lung injury and increased lipid peroxidationin the lung from mice with tissue factor deficiency [79]Precise cellular and molecular mechanisms by which cell-free hemoglobin in the air space could mediate or potenti-ate ARDS are currently under investigation [189] Cell-freeHb could activate chemokine release within the lung and

decompartmentalization of hemoglobin is likely to provide asignificant proinflammatory stimulus in the setting of diffusealveolar damage and hemorrhage during ARDS [80]

314 EFPL Protein Ratio The pathophysiology of ARDSincludes disruption of several physical barriers includingendothelial and epithelial cell layers the basement mem-brane and the extracellularmatrix resulting in increased pul-monary microvascular permeability The pulmonary edemafluid-to-plasma protein (EFPL) ratio is a rapid safe andnoninvasive measure of alveolar-capillary membrane per-meability The EFPL ratio was first proposed as a tool todetermine the etiology of acute pulmonary edema [81] Morerecently in a large study of 390 critically ill patientsWare et aldemonstrated that the EFPL ratio had an excellent discrimi-native value in distinguishing ARDS from hydrostatic edemaand was strongly associated with clinical outcomes Using acutoff of 065 the EFPL ratio had a sensitivity of 81 and aspecificity of 81 for the diagnosis of ARDS [82]

32 Fibroproliferative Phase of ARDS In some patientsimportant and persistent accumulation of macrophagesfibrocytes fibroblasts and myofibroblasts in the alveolarcompartment leads to excessive deposition of ECM com-ponents including fibronectin and collagen types I and IIIamong other proteins An imbalance between profibrotic andantifibrotic mediators may subsequently drive this fibropro-liferative response [190] Growth factors play a major rolein the resolution of ARDS [17] Lung endothelial repair ispromoted by vascular endothelial growth factor (VEGF)A variety of growth factors promote repair of the alveo-lar epithelium including keratinocyte growth factor (KGF)hepatocyte growth factor (HGF) fibroblast growth factor(FGF) and transforming growth factor-120572 (TGF-120572) [17] Twomajor pathways with opposite effects involve growth factorsduring ARDS tyrosine kinase receptor mediation (eg KGFHGF FGF and VEGF) and serine-threonine kinase receptorssuch as TGF-1205731 which tend to have opposed effect on theupregulation that occurs when the tyrosine kinase receptorpathway is involved [85 191 192]

321 Endothelial Proliferation Novel evidence points to apotential role of VEGF in promoting repair of the alveolar-capillarymembrane during recovery fromARDS and under-standing the role of VEGF in this disease process couldbe crucial for developing new therapeutic strategies [85193] In the lung VEGF is produced primarily by epithelialcells it increases microvascular permeability [83] but has animportant role also during the repair phase by stimulatingendothelial cell proliferation and survival [86 149] Thelevels of VEGF are increased in plasma from patients withARDS but are decreased in BAL fluid compared to healthycontrols subsequently BAL levels of VEGF increase duringthe resolution of lung injury [39 84 149]

322 Epithelial Proliferation and Apoptosis KGF also knownas FGF-7 is a potent mitogenic factor for alveolar epithelialcells that is primarily produced by fibroblasts and other

Disease Markers 11

cells such as T lymphocytes KGF regulates transepithelialtransport of sodium by stimulating the epithelial channelNa+-K+-ATPase in alveolar epithelial cells [87]

HGF is a nonspecific mitogen secreted by fibroblastsalveolar macrophages endothelial cells and epithelial cellsSeveral animal and human studies suggest that KGF andHGFcould protect the alveolar space against injury and couldfacilitate the repair of alveolar structures after injury [88 194195] KGF levels could be measured in the BAL from patientswith ARDS but not in the BAL from those without ARDS inaddition BALKGFwas associated with poor prognosis [196]Elevated HGF levels were also associated with outcome [196]In 36 patients with ARDS and 11 patients with hydrostaticlung edema HGF and KGF were proven biologically activein the edema fluid of patients with ARDS and higher levelsof HGFwere associated withmortality in these patients [197]

Apoptosis of alveolar epithelial cells is a major phe-nomenon in the initiation and perpetuation of lung injury[89] The FasFasL system plays an important role in theregulation of cell life and death through its ability to initiateapoptosis [198] This system combines the cell membranesurface receptor Fas (CD95) and its natural ligand FasL(CD95L) Membrane-bound FasL mediates lymphocyte-dependent cytotoxicity clonal deletion of alloreactive T cellsand activation-induced suicide of T cells [199] Its solubleform (sFasL) results from cleavage of membrane FasL byMMPs and induces apoptosis in susceptible cells [200]Apoptosis is inducedwhenmembrane-bound or soluble FasLbinds to Fas-bearing cells By contrast apoptosis is inhibitedwhen soluble Fas binds to either membrane-bound FasL orsFasL thus preventing FasL from interacting withmembrane-bound Fas receptors [201] In patients with ARDS sFasL wasdetectable in the lung before and after the onset of clinicallydefined ARDS and nonsurvivors had significantly higherBAL levels of sFasL on day 1 as compared with survivors[200] Both soluble Fas and soluble FasL were associated withoutcome and higher in the lung edema fluid from patientswith ARDS compared to control patients with hydrostaticpulmonary edema [202] Nevertheless recent findings sug-gested limited role for FasFasL system and apoptosis inairway epithelial cell death during ARDS [90]

323 Fibroblast Proliferation Pulmonary fibroblasts pro-duce procollagen III peptide (PCP-III) that is a precursorof collagen The NT part of procollagen III resulting fromthe enzymatic cleavage of procollagen by specific proteases inthe extracellular space is considered as a marker of collagensynthesis Alveolar levels of N-PCP-III are higher in ARDSpatient as compared with controls [203] The elevation ofN-PCP-III in pulmonary edema fluid begins within the first24 h of ARDS that is during the acute phase of increasedendothelial and epithelial permeability to protein suggestingthat fibrosing alveolitis could begin very early in the course ofclinical ARDS [203] In another study high levels of N-PCP-III were early predictors of poor outcome [204 205] Morerecently Forel et al measured alveolar N-PCP-III in patientswith nonresolving ARDS thus identifying patients who haddeveloped lung fibroproliferation [206] Unfortunately it

is still unknown whether N-PCP-III measurements couldbe useful in selecting patients who would benefit fromglucocorticoid therapy among others to reduce the ARDS-associated lung fibrosis [207]

4 Perspectives

41 Combining Biomarkers Despite advances in the identi-fication of biomarker candidate and better understanding ofARDS pathogenesis no single clinical or biological markerreliably predicts clinical outcomes inARDSThe combinationof clinical and biological marker is attractive in order toimprove the sensitivity andor the specificity of the testespecially through a recent approach aimed at measuring8 biological markers that reflect endothelial and epithelialinjury inflammation and coagulation vWF SP-D TNF-R1IL-6 IL-8 ICAM-1 protein C and PAI-1 in 549 patientsenrolled in the the ARDSNet trial of low versus high positiveend-expiratory pressure [208] Clinical predictors predictedmortality with an area under the ROC curve (AUC) of082 whereas a combination of these 8 biomarkers and theclinical predictors had an AUC of 085 The best performingbiomarkers were the neutrophil chemotactic factor IL-8 andSP-D a product of AT2 cells [208] supporting the conceptthat acute inflammation and alveolar epithelial injury areimportant pathogenetic pathways in human ARDS Morerecently a panel of biomarkers of lung epithelial injuryand inflammation (SP-D sRAGE IL-8 CC16 and IL-6)provided excellent discrimination for diagnosis of ARDSin patients with severe sepsis [20] Therefore and beyondtheir better diagnostic and prognostic values the use of suchbiomarker panels may be useful for selecting patients forclinical trials that are designed to reduce lung epithelial injury[113] Nevertheless whether a therapeutic strategy based onbiomarker measurements would benefit patient outcome hasnever been investigated

42 Lung Imaging as an ARDS Biomarker Studies of lungimaging during ARDS have revealed that adequate ventilatorsettings may vary among patients with the same syndromeIn a large study gas and tissue distribution in the lungs ofARDS patients were assessed using computed tomography(CT) and compared to those of healthy volunteers [11] Lungmorphology in ARDS is characterized by marked excess oflung tissue associated with a major decrease in aerated lungregions and in functional residual capacity Some patientswith ARDS exhibit preserved aeration of the upper lobesdespite the presence of an overall excess of lung tissue (ldquofocalrdquoARDS) as opposed to other patients with more diffuse lossof aeration and excessive lung tissue (ldquodiffuserdquo or ldquononfocalrdquoARDS) [209]

Lung morphology may influence the response to pos-itive end-expiratory pressure (PEEP) recruitment maneu-vers (RM) prone position and patient outcome [12 210]In a prospective study of nineteen patients with ARDSConstantin et al found that lung morphology at zero end-expiratory pressure could predict the response to a RM withcontinuous positive airway pressure of 40 cm H

2O for 40

12 Disease Markers

seconds Nonfocal morphology was associated with higherlung recruitability and PaO

2FiO2was significantly increased

by the RM [12 211] In contrast patients with focal lungmorphology were at risk of significant hyperinflation duringthe RM with no improvement of arterial oxygenation

It has also been hypothesized that the effects of PEEPmay depend on lung morphology Puybasset et al assessedthe responses to PEEP among patients with focal or nonfocalARDS [210] The regional distribution of intrapulmonarygas and lung tissue influences the effects of PEEP in ARDSpatients maximal alveolar recruitment without evidenceof overdistension was observed in patients with nonfocalARDS Nevertheless PEEP induced mild alveolar recruit-ment in patients with focal ARDS along with overdistensionof previously aerated lung regions

Interestingly phenotyping patients with ARDS basedon their lung morphology might be possible by measuringplasma sRAGEwith commercially available kits even thoughthese findings need further validation [100 112] HoweverRAGE pathway is a promising candidate for subphenotypingpatients with ARDS as it is believed to play a major rolein the mechanisms leading to AFC and their regulation[110] Recent findings that support a relationship betweenimpaired AFC and lung morphology may therefore fill a gapin the full recognition of an ARDS phenotype based on lungmorphology that could be linked to an endotype of impairedAFC and activated RAGE pathway [12 100 101 112 113 212]

43 Biomarkers in ARDS Can They Improve Patient CareBiomarkers are broadly used in critically ill patientsespecially during inflammatory andor infectious diseasesBiomarkers have been commonly defined as characteristicsthat are objectively measured and evaluated as indicatorsof normal biological processes pathogenic processes orpharmacologic responses to therapeutic interventions [213214] Biomarkers provide a powerful approach to understanda disease with multiple applications in observational andanalytic epidemiology randomized clinical trials screeningand diagnosis or prognosis [215]

Nevertheless there are important technical attributes fora relevant biomarker First the marker must be present inperipheral body tissue andor fluid (eg blood urine salivabreath or cerebrospinal fluid) second it must be easy todetect or quantify in assays that are both affordable androbust and third its regulation should be associated asspecifically as possible with damage of a particular tissuepreferably in a quantifiable manner Prior to the widespreaduse of a marker of interest it is essential that validation andconfirmation of candidate biomarkers by robust statisticalmethods are performed during biomarker discovery [215]Sensitivity and specificity are common quality parametersfor biomarkers Sensitivity describes the probability of apositive test in cases and specificity describes probability ofnegative test in controls An association between sensitivityand specificity is represented in the ROC curve by graphingsensitivity versus 100 minus specificity Area under the ROC curve(AUROC) is therefore a measure of performance of a markerThere is no absolute cutoff value of AUROC for robustness of

a marker but aminimum of 07 is required and values greaterthan 08 are good particularly in a heterogeneous critically illpatient population [216 217]

To summarize an ideal biomarker should indicate aclear relationship with the pathophysiologic event needsto be reliable reproducible disease specific and sensitiveand should be sampled by simple methods and relativelyinexpensive with little or no diurnal variation DuringARDS no single marker has been validated with all thesecriteria to date yet we believe that sRAGE may fulfill allprerequisites of a biomarker of ARDS First plasma sRAGEhas good diagnostic and prognostic values [96 99 100109 112] Second it is very well correlated with lung injuryseverity and specific pathophysiologic features of ARDS forexample alveolar fluid clearance and lung morphology [9699ndash101 109 112] Previous studies of the predictive value ofearly levels of sRAGE for the development of ARDS in ageneral population of patients admitted to the emergencydepartment were negative [130] but current research focuseson both the kinetics of sRAGE and esRAGE and RAGE genepolymorphisms as predictors of the development of ARDSin at-risk critically ill patients [114] Finally there is someevidence suggesting that monitoring sRAGE could informat least partially on therapeutic responses in patients with orwithout ARDS [24 99 113] If these data are confirmed byfuture studies such findingswould definitely help to reinforcesRAGE a real biomarker of ARDS

5 Conclusion

Biomarker research provides an important translational linkto our understanding of lung pathobiology Through theidentification and testing of candidate biomarkers we havegained insight into the pathogenic importance of endothelialand epithelial injury and have started to unravel the complexpathways that contribute to endothelial and epithelial celldysfunction inflammation fibrosis and apoptosis in ARDSIn addition biomarker studies may help us to explore thecellular and molecular mechanisms of various therapeuticstrategies for ARDS and to better understand the potentialproinflammatory effects of mechanical ventilation Giventhe clinical heterogeneity of patients with ARDS and thecomplexity of the underlying pathobiology it is unlikely thata single biomarker will emerge for ARDS as cardiac-specifictroponin did for myocardial infarction but the develop-ment of small biomarker panels reflecting each importantlung injury pathway would provide valuable predictive andprognostic information for both clinicians and investigatorsWhile biomarkers are currently not recommended for usein clinical practice in ARDS biomarker discovery mayhold significant promise in order to develop and applytargeted therapies and to identify candidates for enrollmentin patient-tailored clinical trials of novel therapies for ARDS

Disclosure

The funders had no influence on the study design conductand analysis or on the preparation of this paper

Disease Markers 13

Conflict of Interests

No conflict of interests other sources of financial supportcorporate involvement patent holdings and so forth are tobe declared for all authors

Authorsrsquo Contribution

Raiko Blondonnet was involved in the conception and designof the review in writing the paper and in its revision priorto submission Jean-Michel Constantin was involved in theconception and design of the review in writing the paperand in its revision prior to submission Vincent Sapin wasinvolved in the conception and design of the review inwriting the paper and in its revision prior to submissionMatthieu Jabaudon takes responsibility for the content ofthe paper and was involved in the conception and design ofthe review in writing the paper and in its revision prior tosubmission

Acknowledgments

This work was supported by grants from the AuvergneRegional Council (ldquoProgramme Nouveau Chercheur de laRegion Auvergnerdquo 2013) the french Agence Nationale de laRecherche and the Direction Generale de lrsquoOffre de Soins(ldquoProgramme de Recherche Translationnelle en Santerdquo ANR-13-PRTS-0010)

References

[1] VM Ranieri G D Rubenfeld P TThompson et al ldquoAcute res-piratory distress syndrome the Berlin definitionrdquo The Journalof the American Medical Association vol 307 no 23 pp 2526ndash2533 2012

[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000

[3] C Brun-Buisson C Minelli G Bertolini et al ldquoEpidemiologyand outcome of acute lung injury in European intensive careunitsrdquo Intensive Care Medicine vol 30 no 1 pp 51ndash61 2004

[4] G D Rubenfeld E Caldwell E Peabody et al ldquoIncidence andoutcomes of acute lung injuryrdquo The New England Journal ofMedicine vol 353 no 16 pp 1685ndash1693 2005

[5] D W Dowdy M P Eid C R Dennison et al ldquoQuality oflife after acute respiratory distress syndrome a meta-analysisrdquoIntensive Care Medicine vol 32 no 8 pp 1115ndash1124 2006

[6] C S Calfee M D Eisner L B Ware et al ldquoTrauma-associatedlung injury differs clinically and biologically from acute lunginjury due to other clinical disordersrdquo Critical Care Medicinevol 35 no 10 pp 2243ndash2250 2007

[7] C S Calfee D R Janz G R Bernard et al ldquoDistinct molecularphenotypes of direct versus indirect ARDS in single and multi-center studiesrdquo Chest vol 147 no 6 pp 1539ndash1548 2015

[8] P Tejera N J Meyer F Chen et al ldquoDistinct and replicablegenetic risk factors for acute respiratory distress syndromeof pulmonary or extrapulmonary originrdquo Journal of MedicalGenetics vol 49 no 11 pp 671ndash680 2012

[9] M A Matthay G A Zimmerman C Esmon et al ldquoFutureresearch directions in acute lung injury summary of a National

Heart Lung and Blood Institute Working Grouprdquo AmericanJournal of Respiratory and Critical Care Medicine vol 167 no7 pp 1027ndash1035 2003

[10] J P Reilly S Bellamy M G S Shashaty et al ldquoHeterogeneousphenotypes of acute respiratory distress syndrome after majortraumardquo Annals of the American Thoracic Society vol 11 no 5pp 728ndash736 2014

[11] L Puybasset P Cluzel N Chao et al ldquoA computed tomographyscan assessment of regional lung volume in acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol158 no 5 pp 1644ndash1655 1998

[12] J-M Constantin S Grasso G Chanques et al ldquoLungmorphol-ogy predicts response to recruitment maneuver in patients withacute respiratory distress syndromerdquo Critical Care Medicinevol 38 no 4 pp 1108ndash1117 2010

[13] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoSubphenotypes in acute respiratorydistress syndrome latent class analysis of data from tworandomised controlled trialsrdquoThe Lancet Respiratory Medicinevol 2 no 8 pp 611ndash620 2014

[14] R Marshall G Bellingan and G Laurent ldquoThe acute respira-tory distress syndrome fibrosis in the fast lanerdquoThorax vol 53no 10 pp 815ndash817 1998

[15] R B Henderson J A R Hobbs M Mathies and N HoggldquoRapid recruitment of inflammatory monocytes is independentof neutrophil migrationrdquo Blood vol 102 no 1 pp 328ndash3352003

[16] HMMarriott andDH Dockrell ldquoThe role of themacrophagein lung disease mediated by bacteriardquo Experimental LungResearch vol 33 no 10 pp 493ndash505 2007

[17] L J M Cross and M A Matthay ldquoBiomarkers in acute lunginjury insights into the pathogenesis of acute lung injuryrdquoCritical Care Clinics vol 27 no 2 pp 355ndash377 2011

[18] H K Gaggin and J L Januzzi ldquoBiomarkers and diagnostics inheart failurerdquo Biochimica et Biophysica Acta (BBA)mdashMolecularBasis of Disease vol 1832 no 12 pp 2442ndash2450 2013

[19] E Christenson and R H Christenson ldquoThe role of cardiacbiomarkers in the diagnosis and management of patientspresenting with suspected acute coronary syndromerdquo Annals ofLaboratory Medicine vol 33 no 5 pp 309ndash318 2013

[20] L B Ware T Koyama Z Zhao et al ldquoBiomarkers of lungepithelial injury and inflammation distinguish severe sepsispatientswith acute respiratory distress syndromerdquoCritical Carevol 17 no 5 article R253 2013

[21] M A Matthay L B Ware and G A Zimmerman ldquoTheacute respiratory distress syndromerdquo The Journal of ClinicalInvestigation vol 122 no 8 pp 2731ndash2740 2012

[22] M Shirasawa N Fujiwara S Hirabayashi et al ldquoReceptor foradvanced glycation end-products is a marker of type I lungalveolar cellsrdquo Genes to Cells vol 9 no 2 pp 165ndash174 2004

[23] M Neeper A M Schmidt J Brett et al ldquoCloning andexpression of a cell surface receptor for advanced glycosylationend products of proteinsrdquo The Journal of Biological Chemistryvol 267 no 21 pp 14998ndash15004 1992

[24] M Jabaudon E Futier L Roszyk V Sapin B Pereira andJ Constantin ldquoAssociation between intraoperative ventilatorsettings and plasma levels of soluble receptor for advancedglycation end-products in patients without pre-existing lunginjuryrdquo Respirology vol 20 no 7 pp 1131ndash1138 2015

[25] L G Dobbs R F Gonzalez L Allen and D K Froh ldquoHTI56an integral membrane protein specific to human alveolar type

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

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Disease Markers

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Disease Markers 7

as compared to controls [84 148 149] In order to betterunderstand such differences between plasma and alveolarexpression of VEGF Ware et al conducted a study with theaim to determine whether changes in alveolar levels of VEGFwere specific to ARDS or not [39] the authors found thatalveolar levels of VEGF were decreased in both patients withARDS and those with hydrostatic edema The mechanismsimplicated in this alveolar decrease in VEGF during ARDSmight not depend on the degree of lung injury but rather onthe degree of alveolar flooding [39]

(e) vWF Early studies of endothelial markers focused on vonWillebrand Factor (vWF) a macromolecular antigen that isproduced predominantly by endothelial cells and to a lesserextent by platelets In the setting of endothelial activationor injury vWF is released from preformed stocks into thecirculation [40 41] VWFhas been investigated as a biologicalmarker of endothelial injury in patients both at-risk forARDSand with established ARDS [40 150] In a prospective studyof 45 ICU patients with sepsis patients with nonpulmonarysepsis had higher levels of plasma vWF with good predictiveand prognostic values for ARDS Indeed elevated plasmalevels of vWF had a sensitivity of 87 and a specificity of77 for the prediction of ARDS development in the settingof nonpulmonary sepsis [151] However subsequent studiesin patients at-risk for ARDS did not confirm these findings[42 152 153] In another study of 559 patients with ARDSenrolled in the National Heart Lung and Blood InstituteARDS Network trial of lower tidal volume nonsurvivorshad higher plasma levels of vWF compared to survivors[40] Higher vWF levels were significantly associated withfewer organ failure-free days suggesting that the degree ofendothelial activation and injury is strongly associated withoutcomes in ARDS nevertheless ventilator settings had noimpact on vWF levels in this study [40]

(f) Lung ExtracellularMatrixThe extracellularmatrix (ECM)forms the region of the lung situated between the alveo-lar epithelium and the vascular endothelium ECM playsa mechanical role as it supports and maintains tissularstructures ECM also represents a complex and dynamicmeshwork influencing many biological cell functions such asdevelopment proliferation and migration [154] Collagensare the main component of ECM along with glycoproteinsand proteoglycans including hyaluronic acid

Laminin Laminins (LM) are ECM proteins with high molec-ular weights that deposit in basal membranes Lamininsare involved in cell processes such as cellular adhesiongrowth and differentiation [43] Laminin-5 (LM-5) plays animportant role in cell migration and in the remodeling ofepithelial tissue LM-5 is activated through its cleavage bymatrix metalloproteinases (MMPs) thus releasing a solubleLN 1205742 NH2-terminal fragment (G2F) that does not depositin the ECM and can therefore be detected in the peripheralblood In a small single center study lamininwasmeasured inthe plasma and lung edema fluid from 17 patients with ARDSwith higher levels found in patients with ARDS as comparedto healthy volunteers [44] Interestingly nonsurvivors had

higher plasma levels of laminin as measured 5 days afterARDS onset than survivors and survivors had decreasinglevels of the marker over time suggesting that its secretionis suppressed during ARDS recovery

ElastinDesmosine Elastin is another critical protein of theECM that gives the lung its elastic recoil ability In adultselastin which is expressed by lungs and other tissues isusually excreted in the urine During lung epithelial andendothelial injury elastin can be broken down by proteasessuch as neutrophil elastase [45] Elastin breakdown results insmaller fragments containing desmosine and isodesmosine[155] In a large study of 579 patients with ARDS thoseventilated with lower tidal volumes had lower urine desmo-sine levels a finding that may reflect reduced extracellularmatrix breakdown however no correlation with mortalitywas found in patients with ARDS [46]

MMPs Matrix metalloproteinases (MMPs) are zinc-depend-ent endopeptidases that are able to degrade almost allextracellular matrix components MMP-8 a member of theleukocyte-derived MMPs contributes to the degradationturnover and remodeling of the extracellular matrix digest-ing type I collagen [47 48] MMPs are major actors inalmost all phases of the inflammatory response and theirfunction is highly regulated At the tissue level most impor-tant inhibitors are the tissue inhibitors of metalloproteinases(TIMPs) In fulminant inflammation the inhibitory capacityof TIMPs may be overwhelmed leading to excessive tissuedamage and adverse outcome [47] Previous studies suggestthat MMPs may have an important role in ARDS althoughthis role may be either harmful or beneficial [156 157] In arecent study despiteMMP-8 levels did not predict outcome inARDS patients higher levels of TIMP-1 were independentlyassociated with increased 90-day mortality in a large groupof critically ill mechanically ventilated patients [47] Thesefindings are in contradiction to those from a study inpediatric ARDS patients in which higher MMP-8 and activeMMP-9 levels as measured 48 hours after disease onset wereassociated with longer durations of mechanical ventilationand fewer ventilator-free days [158] ElevatedMMP-2 MMP-8 and MMP-9 in the BAL fluid from ARDS patients wereassociated with patterns of acute inflammation but with pooroutcome [157] Interestingly MMP-3 and MMP-13 may beprotective against lung injury by cleaving transmembranereceptor RAGE into sRAGE thus regulating RAGE activationby its ligands [48 49]

312 Inflammatory Cascades During ARDS inflammatoryresponses can either be related to an ongoing primaryinfectious stimulus such as pneumonia or to systemic inflam-mation such as in sepsis or in pancreatitis [2] The inflam-matory cascade involves inflammatory cells and the releaseof inflammatory mediators as driven by a complex networkof cytokines A comparison between blood and alveolarcytokines suggests that most inflammatory mediators orig-inate from the lung [17] Alarmins or damage-associatedmolecular patterns (DAMPs) are released by dead cells orlocal inflammatory cells (eg alveolar macrophages) They

8 Disease Markers

activate and recruit immune cells via binding to differentreceptors such as TLR IL-1 receptor (IL-1R) or RAGEthereby initiating and perpetuating multiple proinflamma-tory pathways [21 159]

Regulation of the inflammatory response is a complexprocess that requires interplay between several immunemediators [160] Both pro- and anti-inflammatory biomark-ers have been studied in ARDS

(1) Proinflammatory Cytokines

(a) IL-1120573 and TNF-120572 IL-1120573 and TNF-120572 are the most biolog-ically potent cytokines secreted by activated macrophages inthe early phase of ARDS They cause the release of a varietyof proinflammatory chemokines such as monocyte chemo-tactic protein-1 (MCP-1) macrophage inflammatory protein-1120572 (MIP-1120572) IL-6 and IL-8 with subsequent recruitmentof inflammatory cells into the air spaces alteration of theendothelial-epithelial barrier permeability and impairmentof fluid transport leading to alveolar edema [17] TNF-120572 alsopromotes lung edema indirectly through the production ofreactive oxygen species (ROS) and a decreased expressionof epithelial sodium (ENaC) and Na+-K+-ATPase channels[161] Finally TNF-120572 a potent chemoattractant for fibrob-lasts is a promoter of lung fibrosis in experimental studies[162 163] Interestingly the ratio of BAL to serum levelsof both TNF-120572 and IL-1120573 is typically high suggesting thatsuch cytokines may originate from the lung in the settingof ARDS [164] Persistent elevation of plasma and BAL IL-1120573 is associated with worse outcome [165 166] Both TNF-120572 and IL-1120573 are elevated in the plasma and BAL fluid frompatients at risk of and with ARDS [164 167] and associatedwith mortality [166]

(b) IL-18 Inflammasomes are intracellular macromolecularcomplexes that serve as platforms for the activation of theproinflammatory enzyme caspase-1 which in turn cleavespro-IL-1120573 and pro-IL-18 into IL-1120573 and IL-18 [50] Theseinflammasome-activated cytokines play central roles in thepropagation of the acute inflammatory response IL-18 andcaspase-1 play critical roles in the development of lunginjury and higher levels of IL-18 are correlated with diseaseseverity and mortality in patients with ARDS [168] Among38 patients with acute respiratory failure those with ARDShad significantly higher serum levels of IL-18 and serum IL-18 was significantly higher in nonsurvivors [51]

(c) IL-6 IL-6 is produced by a wide range of cells includingmonocytesmacrophages endothelial cells fibroblasts andsmoothmuscle cells in response to stimulation by endotoxinIL-1120573 and TNF-120572 [52] IL-6 is one of the most importantmediators of fever and is critical for B-cell differentiation andmaturation with secretion of immunoglobulins cytotoxic Tcell differentiation macrophage and monocyte function andproduction of acute phase proteins Although IL-6 activatesboth proinflammatory and anti-inflammatory mechanismsIL-6 primarily correlates with a proinflammatory profileduring the early phase of ARDS Plasma IL-6 increases earlyin patients at risk of developing ARDS [53] IL-6 is elevated in

both plasma and BAL fluid during ARDS [59] and correlateswith mortality [54 55]

(d) IL-8 IL-8 is a proinflammatory cytokine with a role inneutrophilmonocyte chemotaxis and neutrophil apoptosisinhibitionHighplasma andBAL levels of IL-8 are found earlyduring ARDS and predict outcome [169] However previousstudies did not support such findings [170 171] In a recentmonocenter study of 100 patients only baseline IL-8 (among6 other biomarkers) was associated with the development ofmultiorgan failure even after adjustment for other relevantvariables [32] Also several studies have evaluated the roleof the anti-IL-8 autoantibodyIL-8 immune complexes inARDS a pathway that could lead to the identification of novelbiomarkers and therapeutic targets [17 172ndash175]

In a recent study Calfee et al used latent class analysisto integrate both clinical and biological data to identifytwo ARDS endotypes in an analysis of 1022 patients fromtwo ARDSNet trials (ARMA and ALVEOLI) [13] A firstendotype was categorized by more severe inflammation asassessed by both IL-6 and IL-8 levels and worse clinicaloutcomes whereas a second endotype had less inflammationless shock and better clinical outcomes Based on the datafrom the ALVEOLI trial a ldquoproinflammatoryrdquo endotypewas associated with higher mortality and better response tohigher levels of positive end-expiratory pressure [176]

(2) Anti-Inflammatory Cytokines The inflammatory responseis also strongly influenced by anti-inflammatory systemsincluding nonspecific (eg 2-macroglobulin IL-10) andspecific (eg IL-1 receptor antagonist (IL-1RA) antagonistssoluble IL-1 receptor II (sIL-1RII) soluble TNF receptorI (sTNF-RI) and soluble TNF receptor II (sTNF-RII)) ofproinflammatory cytokines

(a) IL-1RA Circulating IL-1RA levels are increased but donot predict the development of ARDS in at-risk patients[56] Studies of gene expression in alveolar macrophagesand circulating leukocytes from healthy control subjects andpatients with ARDS revealed that sIL-1RII may be valuable asa biomarker because of increased levels in both the lung andcirculation during ARDS [57]

(b) sTNF-RIsTNF-RII Soluble TNF-120572 receptors (sTNF-R)I and II can bind TNF and compete with its binding tothe cellular receptor thus reducing its bioavailability SolubleTNF-RI and TNF-II are associated with morbidity andmortality in patients with ARDS [54] and a strategy of lowtidal volume ventilation is associated with decreased sTNF-RI levels [54] Trauma-associated ARDS differs clinically andbiologically from ARDS due to other clinical disorders withlower levels of sTNF-RI patients with trauma as a primarycause of ARDS [6 58]

(c) IL-10 Interleukin-10 (IL-10) is an anti-inflammatorycytokine that is produced by several cells including B lym-phocytes monocytes and alveolar macrophages [60] Asidefrom inhibiting the production of IL-1 and TNF-120572 IL-10

Disease Markers 9

upregulates TNF receptors [177] and stimulates the produc-tion of the naturally occurring IL-1RAand the release of sTNFreceptors [178] IL-10 inhibits the production of proinflam-matory mediators by alveolar macrophages involved duringARDS [179] ARDS patients have lower plasma and BALlevels of IL-10 than at-risk patients who did not develop thesyndrome [61] Higher baseline IL-10 levels were associatedwith higher morbidity and mortality [59]

(3) Additional Markers Other markers with potential clinicalimportance in ARDS-associated inflammation have beenidentified as putative biomarkers during ARDS

High mobility group box nuclear protein 1 (HMGB1) is aDNAnuclear binding protein that is secreted by immune cellsincluding monocytes and macrophages HMGB1 increasesearly after severe trauma and correlates with systemic inflam-matory response and development of ARDS [62] Alveolarand plasma levels of HMGB1 (as measured in the arterial orcentral venous blood) are elevated in patients with ARDS andassociated with outcome [109] In 20 patients with ARDSplasma levels of HMGB1 were also higher in nonsurvivorsand correlated with levels of sRAGE [63]

Lipopolysaccharide binding protein (LBP) is an acutephase protein that is correlated with lung inflammationduring ARDS [64] More recently it has also been demon-strated that serum levels of LBPwere strongly associated withincreasedmortality and the development of ARDS in patientswith severe sepsis [65]

Nitric oxide (NO) is a marker of oxidative stress thathas also been investigated as a marker of ARDS In patientswith persistent ARDS higher levels of nitric oxide andof its end-products (eg nitrotyrosine) are associated withmortality [66] In contrast higher urine NO levels werestrongly associated with better clinical outcomes includingmortality and ventilator-free days in patients enrolled in theARDSNet low tidal volume trial [46] Extracellular citrullinethe effective precursor of NO is lower in the plasma frompatients with severe sepsis and lower plasma citrulline isassociated with the presence of ARDS [67] Mechanismsinvolved in the regulation of lung injury by NO-dependentpathways remain unknown

Although C-reactive protein (CRP) is widely consideredas a marker of systemic inflammation higher levels of CRPare associated with better outcome among patients withARDS [68] Nevertheless a recent study found that albuminlevels rather than CRP may help to predict and monitor theseverity and course of ARDS in febrile critically ill patientswith ARDS or at risk for the syndrome [69] In the samestudy levels of lactate dehydrogenase (LDH) predicted 28-day mortality but were not correlated with severity [69]

313 Coagulation and Fibrinolysis During early ARDS acti-vation of the inflammatory cascades results in the activationof the coagulation system which in turn can influenceinflammatory responses by affecting the expression of variouscytokines such as IL-1 IL-6 and IL-8 Activation of coagula-tion pathways induces migration of inflammatory cells intoalveoli through the endothelial and epithelial barriers and

generates thrombin formation In addition proinflammatoryevents may also inhibit fibrinolysis and induce platelet acti-vation [17]

Extravascular fibrin deposition when localized predomi-nantly in the alveolar compartment is found in several acuteinflammatory lung diseases and enhanced alveolar procoag-ulant activity is reported inARDS patients [180] Fibrin depo-sition may be beneficial for gas exchange by sealing leakagesites when lung capillary endothelial and epithelial barriersare disrupted Nevertheless fibrin alveolar deposition maybe harmful since it can lead to activation of neutrophilsand fibroblasts endothelial injury loss of surfactant activityfavoring alveolar collapse impaired alveolar fluid clearanceand thrombotic obstruction of the microcirculation [180]

(1) PAI-1 The balance between activation of coagulationand activation of fibrinolysis is an important determinantof the amount and duration of fibrin deposition duringlung injury Plasminogen activator (PA) and plasminogenactivator inhibitor-1 (PAI-1) regulate fibrinolysis through theconversion of plasminogen to plasmin a fibrinolytic enzymePA-1 is amajor endogenous inhibitor of PA Both PA and PA-1are secreted by various cells including macrophages fibrob-lasts and lung endothelial and epithelial cells [71] DuringARDS alveolar epithelial cells and activated macrophagesoverexpress PAI-1 thus contributing to decreased alveolarfibrinolytic activity Nevertheless the value of PAI-1 asa biomarker in ARDS remains controversial PAI-1 levelswere higher in patients with ARDS than in patients withhydrostatic lung edema [72] and higher PAI-1 levels areassociated withmortality and higher durations ofmechanicalventilation in patients with ARDS [72 169] In a large Finnishstudy PAI-1 levels were not correlated with mortality ordevelopment of ARDS in critically ill patients undermechan-ical ventilation but low baseline plasma levels of the solubleurokinase plasminogen activator receptor (suPAR) were pre-dictive of survival [181] In a secondary analysis of two largerandomized controlled trials PAI-1 was associated with lunginjury (as defined as decreased oxygenation index) but notwithmortality [28] Nevertheless in another study of patientsfrom the ARDSNet ARMA study higher levels of PAI-1were independently associated with higher mortality andclinical outcomes including organ failure [182] Howeverthis association between PAI-1 levels and the development ofmultiorgan failure was not confirmed in a recent study of 100ARDS patients [32]

(2) Protein C Protein C system is an important endogenousregulator of coagulation and fibrinolysis Protein C is synthe-sized by the liver and circulates as an inactive compoundIt is transformed to its active form on cell surface by thethrombomodulin- (TM-) thrombin complex [75 76] Theendothelial cell protein C receptor (EPCR) is another cellsurface protein that can further enhance protein activationby binding the TM-thrombin complex [183] In additionto suppressing thrombin formation activated protein C hasanti-inflammatory properties such as decreasing the levelsof proinflammatory cytokines [184] Protein C can improveendothelial permeability and exert antiapoptotic effects via

10 Disease Markers

p53 pathways [185] Activated protein C can also inactivatePAI-1 thus promoting fibrinolysis [186] Plasma protein Cwas significantly lower in patients with ARDS as comparedto controls and it was associated with worse clinical out-comes including higher hospital mortality shorter durationof unassisted ventilation and increased risk ofmultiple organfailure [73] In a larger cohort of patients with early ARDSlow plasma levels of protein C were again associated withmortality and adverse clinical outcomes [182] Decreasedlevels of protein C during ARDS suggest a link betweenhypercoagulability and mortality

(3) Thrombomodulin Thrombomodulin (TM) is a mul-tidomain transmembrane-bound glycoprotein found on thesurface of endothelial cell Its main role is to neutralize theprocoagulant effects of thrombin and accelerate activationof protein C In addition to its membrane-bound form TMalso exists as a circulating soluble isoform in the plasmaIn patients with ARDS levels of soluble thrombomodulin(sTM) are higher in the pulmonary edema fluid than inplasma [73] suggesting an alveolar source but no correlationwas found between plasma sTM and the development ofARDS yet higher levels of sTM were observed in patientsat high risk for ARDS In patients with established ARDShigher plasma and alveolar levels of sTM were correlatedwith severity of illness and multiple organ failure [73] Ina larger analysis of 449 patients elevated levels of plasmasTM were associated with increased mortality thus possiblyreflecting an increased degree of inflammation and both lungand systemic endothelial damage [74]

(4) Tissue Factor (TF) Tissue factor (TF) is a 47 kDa trans-membrane glycoprotein that is the most potent stimulator ofthe extrinsic coagulation cascade TF initiates the coagulationcascade by binding and allosterically activating coagulationfactor VIIa The resulting TF-VIIa complex binds the sub-strate coagulation factor X via multiple interactions alongan extended interface to produce the TF-VIIa-X complexThis complex leads eventually to thrombin formation andfibrin deposition [77] Levels of TF in lung edema fluid arehigher than plasma levels in patients with ARDS supportinga lung origin for TF in this setting and both plasma andalveolar levels of TF are higher in ARDS patients as comparedto patients with hydrostatic edema [187] Notably patientswith sepsis-induced ARDS may have higher levels of TF ascompared to patients without ARDS [78]

(5) Cell-Free Hb Levels of cell-free hemoglobin (Hb) arehigher in the air space of ARDS patients as comparedto critically ill patients with hydrostatic lung edema [79]Instillation of red blood cells or cell-free hemoglobin causeslung injury in rats [188] and intra-alveolar hemorrhage isassociated with high levels of intra-alveolar cell-free Hbmore severe lung injury and increased lipid peroxidationin the lung from mice with tissue factor deficiency [79]Precise cellular and molecular mechanisms by which cell-free hemoglobin in the air space could mediate or potenti-ate ARDS are currently under investigation [189] Cell-freeHb could activate chemokine release within the lung and

decompartmentalization of hemoglobin is likely to provide asignificant proinflammatory stimulus in the setting of diffusealveolar damage and hemorrhage during ARDS [80]

314 EFPL Protein Ratio The pathophysiology of ARDSincludes disruption of several physical barriers includingendothelial and epithelial cell layers the basement mem-brane and the extracellularmatrix resulting in increased pul-monary microvascular permeability The pulmonary edemafluid-to-plasma protein (EFPL) ratio is a rapid safe andnoninvasive measure of alveolar-capillary membrane per-meability The EFPL ratio was first proposed as a tool todetermine the etiology of acute pulmonary edema [81] Morerecently in a large study of 390 critically ill patientsWare et aldemonstrated that the EFPL ratio had an excellent discrimi-native value in distinguishing ARDS from hydrostatic edemaand was strongly associated with clinical outcomes Using acutoff of 065 the EFPL ratio had a sensitivity of 81 and aspecificity of 81 for the diagnosis of ARDS [82]

32 Fibroproliferative Phase of ARDS In some patientsimportant and persistent accumulation of macrophagesfibrocytes fibroblasts and myofibroblasts in the alveolarcompartment leads to excessive deposition of ECM com-ponents including fibronectin and collagen types I and IIIamong other proteins An imbalance between profibrotic andantifibrotic mediators may subsequently drive this fibropro-liferative response [190] Growth factors play a major rolein the resolution of ARDS [17] Lung endothelial repair ispromoted by vascular endothelial growth factor (VEGF)A variety of growth factors promote repair of the alveo-lar epithelium including keratinocyte growth factor (KGF)hepatocyte growth factor (HGF) fibroblast growth factor(FGF) and transforming growth factor-120572 (TGF-120572) [17] Twomajor pathways with opposite effects involve growth factorsduring ARDS tyrosine kinase receptor mediation (eg KGFHGF FGF and VEGF) and serine-threonine kinase receptorssuch as TGF-1205731 which tend to have opposed effect on theupregulation that occurs when the tyrosine kinase receptorpathway is involved [85 191 192]

321 Endothelial Proliferation Novel evidence points to apotential role of VEGF in promoting repair of the alveolar-capillarymembrane during recovery fromARDS and under-standing the role of VEGF in this disease process couldbe crucial for developing new therapeutic strategies [85193] In the lung VEGF is produced primarily by epithelialcells it increases microvascular permeability [83] but has animportant role also during the repair phase by stimulatingendothelial cell proliferation and survival [86 149] Thelevels of VEGF are increased in plasma from patients withARDS but are decreased in BAL fluid compared to healthycontrols subsequently BAL levels of VEGF increase duringthe resolution of lung injury [39 84 149]

322 Epithelial Proliferation and Apoptosis KGF also knownas FGF-7 is a potent mitogenic factor for alveolar epithelialcells that is primarily produced by fibroblasts and other

Disease Markers 11

cells such as T lymphocytes KGF regulates transepithelialtransport of sodium by stimulating the epithelial channelNa+-K+-ATPase in alveolar epithelial cells [87]

HGF is a nonspecific mitogen secreted by fibroblastsalveolar macrophages endothelial cells and epithelial cellsSeveral animal and human studies suggest that KGF andHGFcould protect the alveolar space against injury and couldfacilitate the repair of alveolar structures after injury [88 194195] KGF levels could be measured in the BAL from patientswith ARDS but not in the BAL from those without ARDS inaddition BALKGFwas associated with poor prognosis [196]Elevated HGF levels were also associated with outcome [196]In 36 patients with ARDS and 11 patients with hydrostaticlung edema HGF and KGF were proven biologically activein the edema fluid of patients with ARDS and higher levelsof HGFwere associated withmortality in these patients [197]

Apoptosis of alveolar epithelial cells is a major phe-nomenon in the initiation and perpetuation of lung injury[89] The FasFasL system plays an important role in theregulation of cell life and death through its ability to initiateapoptosis [198] This system combines the cell membranesurface receptor Fas (CD95) and its natural ligand FasL(CD95L) Membrane-bound FasL mediates lymphocyte-dependent cytotoxicity clonal deletion of alloreactive T cellsand activation-induced suicide of T cells [199] Its solubleform (sFasL) results from cleavage of membrane FasL byMMPs and induces apoptosis in susceptible cells [200]Apoptosis is inducedwhenmembrane-bound or soluble FasLbinds to Fas-bearing cells By contrast apoptosis is inhibitedwhen soluble Fas binds to either membrane-bound FasL orsFasL thus preventing FasL from interacting withmembrane-bound Fas receptors [201] In patients with ARDS sFasL wasdetectable in the lung before and after the onset of clinicallydefined ARDS and nonsurvivors had significantly higherBAL levels of sFasL on day 1 as compared with survivors[200] Both soluble Fas and soluble FasL were associated withoutcome and higher in the lung edema fluid from patientswith ARDS compared to control patients with hydrostaticpulmonary edema [202] Nevertheless recent findings sug-gested limited role for FasFasL system and apoptosis inairway epithelial cell death during ARDS [90]

323 Fibroblast Proliferation Pulmonary fibroblasts pro-duce procollagen III peptide (PCP-III) that is a precursorof collagen The NT part of procollagen III resulting fromthe enzymatic cleavage of procollagen by specific proteases inthe extracellular space is considered as a marker of collagensynthesis Alveolar levels of N-PCP-III are higher in ARDSpatient as compared with controls [203] The elevation ofN-PCP-III in pulmonary edema fluid begins within the first24 h of ARDS that is during the acute phase of increasedendothelial and epithelial permeability to protein suggestingthat fibrosing alveolitis could begin very early in the course ofclinical ARDS [203] In another study high levels of N-PCP-III were early predictors of poor outcome [204 205] Morerecently Forel et al measured alveolar N-PCP-III in patientswith nonresolving ARDS thus identifying patients who haddeveloped lung fibroproliferation [206] Unfortunately it

is still unknown whether N-PCP-III measurements couldbe useful in selecting patients who would benefit fromglucocorticoid therapy among others to reduce the ARDS-associated lung fibrosis [207]

4 Perspectives

41 Combining Biomarkers Despite advances in the identi-fication of biomarker candidate and better understanding ofARDS pathogenesis no single clinical or biological markerreliably predicts clinical outcomes inARDSThe combinationof clinical and biological marker is attractive in order toimprove the sensitivity andor the specificity of the testespecially through a recent approach aimed at measuring8 biological markers that reflect endothelial and epithelialinjury inflammation and coagulation vWF SP-D TNF-R1IL-6 IL-8 ICAM-1 protein C and PAI-1 in 549 patientsenrolled in the the ARDSNet trial of low versus high positiveend-expiratory pressure [208] Clinical predictors predictedmortality with an area under the ROC curve (AUC) of082 whereas a combination of these 8 biomarkers and theclinical predictors had an AUC of 085 The best performingbiomarkers were the neutrophil chemotactic factor IL-8 andSP-D a product of AT2 cells [208] supporting the conceptthat acute inflammation and alveolar epithelial injury areimportant pathogenetic pathways in human ARDS Morerecently a panel of biomarkers of lung epithelial injuryand inflammation (SP-D sRAGE IL-8 CC16 and IL-6)provided excellent discrimination for diagnosis of ARDSin patients with severe sepsis [20] Therefore and beyondtheir better diagnostic and prognostic values the use of suchbiomarker panels may be useful for selecting patients forclinical trials that are designed to reduce lung epithelial injury[113] Nevertheless whether a therapeutic strategy based onbiomarker measurements would benefit patient outcome hasnever been investigated

42 Lung Imaging as an ARDS Biomarker Studies of lungimaging during ARDS have revealed that adequate ventilatorsettings may vary among patients with the same syndromeIn a large study gas and tissue distribution in the lungs ofARDS patients were assessed using computed tomography(CT) and compared to those of healthy volunteers [11] Lungmorphology in ARDS is characterized by marked excess oflung tissue associated with a major decrease in aerated lungregions and in functional residual capacity Some patientswith ARDS exhibit preserved aeration of the upper lobesdespite the presence of an overall excess of lung tissue (ldquofocalrdquoARDS) as opposed to other patients with more diffuse lossof aeration and excessive lung tissue (ldquodiffuserdquo or ldquononfocalrdquoARDS) [209]

Lung morphology may influence the response to pos-itive end-expiratory pressure (PEEP) recruitment maneu-vers (RM) prone position and patient outcome [12 210]In a prospective study of nineteen patients with ARDSConstantin et al found that lung morphology at zero end-expiratory pressure could predict the response to a RM withcontinuous positive airway pressure of 40 cm H

2O for 40

12 Disease Markers

seconds Nonfocal morphology was associated with higherlung recruitability and PaO

2FiO2was significantly increased

by the RM [12 211] In contrast patients with focal lungmorphology were at risk of significant hyperinflation duringthe RM with no improvement of arterial oxygenation

It has also been hypothesized that the effects of PEEPmay depend on lung morphology Puybasset et al assessedthe responses to PEEP among patients with focal or nonfocalARDS [210] The regional distribution of intrapulmonarygas and lung tissue influences the effects of PEEP in ARDSpatients maximal alveolar recruitment without evidenceof overdistension was observed in patients with nonfocalARDS Nevertheless PEEP induced mild alveolar recruit-ment in patients with focal ARDS along with overdistensionof previously aerated lung regions

Interestingly phenotyping patients with ARDS basedon their lung morphology might be possible by measuringplasma sRAGEwith commercially available kits even thoughthese findings need further validation [100 112] HoweverRAGE pathway is a promising candidate for subphenotypingpatients with ARDS as it is believed to play a major rolein the mechanisms leading to AFC and their regulation[110] Recent findings that support a relationship betweenimpaired AFC and lung morphology may therefore fill a gapin the full recognition of an ARDS phenotype based on lungmorphology that could be linked to an endotype of impairedAFC and activated RAGE pathway [12 100 101 112 113 212]

43 Biomarkers in ARDS Can They Improve Patient CareBiomarkers are broadly used in critically ill patientsespecially during inflammatory andor infectious diseasesBiomarkers have been commonly defined as characteristicsthat are objectively measured and evaluated as indicatorsof normal biological processes pathogenic processes orpharmacologic responses to therapeutic interventions [213214] Biomarkers provide a powerful approach to understanda disease with multiple applications in observational andanalytic epidemiology randomized clinical trials screeningand diagnosis or prognosis [215]

Nevertheless there are important technical attributes fora relevant biomarker First the marker must be present inperipheral body tissue andor fluid (eg blood urine salivabreath or cerebrospinal fluid) second it must be easy todetect or quantify in assays that are both affordable androbust and third its regulation should be associated asspecifically as possible with damage of a particular tissuepreferably in a quantifiable manner Prior to the widespreaduse of a marker of interest it is essential that validation andconfirmation of candidate biomarkers by robust statisticalmethods are performed during biomarker discovery [215]Sensitivity and specificity are common quality parametersfor biomarkers Sensitivity describes the probability of apositive test in cases and specificity describes probability ofnegative test in controls An association between sensitivityand specificity is represented in the ROC curve by graphingsensitivity versus 100 minus specificity Area under the ROC curve(AUROC) is therefore a measure of performance of a markerThere is no absolute cutoff value of AUROC for robustness of

a marker but aminimum of 07 is required and values greaterthan 08 are good particularly in a heterogeneous critically illpatient population [216 217]

To summarize an ideal biomarker should indicate aclear relationship with the pathophysiologic event needsto be reliable reproducible disease specific and sensitiveand should be sampled by simple methods and relativelyinexpensive with little or no diurnal variation DuringARDS no single marker has been validated with all thesecriteria to date yet we believe that sRAGE may fulfill allprerequisites of a biomarker of ARDS First plasma sRAGEhas good diagnostic and prognostic values [96 99 100109 112] Second it is very well correlated with lung injuryseverity and specific pathophysiologic features of ARDS forexample alveolar fluid clearance and lung morphology [9699ndash101 109 112] Previous studies of the predictive value ofearly levels of sRAGE for the development of ARDS in ageneral population of patients admitted to the emergencydepartment were negative [130] but current research focuseson both the kinetics of sRAGE and esRAGE and RAGE genepolymorphisms as predictors of the development of ARDSin at-risk critically ill patients [114] Finally there is someevidence suggesting that monitoring sRAGE could informat least partially on therapeutic responses in patients with orwithout ARDS [24 99 113] If these data are confirmed byfuture studies such findingswould definitely help to reinforcesRAGE a real biomarker of ARDS

5 Conclusion

Biomarker research provides an important translational linkto our understanding of lung pathobiology Through theidentification and testing of candidate biomarkers we havegained insight into the pathogenic importance of endothelialand epithelial injury and have started to unravel the complexpathways that contribute to endothelial and epithelial celldysfunction inflammation fibrosis and apoptosis in ARDSIn addition biomarker studies may help us to explore thecellular and molecular mechanisms of various therapeuticstrategies for ARDS and to better understand the potentialproinflammatory effects of mechanical ventilation Giventhe clinical heterogeneity of patients with ARDS and thecomplexity of the underlying pathobiology it is unlikely thata single biomarker will emerge for ARDS as cardiac-specifictroponin did for myocardial infarction but the develop-ment of small biomarker panels reflecting each importantlung injury pathway would provide valuable predictive andprognostic information for both clinicians and investigatorsWhile biomarkers are currently not recommended for usein clinical practice in ARDS biomarker discovery mayhold significant promise in order to develop and applytargeted therapies and to identify candidates for enrollmentin patient-tailored clinical trials of novel therapies for ARDS

Disclosure

The funders had no influence on the study design conductand analysis or on the preparation of this paper

Disease Markers 13

Conflict of Interests

No conflict of interests other sources of financial supportcorporate involvement patent holdings and so forth are tobe declared for all authors

Authorsrsquo Contribution

Raiko Blondonnet was involved in the conception and designof the review in writing the paper and in its revision priorto submission Jean-Michel Constantin was involved in theconception and design of the review in writing the paperand in its revision prior to submission Vincent Sapin wasinvolved in the conception and design of the review inwriting the paper and in its revision prior to submissionMatthieu Jabaudon takes responsibility for the content ofthe paper and was involved in the conception and design ofthe review in writing the paper and in its revision prior tosubmission

Acknowledgments

This work was supported by grants from the AuvergneRegional Council (ldquoProgramme Nouveau Chercheur de laRegion Auvergnerdquo 2013) the french Agence Nationale de laRecherche and the Direction Generale de lrsquoOffre de Soins(ldquoProgramme de Recherche Translationnelle en Santerdquo ANR-13-PRTS-0010)

References

[1] VM Ranieri G D Rubenfeld P TThompson et al ldquoAcute res-piratory distress syndrome the Berlin definitionrdquo The Journalof the American Medical Association vol 307 no 23 pp 2526ndash2533 2012

[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000

[3] C Brun-Buisson C Minelli G Bertolini et al ldquoEpidemiologyand outcome of acute lung injury in European intensive careunitsrdquo Intensive Care Medicine vol 30 no 1 pp 51ndash61 2004

[4] G D Rubenfeld E Caldwell E Peabody et al ldquoIncidence andoutcomes of acute lung injuryrdquo The New England Journal ofMedicine vol 353 no 16 pp 1685ndash1693 2005

[5] D W Dowdy M P Eid C R Dennison et al ldquoQuality oflife after acute respiratory distress syndrome a meta-analysisrdquoIntensive Care Medicine vol 32 no 8 pp 1115ndash1124 2006

[6] C S Calfee M D Eisner L B Ware et al ldquoTrauma-associatedlung injury differs clinically and biologically from acute lunginjury due to other clinical disordersrdquo Critical Care Medicinevol 35 no 10 pp 2243ndash2250 2007

[7] C S Calfee D R Janz G R Bernard et al ldquoDistinct molecularphenotypes of direct versus indirect ARDS in single and multi-center studiesrdquo Chest vol 147 no 6 pp 1539ndash1548 2015

[8] P Tejera N J Meyer F Chen et al ldquoDistinct and replicablegenetic risk factors for acute respiratory distress syndromeof pulmonary or extrapulmonary originrdquo Journal of MedicalGenetics vol 49 no 11 pp 671ndash680 2012

[9] M A Matthay G A Zimmerman C Esmon et al ldquoFutureresearch directions in acute lung injury summary of a National

Heart Lung and Blood Institute Working Grouprdquo AmericanJournal of Respiratory and Critical Care Medicine vol 167 no7 pp 1027ndash1035 2003

[10] J P Reilly S Bellamy M G S Shashaty et al ldquoHeterogeneousphenotypes of acute respiratory distress syndrome after majortraumardquo Annals of the American Thoracic Society vol 11 no 5pp 728ndash736 2014

[11] L Puybasset P Cluzel N Chao et al ldquoA computed tomographyscan assessment of regional lung volume in acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol158 no 5 pp 1644ndash1655 1998

[12] J-M Constantin S Grasso G Chanques et al ldquoLungmorphol-ogy predicts response to recruitment maneuver in patients withacute respiratory distress syndromerdquo Critical Care Medicinevol 38 no 4 pp 1108ndash1117 2010

[13] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoSubphenotypes in acute respiratorydistress syndrome latent class analysis of data from tworandomised controlled trialsrdquoThe Lancet Respiratory Medicinevol 2 no 8 pp 611ndash620 2014

[14] R Marshall G Bellingan and G Laurent ldquoThe acute respira-tory distress syndrome fibrosis in the fast lanerdquoThorax vol 53no 10 pp 815ndash817 1998

[15] R B Henderson J A R Hobbs M Mathies and N HoggldquoRapid recruitment of inflammatory monocytes is independentof neutrophil migrationrdquo Blood vol 102 no 1 pp 328ndash3352003

[16] HMMarriott andDH Dockrell ldquoThe role of themacrophagein lung disease mediated by bacteriardquo Experimental LungResearch vol 33 no 10 pp 493ndash505 2007

[17] L J M Cross and M A Matthay ldquoBiomarkers in acute lunginjury insights into the pathogenesis of acute lung injuryrdquoCritical Care Clinics vol 27 no 2 pp 355ndash377 2011

[18] H K Gaggin and J L Januzzi ldquoBiomarkers and diagnostics inheart failurerdquo Biochimica et Biophysica Acta (BBA)mdashMolecularBasis of Disease vol 1832 no 12 pp 2442ndash2450 2013

[19] E Christenson and R H Christenson ldquoThe role of cardiacbiomarkers in the diagnosis and management of patientspresenting with suspected acute coronary syndromerdquo Annals ofLaboratory Medicine vol 33 no 5 pp 309ndash318 2013

[20] L B Ware T Koyama Z Zhao et al ldquoBiomarkers of lungepithelial injury and inflammation distinguish severe sepsispatientswith acute respiratory distress syndromerdquoCritical Carevol 17 no 5 article R253 2013

[21] M A Matthay L B Ware and G A Zimmerman ldquoTheacute respiratory distress syndromerdquo The Journal of ClinicalInvestigation vol 122 no 8 pp 2731ndash2740 2012

[22] M Shirasawa N Fujiwara S Hirabayashi et al ldquoReceptor foradvanced glycation end-products is a marker of type I lungalveolar cellsrdquo Genes to Cells vol 9 no 2 pp 165ndash174 2004

[23] M Neeper A M Schmidt J Brett et al ldquoCloning andexpression of a cell surface receptor for advanced glycosylationend products of proteinsrdquo The Journal of Biological Chemistryvol 267 no 21 pp 14998ndash15004 1992

[24] M Jabaudon E Futier L Roszyk V Sapin B Pereira andJ Constantin ldquoAssociation between intraoperative ventilatorsettings and plasma levels of soluble receptor for advancedglycation end-products in patients without pre-existing lunginjuryrdquo Respirology vol 20 no 7 pp 1131ndash1138 2015

[25] L G Dobbs R F Gonzalez L Allen and D K Froh ldquoHTI56an integral membrane protein specific to human alveolar type

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ObesityJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

8 Disease Markers

activate and recruit immune cells via binding to differentreceptors such as TLR IL-1 receptor (IL-1R) or RAGEthereby initiating and perpetuating multiple proinflamma-tory pathways [21 159]

Regulation of the inflammatory response is a complexprocess that requires interplay between several immunemediators [160] Both pro- and anti-inflammatory biomark-ers have been studied in ARDS

(1) Proinflammatory Cytokines

(a) IL-1120573 and TNF-120572 IL-1120573 and TNF-120572 are the most biolog-ically potent cytokines secreted by activated macrophages inthe early phase of ARDS They cause the release of a varietyof proinflammatory chemokines such as monocyte chemo-tactic protein-1 (MCP-1) macrophage inflammatory protein-1120572 (MIP-1120572) IL-6 and IL-8 with subsequent recruitmentof inflammatory cells into the air spaces alteration of theendothelial-epithelial barrier permeability and impairmentof fluid transport leading to alveolar edema [17] TNF-120572 alsopromotes lung edema indirectly through the production ofreactive oxygen species (ROS) and a decreased expressionof epithelial sodium (ENaC) and Na+-K+-ATPase channels[161] Finally TNF-120572 a potent chemoattractant for fibrob-lasts is a promoter of lung fibrosis in experimental studies[162 163] Interestingly the ratio of BAL to serum levelsof both TNF-120572 and IL-1120573 is typically high suggesting thatsuch cytokines may originate from the lung in the settingof ARDS [164] Persistent elevation of plasma and BAL IL-1120573 is associated with worse outcome [165 166] Both TNF-120572 and IL-1120573 are elevated in the plasma and BAL fluid frompatients at risk of and with ARDS [164 167] and associatedwith mortality [166]

(b) IL-18 Inflammasomes are intracellular macromolecularcomplexes that serve as platforms for the activation of theproinflammatory enzyme caspase-1 which in turn cleavespro-IL-1120573 and pro-IL-18 into IL-1120573 and IL-18 [50] Theseinflammasome-activated cytokines play central roles in thepropagation of the acute inflammatory response IL-18 andcaspase-1 play critical roles in the development of lunginjury and higher levels of IL-18 are correlated with diseaseseverity and mortality in patients with ARDS [168] Among38 patients with acute respiratory failure those with ARDShad significantly higher serum levels of IL-18 and serum IL-18 was significantly higher in nonsurvivors [51]

(c) IL-6 IL-6 is produced by a wide range of cells includingmonocytesmacrophages endothelial cells fibroblasts andsmoothmuscle cells in response to stimulation by endotoxinIL-1120573 and TNF-120572 [52] IL-6 is one of the most importantmediators of fever and is critical for B-cell differentiation andmaturation with secretion of immunoglobulins cytotoxic Tcell differentiation macrophage and monocyte function andproduction of acute phase proteins Although IL-6 activatesboth proinflammatory and anti-inflammatory mechanismsIL-6 primarily correlates with a proinflammatory profileduring the early phase of ARDS Plasma IL-6 increases earlyin patients at risk of developing ARDS [53] IL-6 is elevated in

both plasma and BAL fluid during ARDS [59] and correlateswith mortality [54 55]

(d) IL-8 IL-8 is a proinflammatory cytokine with a role inneutrophilmonocyte chemotaxis and neutrophil apoptosisinhibitionHighplasma andBAL levels of IL-8 are found earlyduring ARDS and predict outcome [169] However previousstudies did not support such findings [170 171] In a recentmonocenter study of 100 patients only baseline IL-8 (among6 other biomarkers) was associated with the development ofmultiorgan failure even after adjustment for other relevantvariables [32] Also several studies have evaluated the roleof the anti-IL-8 autoantibodyIL-8 immune complexes inARDS a pathway that could lead to the identification of novelbiomarkers and therapeutic targets [17 172ndash175]

In a recent study Calfee et al used latent class analysisto integrate both clinical and biological data to identifytwo ARDS endotypes in an analysis of 1022 patients fromtwo ARDSNet trials (ARMA and ALVEOLI) [13] A firstendotype was categorized by more severe inflammation asassessed by both IL-6 and IL-8 levels and worse clinicaloutcomes whereas a second endotype had less inflammationless shock and better clinical outcomes Based on the datafrom the ALVEOLI trial a ldquoproinflammatoryrdquo endotypewas associated with higher mortality and better response tohigher levels of positive end-expiratory pressure [176]

(2) Anti-Inflammatory Cytokines The inflammatory responseis also strongly influenced by anti-inflammatory systemsincluding nonspecific (eg 2-macroglobulin IL-10) andspecific (eg IL-1 receptor antagonist (IL-1RA) antagonistssoluble IL-1 receptor II (sIL-1RII) soluble TNF receptorI (sTNF-RI) and soluble TNF receptor II (sTNF-RII)) ofproinflammatory cytokines

(a) IL-1RA Circulating IL-1RA levels are increased but donot predict the development of ARDS in at-risk patients[56] Studies of gene expression in alveolar macrophagesand circulating leukocytes from healthy control subjects andpatients with ARDS revealed that sIL-1RII may be valuable asa biomarker because of increased levels in both the lung andcirculation during ARDS [57]

(b) sTNF-RIsTNF-RII Soluble TNF-120572 receptors (sTNF-R)I and II can bind TNF and compete with its binding tothe cellular receptor thus reducing its bioavailability SolubleTNF-RI and TNF-II are associated with morbidity andmortality in patients with ARDS [54] and a strategy of lowtidal volume ventilation is associated with decreased sTNF-RI levels [54] Trauma-associated ARDS differs clinically andbiologically from ARDS due to other clinical disorders withlower levels of sTNF-RI patients with trauma as a primarycause of ARDS [6 58]

(c) IL-10 Interleukin-10 (IL-10) is an anti-inflammatorycytokine that is produced by several cells including B lym-phocytes monocytes and alveolar macrophages [60] Asidefrom inhibiting the production of IL-1 and TNF-120572 IL-10

Disease Markers 9

upregulates TNF receptors [177] and stimulates the produc-tion of the naturally occurring IL-1RAand the release of sTNFreceptors [178] IL-10 inhibits the production of proinflam-matory mediators by alveolar macrophages involved duringARDS [179] ARDS patients have lower plasma and BALlevels of IL-10 than at-risk patients who did not develop thesyndrome [61] Higher baseline IL-10 levels were associatedwith higher morbidity and mortality [59]

(3) Additional Markers Other markers with potential clinicalimportance in ARDS-associated inflammation have beenidentified as putative biomarkers during ARDS

High mobility group box nuclear protein 1 (HMGB1) is aDNAnuclear binding protein that is secreted by immune cellsincluding monocytes and macrophages HMGB1 increasesearly after severe trauma and correlates with systemic inflam-matory response and development of ARDS [62] Alveolarand plasma levels of HMGB1 (as measured in the arterial orcentral venous blood) are elevated in patients with ARDS andassociated with outcome [109] In 20 patients with ARDSplasma levels of HMGB1 were also higher in nonsurvivorsand correlated with levels of sRAGE [63]

Lipopolysaccharide binding protein (LBP) is an acutephase protein that is correlated with lung inflammationduring ARDS [64] More recently it has also been demon-strated that serum levels of LBPwere strongly associated withincreasedmortality and the development of ARDS in patientswith severe sepsis [65]

Nitric oxide (NO) is a marker of oxidative stress thathas also been investigated as a marker of ARDS In patientswith persistent ARDS higher levels of nitric oxide andof its end-products (eg nitrotyrosine) are associated withmortality [66] In contrast higher urine NO levels werestrongly associated with better clinical outcomes includingmortality and ventilator-free days in patients enrolled in theARDSNet low tidal volume trial [46] Extracellular citrullinethe effective precursor of NO is lower in the plasma frompatients with severe sepsis and lower plasma citrulline isassociated with the presence of ARDS [67] Mechanismsinvolved in the regulation of lung injury by NO-dependentpathways remain unknown

Although C-reactive protein (CRP) is widely consideredas a marker of systemic inflammation higher levels of CRPare associated with better outcome among patients withARDS [68] Nevertheless a recent study found that albuminlevels rather than CRP may help to predict and monitor theseverity and course of ARDS in febrile critically ill patientswith ARDS or at risk for the syndrome [69] In the samestudy levels of lactate dehydrogenase (LDH) predicted 28-day mortality but were not correlated with severity [69]

313 Coagulation and Fibrinolysis During early ARDS acti-vation of the inflammatory cascades results in the activationof the coagulation system which in turn can influenceinflammatory responses by affecting the expression of variouscytokines such as IL-1 IL-6 and IL-8 Activation of coagula-tion pathways induces migration of inflammatory cells intoalveoli through the endothelial and epithelial barriers and

generates thrombin formation In addition proinflammatoryevents may also inhibit fibrinolysis and induce platelet acti-vation [17]

Extravascular fibrin deposition when localized predomi-nantly in the alveolar compartment is found in several acuteinflammatory lung diseases and enhanced alveolar procoag-ulant activity is reported inARDS patients [180] Fibrin depo-sition may be beneficial for gas exchange by sealing leakagesites when lung capillary endothelial and epithelial barriersare disrupted Nevertheless fibrin alveolar deposition maybe harmful since it can lead to activation of neutrophilsand fibroblasts endothelial injury loss of surfactant activityfavoring alveolar collapse impaired alveolar fluid clearanceand thrombotic obstruction of the microcirculation [180]

(1) PAI-1 The balance between activation of coagulationand activation of fibrinolysis is an important determinantof the amount and duration of fibrin deposition duringlung injury Plasminogen activator (PA) and plasminogenactivator inhibitor-1 (PAI-1) regulate fibrinolysis through theconversion of plasminogen to plasmin a fibrinolytic enzymePA-1 is amajor endogenous inhibitor of PA Both PA and PA-1are secreted by various cells including macrophages fibrob-lasts and lung endothelial and epithelial cells [71] DuringARDS alveolar epithelial cells and activated macrophagesoverexpress PAI-1 thus contributing to decreased alveolarfibrinolytic activity Nevertheless the value of PAI-1 asa biomarker in ARDS remains controversial PAI-1 levelswere higher in patients with ARDS than in patients withhydrostatic lung edema [72] and higher PAI-1 levels areassociated withmortality and higher durations ofmechanicalventilation in patients with ARDS [72 169] In a large Finnishstudy PAI-1 levels were not correlated with mortality ordevelopment of ARDS in critically ill patients undermechan-ical ventilation but low baseline plasma levels of the solubleurokinase plasminogen activator receptor (suPAR) were pre-dictive of survival [181] In a secondary analysis of two largerandomized controlled trials PAI-1 was associated with lunginjury (as defined as decreased oxygenation index) but notwithmortality [28] Nevertheless in another study of patientsfrom the ARDSNet ARMA study higher levels of PAI-1were independently associated with higher mortality andclinical outcomes including organ failure [182] Howeverthis association between PAI-1 levels and the development ofmultiorgan failure was not confirmed in a recent study of 100ARDS patients [32]

(2) Protein C Protein C system is an important endogenousregulator of coagulation and fibrinolysis Protein C is synthe-sized by the liver and circulates as an inactive compoundIt is transformed to its active form on cell surface by thethrombomodulin- (TM-) thrombin complex [75 76] Theendothelial cell protein C receptor (EPCR) is another cellsurface protein that can further enhance protein activationby binding the TM-thrombin complex [183] In additionto suppressing thrombin formation activated protein C hasanti-inflammatory properties such as decreasing the levelsof proinflammatory cytokines [184] Protein C can improveendothelial permeability and exert antiapoptotic effects via

10 Disease Markers

p53 pathways [185] Activated protein C can also inactivatePAI-1 thus promoting fibrinolysis [186] Plasma protein Cwas significantly lower in patients with ARDS as comparedto controls and it was associated with worse clinical out-comes including higher hospital mortality shorter durationof unassisted ventilation and increased risk ofmultiple organfailure [73] In a larger cohort of patients with early ARDSlow plasma levels of protein C were again associated withmortality and adverse clinical outcomes [182] Decreasedlevels of protein C during ARDS suggest a link betweenhypercoagulability and mortality

(3) Thrombomodulin Thrombomodulin (TM) is a mul-tidomain transmembrane-bound glycoprotein found on thesurface of endothelial cell Its main role is to neutralize theprocoagulant effects of thrombin and accelerate activationof protein C In addition to its membrane-bound form TMalso exists as a circulating soluble isoform in the plasmaIn patients with ARDS levels of soluble thrombomodulin(sTM) are higher in the pulmonary edema fluid than inplasma [73] suggesting an alveolar source but no correlationwas found between plasma sTM and the development ofARDS yet higher levels of sTM were observed in patientsat high risk for ARDS In patients with established ARDShigher plasma and alveolar levels of sTM were correlatedwith severity of illness and multiple organ failure [73] Ina larger analysis of 449 patients elevated levels of plasmasTM were associated with increased mortality thus possiblyreflecting an increased degree of inflammation and both lungand systemic endothelial damage [74]

(4) Tissue Factor (TF) Tissue factor (TF) is a 47 kDa trans-membrane glycoprotein that is the most potent stimulator ofthe extrinsic coagulation cascade TF initiates the coagulationcascade by binding and allosterically activating coagulationfactor VIIa The resulting TF-VIIa complex binds the sub-strate coagulation factor X via multiple interactions alongan extended interface to produce the TF-VIIa-X complexThis complex leads eventually to thrombin formation andfibrin deposition [77] Levels of TF in lung edema fluid arehigher than plasma levels in patients with ARDS supportinga lung origin for TF in this setting and both plasma andalveolar levels of TF are higher in ARDS patients as comparedto patients with hydrostatic edema [187] Notably patientswith sepsis-induced ARDS may have higher levels of TF ascompared to patients without ARDS [78]

(5) Cell-Free Hb Levels of cell-free hemoglobin (Hb) arehigher in the air space of ARDS patients as comparedto critically ill patients with hydrostatic lung edema [79]Instillation of red blood cells or cell-free hemoglobin causeslung injury in rats [188] and intra-alveolar hemorrhage isassociated with high levels of intra-alveolar cell-free Hbmore severe lung injury and increased lipid peroxidationin the lung from mice with tissue factor deficiency [79]Precise cellular and molecular mechanisms by which cell-free hemoglobin in the air space could mediate or potenti-ate ARDS are currently under investigation [189] Cell-freeHb could activate chemokine release within the lung and

decompartmentalization of hemoglobin is likely to provide asignificant proinflammatory stimulus in the setting of diffusealveolar damage and hemorrhage during ARDS [80]

314 EFPL Protein Ratio The pathophysiology of ARDSincludes disruption of several physical barriers includingendothelial and epithelial cell layers the basement mem-brane and the extracellularmatrix resulting in increased pul-monary microvascular permeability The pulmonary edemafluid-to-plasma protein (EFPL) ratio is a rapid safe andnoninvasive measure of alveolar-capillary membrane per-meability The EFPL ratio was first proposed as a tool todetermine the etiology of acute pulmonary edema [81] Morerecently in a large study of 390 critically ill patientsWare et aldemonstrated that the EFPL ratio had an excellent discrimi-native value in distinguishing ARDS from hydrostatic edemaand was strongly associated with clinical outcomes Using acutoff of 065 the EFPL ratio had a sensitivity of 81 and aspecificity of 81 for the diagnosis of ARDS [82]

32 Fibroproliferative Phase of ARDS In some patientsimportant and persistent accumulation of macrophagesfibrocytes fibroblasts and myofibroblasts in the alveolarcompartment leads to excessive deposition of ECM com-ponents including fibronectin and collagen types I and IIIamong other proteins An imbalance between profibrotic andantifibrotic mediators may subsequently drive this fibropro-liferative response [190] Growth factors play a major rolein the resolution of ARDS [17] Lung endothelial repair ispromoted by vascular endothelial growth factor (VEGF)A variety of growth factors promote repair of the alveo-lar epithelium including keratinocyte growth factor (KGF)hepatocyte growth factor (HGF) fibroblast growth factor(FGF) and transforming growth factor-120572 (TGF-120572) [17] Twomajor pathways with opposite effects involve growth factorsduring ARDS tyrosine kinase receptor mediation (eg KGFHGF FGF and VEGF) and serine-threonine kinase receptorssuch as TGF-1205731 which tend to have opposed effect on theupregulation that occurs when the tyrosine kinase receptorpathway is involved [85 191 192]

321 Endothelial Proliferation Novel evidence points to apotential role of VEGF in promoting repair of the alveolar-capillarymembrane during recovery fromARDS and under-standing the role of VEGF in this disease process couldbe crucial for developing new therapeutic strategies [85193] In the lung VEGF is produced primarily by epithelialcells it increases microvascular permeability [83] but has animportant role also during the repair phase by stimulatingendothelial cell proliferation and survival [86 149] Thelevels of VEGF are increased in plasma from patients withARDS but are decreased in BAL fluid compared to healthycontrols subsequently BAL levels of VEGF increase duringthe resolution of lung injury [39 84 149]

322 Epithelial Proliferation and Apoptosis KGF also knownas FGF-7 is a potent mitogenic factor for alveolar epithelialcells that is primarily produced by fibroblasts and other

Disease Markers 11

cells such as T lymphocytes KGF regulates transepithelialtransport of sodium by stimulating the epithelial channelNa+-K+-ATPase in alveolar epithelial cells [87]

HGF is a nonspecific mitogen secreted by fibroblastsalveolar macrophages endothelial cells and epithelial cellsSeveral animal and human studies suggest that KGF andHGFcould protect the alveolar space against injury and couldfacilitate the repair of alveolar structures after injury [88 194195] KGF levels could be measured in the BAL from patientswith ARDS but not in the BAL from those without ARDS inaddition BALKGFwas associated with poor prognosis [196]Elevated HGF levels were also associated with outcome [196]In 36 patients with ARDS and 11 patients with hydrostaticlung edema HGF and KGF were proven biologically activein the edema fluid of patients with ARDS and higher levelsof HGFwere associated withmortality in these patients [197]

Apoptosis of alveolar epithelial cells is a major phe-nomenon in the initiation and perpetuation of lung injury[89] The FasFasL system plays an important role in theregulation of cell life and death through its ability to initiateapoptosis [198] This system combines the cell membranesurface receptor Fas (CD95) and its natural ligand FasL(CD95L) Membrane-bound FasL mediates lymphocyte-dependent cytotoxicity clonal deletion of alloreactive T cellsand activation-induced suicide of T cells [199] Its solubleform (sFasL) results from cleavage of membrane FasL byMMPs and induces apoptosis in susceptible cells [200]Apoptosis is inducedwhenmembrane-bound or soluble FasLbinds to Fas-bearing cells By contrast apoptosis is inhibitedwhen soluble Fas binds to either membrane-bound FasL orsFasL thus preventing FasL from interacting withmembrane-bound Fas receptors [201] In patients with ARDS sFasL wasdetectable in the lung before and after the onset of clinicallydefined ARDS and nonsurvivors had significantly higherBAL levels of sFasL on day 1 as compared with survivors[200] Both soluble Fas and soluble FasL were associated withoutcome and higher in the lung edema fluid from patientswith ARDS compared to control patients with hydrostaticpulmonary edema [202] Nevertheless recent findings sug-gested limited role for FasFasL system and apoptosis inairway epithelial cell death during ARDS [90]

323 Fibroblast Proliferation Pulmonary fibroblasts pro-duce procollagen III peptide (PCP-III) that is a precursorof collagen The NT part of procollagen III resulting fromthe enzymatic cleavage of procollagen by specific proteases inthe extracellular space is considered as a marker of collagensynthesis Alveolar levels of N-PCP-III are higher in ARDSpatient as compared with controls [203] The elevation ofN-PCP-III in pulmonary edema fluid begins within the first24 h of ARDS that is during the acute phase of increasedendothelial and epithelial permeability to protein suggestingthat fibrosing alveolitis could begin very early in the course ofclinical ARDS [203] In another study high levels of N-PCP-III were early predictors of poor outcome [204 205] Morerecently Forel et al measured alveolar N-PCP-III in patientswith nonresolving ARDS thus identifying patients who haddeveloped lung fibroproliferation [206] Unfortunately it

is still unknown whether N-PCP-III measurements couldbe useful in selecting patients who would benefit fromglucocorticoid therapy among others to reduce the ARDS-associated lung fibrosis [207]

4 Perspectives

41 Combining Biomarkers Despite advances in the identi-fication of biomarker candidate and better understanding ofARDS pathogenesis no single clinical or biological markerreliably predicts clinical outcomes inARDSThe combinationof clinical and biological marker is attractive in order toimprove the sensitivity andor the specificity of the testespecially through a recent approach aimed at measuring8 biological markers that reflect endothelial and epithelialinjury inflammation and coagulation vWF SP-D TNF-R1IL-6 IL-8 ICAM-1 protein C and PAI-1 in 549 patientsenrolled in the the ARDSNet trial of low versus high positiveend-expiratory pressure [208] Clinical predictors predictedmortality with an area under the ROC curve (AUC) of082 whereas a combination of these 8 biomarkers and theclinical predictors had an AUC of 085 The best performingbiomarkers were the neutrophil chemotactic factor IL-8 andSP-D a product of AT2 cells [208] supporting the conceptthat acute inflammation and alveolar epithelial injury areimportant pathogenetic pathways in human ARDS Morerecently a panel of biomarkers of lung epithelial injuryand inflammation (SP-D sRAGE IL-8 CC16 and IL-6)provided excellent discrimination for diagnosis of ARDSin patients with severe sepsis [20] Therefore and beyondtheir better diagnostic and prognostic values the use of suchbiomarker panels may be useful for selecting patients forclinical trials that are designed to reduce lung epithelial injury[113] Nevertheless whether a therapeutic strategy based onbiomarker measurements would benefit patient outcome hasnever been investigated

42 Lung Imaging as an ARDS Biomarker Studies of lungimaging during ARDS have revealed that adequate ventilatorsettings may vary among patients with the same syndromeIn a large study gas and tissue distribution in the lungs ofARDS patients were assessed using computed tomography(CT) and compared to those of healthy volunteers [11] Lungmorphology in ARDS is characterized by marked excess oflung tissue associated with a major decrease in aerated lungregions and in functional residual capacity Some patientswith ARDS exhibit preserved aeration of the upper lobesdespite the presence of an overall excess of lung tissue (ldquofocalrdquoARDS) as opposed to other patients with more diffuse lossof aeration and excessive lung tissue (ldquodiffuserdquo or ldquononfocalrdquoARDS) [209]

Lung morphology may influence the response to pos-itive end-expiratory pressure (PEEP) recruitment maneu-vers (RM) prone position and patient outcome [12 210]In a prospective study of nineteen patients with ARDSConstantin et al found that lung morphology at zero end-expiratory pressure could predict the response to a RM withcontinuous positive airway pressure of 40 cm H

2O for 40

12 Disease Markers

seconds Nonfocal morphology was associated with higherlung recruitability and PaO

2FiO2was significantly increased

by the RM [12 211] In contrast patients with focal lungmorphology were at risk of significant hyperinflation duringthe RM with no improvement of arterial oxygenation

It has also been hypothesized that the effects of PEEPmay depend on lung morphology Puybasset et al assessedthe responses to PEEP among patients with focal or nonfocalARDS [210] The regional distribution of intrapulmonarygas and lung tissue influences the effects of PEEP in ARDSpatients maximal alveolar recruitment without evidenceof overdistension was observed in patients with nonfocalARDS Nevertheless PEEP induced mild alveolar recruit-ment in patients with focal ARDS along with overdistensionof previously aerated lung regions

Interestingly phenotyping patients with ARDS basedon their lung morphology might be possible by measuringplasma sRAGEwith commercially available kits even thoughthese findings need further validation [100 112] HoweverRAGE pathway is a promising candidate for subphenotypingpatients with ARDS as it is believed to play a major rolein the mechanisms leading to AFC and their regulation[110] Recent findings that support a relationship betweenimpaired AFC and lung morphology may therefore fill a gapin the full recognition of an ARDS phenotype based on lungmorphology that could be linked to an endotype of impairedAFC and activated RAGE pathway [12 100 101 112 113 212]

43 Biomarkers in ARDS Can They Improve Patient CareBiomarkers are broadly used in critically ill patientsespecially during inflammatory andor infectious diseasesBiomarkers have been commonly defined as characteristicsthat are objectively measured and evaluated as indicatorsof normal biological processes pathogenic processes orpharmacologic responses to therapeutic interventions [213214] Biomarkers provide a powerful approach to understanda disease with multiple applications in observational andanalytic epidemiology randomized clinical trials screeningand diagnosis or prognosis [215]

Nevertheless there are important technical attributes fora relevant biomarker First the marker must be present inperipheral body tissue andor fluid (eg blood urine salivabreath or cerebrospinal fluid) second it must be easy todetect or quantify in assays that are both affordable androbust and third its regulation should be associated asspecifically as possible with damage of a particular tissuepreferably in a quantifiable manner Prior to the widespreaduse of a marker of interest it is essential that validation andconfirmation of candidate biomarkers by robust statisticalmethods are performed during biomarker discovery [215]Sensitivity and specificity are common quality parametersfor biomarkers Sensitivity describes the probability of apositive test in cases and specificity describes probability ofnegative test in controls An association between sensitivityand specificity is represented in the ROC curve by graphingsensitivity versus 100 minus specificity Area under the ROC curve(AUROC) is therefore a measure of performance of a markerThere is no absolute cutoff value of AUROC for robustness of

a marker but aminimum of 07 is required and values greaterthan 08 are good particularly in a heterogeneous critically illpatient population [216 217]

To summarize an ideal biomarker should indicate aclear relationship with the pathophysiologic event needsto be reliable reproducible disease specific and sensitiveand should be sampled by simple methods and relativelyinexpensive with little or no diurnal variation DuringARDS no single marker has been validated with all thesecriteria to date yet we believe that sRAGE may fulfill allprerequisites of a biomarker of ARDS First plasma sRAGEhas good diagnostic and prognostic values [96 99 100109 112] Second it is very well correlated with lung injuryseverity and specific pathophysiologic features of ARDS forexample alveolar fluid clearance and lung morphology [9699ndash101 109 112] Previous studies of the predictive value ofearly levels of sRAGE for the development of ARDS in ageneral population of patients admitted to the emergencydepartment were negative [130] but current research focuseson both the kinetics of sRAGE and esRAGE and RAGE genepolymorphisms as predictors of the development of ARDSin at-risk critically ill patients [114] Finally there is someevidence suggesting that monitoring sRAGE could informat least partially on therapeutic responses in patients with orwithout ARDS [24 99 113] If these data are confirmed byfuture studies such findingswould definitely help to reinforcesRAGE a real biomarker of ARDS

5 Conclusion

Biomarker research provides an important translational linkto our understanding of lung pathobiology Through theidentification and testing of candidate biomarkers we havegained insight into the pathogenic importance of endothelialand epithelial injury and have started to unravel the complexpathways that contribute to endothelial and epithelial celldysfunction inflammation fibrosis and apoptosis in ARDSIn addition biomarker studies may help us to explore thecellular and molecular mechanisms of various therapeuticstrategies for ARDS and to better understand the potentialproinflammatory effects of mechanical ventilation Giventhe clinical heterogeneity of patients with ARDS and thecomplexity of the underlying pathobiology it is unlikely thata single biomarker will emerge for ARDS as cardiac-specifictroponin did for myocardial infarction but the develop-ment of small biomarker panels reflecting each importantlung injury pathway would provide valuable predictive andprognostic information for both clinicians and investigatorsWhile biomarkers are currently not recommended for usein clinical practice in ARDS biomarker discovery mayhold significant promise in order to develop and applytargeted therapies and to identify candidates for enrollmentin patient-tailored clinical trials of novel therapies for ARDS

Disclosure

The funders had no influence on the study design conductand analysis or on the preparation of this paper

Disease Markers 13

Conflict of Interests

No conflict of interests other sources of financial supportcorporate involvement patent holdings and so forth are tobe declared for all authors

Authorsrsquo Contribution

Raiko Blondonnet was involved in the conception and designof the review in writing the paper and in its revision priorto submission Jean-Michel Constantin was involved in theconception and design of the review in writing the paperand in its revision prior to submission Vincent Sapin wasinvolved in the conception and design of the review inwriting the paper and in its revision prior to submissionMatthieu Jabaudon takes responsibility for the content ofthe paper and was involved in the conception and design ofthe review in writing the paper and in its revision prior tosubmission

Acknowledgments

This work was supported by grants from the AuvergneRegional Council (ldquoProgramme Nouveau Chercheur de laRegion Auvergnerdquo 2013) the french Agence Nationale de laRecherche and the Direction Generale de lrsquoOffre de Soins(ldquoProgramme de Recherche Translationnelle en Santerdquo ANR-13-PRTS-0010)

References

[1] VM Ranieri G D Rubenfeld P TThompson et al ldquoAcute res-piratory distress syndrome the Berlin definitionrdquo The Journalof the American Medical Association vol 307 no 23 pp 2526ndash2533 2012

[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000

[3] C Brun-Buisson C Minelli G Bertolini et al ldquoEpidemiologyand outcome of acute lung injury in European intensive careunitsrdquo Intensive Care Medicine vol 30 no 1 pp 51ndash61 2004

[4] G D Rubenfeld E Caldwell E Peabody et al ldquoIncidence andoutcomes of acute lung injuryrdquo The New England Journal ofMedicine vol 353 no 16 pp 1685ndash1693 2005

[5] D W Dowdy M P Eid C R Dennison et al ldquoQuality oflife after acute respiratory distress syndrome a meta-analysisrdquoIntensive Care Medicine vol 32 no 8 pp 1115ndash1124 2006

[6] C S Calfee M D Eisner L B Ware et al ldquoTrauma-associatedlung injury differs clinically and biologically from acute lunginjury due to other clinical disordersrdquo Critical Care Medicinevol 35 no 10 pp 2243ndash2250 2007

[7] C S Calfee D R Janz G R Bernard et al ldquoDistinct molecularphenotypes of direct versus indirect ARDS in single and multi-center studiesrdquo Chest vol 147 no 6 pp 1539ndash1548 2015

[8] P Tejera N J Meyer F Chen et al ldquoDistinct and replicablegenetic risk factors for acute respiratory distress syndromeof pulmonary or extrapulmonary originrdquo Journal of MedicalGenetics vol 49 no 11 pp 671ndash680 2012

[9] M A Matthay G A Zimmerman C Esmon et al ldquoFutureresearch directions in acute lung injury summary of a National

Heart Lung and Blood Institute Working Grouprdquo AmericanJournal of Respiratory and Critical Care Medicine vol 167 no7 pp 1027ndash1035 2003

[10] J P Reilly S Bellamy M G S Shashaty et al ldquoHeterogeneousphenotypes of acute respiratory distress syndrome after majortraumardquo Annals of the American Thoracic Society vol 11 no 5pp 728ndash736 2014

[11] L Puybasset P Cluzel N Chao et al ldquoA computed tomographyscan assessment of regional lung volume in acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol158 no 5 pp 1644ndash1655 1998

[12] J-M Constantin S Grasso G Chanques et al ldquoLungmorphol-ogy predicts response to recruitment maneuver in patients withacute respiratory distress syndromerdquo Critical Care Medicinevol 38 no 4 pp 1108ndash1117 2010

[13] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoSubphenotypes in acute respiratorydistress syndrome latent class analysis of data from tworandomised controlled trialsrdquoThe Lancet Respiratory Medicinevol 2 no 8 pp 611ndash620 2014

[14] R Marshall G Bellingan and G Laurent ldquoThe acute respira-tory distress syndrome fibrosis in the fast lanerdquoThorax vol 53no 10 pp 815ndash817 1998

[15] R B Henderson J A R Hobbs M Mathies and N HoggldquoRapid recruitment of inflammatory monocytes is independentof neutrophil migrationrdquo Blood vol 102 no 1 pp 328ndash3352003

[16] HMMarriott andDH Dockrell ldquoThe role of themacrophagein lung disease mediated by bacteriardquo Experimental LungResearch vol 33 no 10 pp 493ndash505 2007

[17] L J M Cross and M A Matthay ldquoBiomarkers in acute lunginjury insights into the pathogenesis of acute lung injuryrdquoCritical Care Clinics vol 27 no 2 pp 355ndash377 2011

[18] H K Gaggin and J L Januzzi ldquoBiomarkers and diagnostics inheart failurerdquo Biochimica et Biophysica Acta (BBA)mdashMolecularBasis of Disease vol 1832 no 12 pp 2442ndash2450 2013

[19] E Christenson and R H Christenson ldquoThe role of cardiacbiomarkers in the diagnosis and management of patientspresenting with suspected acute coronary syndromerdquo Annals ofLaboratory Medicine vol 33 no 5 pp 309ndash318 2013

[20] L B Ware T Koyama Z Zhao et al ldquoBiomarkers of lungepithelial injury and inflammation distinguish severe sepsispatientswith acute respiratory distress syndromerdquoCritical Carevol 17 no 5 article R253 2013

[21] M A Matthay L B Ware and G A Zimmerman ldquoTheacute respiratory distress syndromerdquo The Journal of ClinicalInvestigation vol 122 no 8 pp 2731ndash2740 2012

[22] M Shirasawa N Fujiwara S Hirabayashi et al ldquoReceptor foradvanced glycation end-products is a marker of type I lungalveolar cellsrdquo Genes to Cells vol 9 no 2 pp 165ndash174 2004

[23] M Neeper A M Schmidt J Brett et al ldquoCloning andexpression of a cell surface receptor for advanced glycosylationend products of proteinsrdquo The Journal of Biological Chemistryvol 267 no 21 pp 14998ndash15004 1992

[24] M Jabaudon E Futier L Roszyk V Sapin B Pereira andJ Constantin ldquoAssociation between intraoperative ventilatorsettings and plasma levels of soluble receptor for advancedglycation end-products in patients without pre-existing lunginjuryrdquo Respirology vol 20 no 7 pp 1131ndash1138 2015

[25] L G Dobbs R F Gonzalez L Allen and D K Froh ldquoHTI56an integral membrane protein specific to human alveolar type

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Disease Markers 9

upregulates TNF receptors [177] and stimulates the produc-tion of the naturally occurring IL-1RAand the release of sTNFreceptors [178] IL-10 inhibits the production of proinflam-matory mediators by alveolar macrophages involved duringARDS [179] ARDS patients have lower plasma and BALlevels of IL-10 than at-risk patients who did not develop thesyndrome [61] Higher baseline IL-10 levels were associatedwith higher morbidity and mortality [59]

(3) Additional Markers Other markers with potential clinicalimportance in ARDS-associated inflammation have beenidentified as putative biomarkers during ARDS

High mobility group box nuclear protein 1 (HMGB1) is aDNAnuclear binding protein that is secreted by immune cellsincluding monocytes and macrophages HMGB1 increasesearly after severe trauma and correlates with systemic inflam-matory response and development of ARDS [62] Alveolarand plasma levels of HMGB1 (as measured in the arterial orcentral venous blood) are elevated in patients with ARDS andassociated with outcome [109] In 20 patients with ARDSplasma levels of HMGB1 were also higher in nonsurvivorsand correlated with levels of sRAGE [63]

Lipopolysaccharide binding protein (LBP) is an acutephase protein that is correlated with lung inflammationduring ARDS [64] More recently it has also been demon-strated that serum levels of LBPwere strongly associated withincreasedmortality and the development of ARDS in patientswith severe sepsis [65]

Nitric oxide (NO) is a marker of oxidative stress thathas also been investigated as a marker of ARDS In patientswith persistent ARDS higher levels of nitric oxide andof its end-products (eg nitrotyrosine) are associated withmortality [66] In contrast higher urine NO levels werestrongly associated with better clinical outcomes includingmortality and ventilator-free days in patients enrolled in theARDSNet low tidal volume trial [46] Extracellular citrullinethe effective precursor of NO is lower in the plasma frompatients with severe sepsis and lower plasma citrulline isassociated with the presence of ARDS [67] Mechanismsinvolved in the regulation of lung injury by NO-dependentpathways remain unknown

Although C-reactive protein (CRP) is widely consideredas a marker of systemic inflammation higher levels of CRPare associated with better outcome among patients withARDS [68] Nevertheless a recent study found that albuminlevels rather than CRP may help to predict and monitor theseverity and course of ARDS in febrile critically ill patientswith ARDS or at risk for the syndrome [69] In the samestudy levels of lactate dehydrogenase (LDH) predicted 28-day mortality but were not correlated with severity [69]

313 Coagulation and Fibrinolysis During early ARDS acti-vation of the inflammatory cascades results in the activationof the coagulation system which in turn can influenceinflammatory responses by affecting the expression of variouscytokines such as IL-1 IL-6 and IL-8 Activation of coagula-tion pathways induces migration of inflammatory cells intoalveoli through the endothelial and epithelial barriers and

generates thrombin formation In addition proinflammatoryevents may also inhibit fibrinolysis and induce platelet acti-vation [17]

Extravascular fibrin deposition when localized predomi-nantly in the alveolar compartment is found in several acuteinflammatory lung diseases and enhanced alveolar procoag-ulant activity is reported inARDS patients [180] Fibrin depo-sition may be beneficial for gas exchange by sealing leakagesites when lung capillary endothelial and epithelial barriersare disrupted Nevertheless fibrin alveolar deposition maybe harmful since it can lead to activation of neutrophilsand fibroblasts endothelial injury loss of surfactant activityfavoring alveolar collapse impaired alveolar fluid clearanceand thrombotic obstruction of the microcirculation [180]

(1) PAI-1 The balance between activation of coagulationand activation of fibrinolysis is an important determinantof the amount and duration of fibrin deposition duringlung injury Plasminogen activator (PA) and plasminogenactivator inhibitor-1 (PAI-1) regulate fibrinolysis through theconversion of plasminogen to plasmin a fibrinolytic enzymePA-1 is amajor endogenous inhibitor of PA Both PA and PA-1are secreted by various cells including macrophages fibrob-lasts and lung endothelial and epithelial cells [71] DuringARDS alveolar epithelial cells and activated macrophagesoverexpress PAI-1 thus contributing to decreased alveolarfibrinolytic activity Nevertheless the value of PAI-1 asa biomarker in ARDS remains controversial PAI-1 levelswere higher in patients with ARDS than in patients withhydrostatic lung edema [72] and higher PAI-1 levels areassociated withmortality and higher durations ofmechanicalventilation in patients with ARDS [72 169] In a large Finnishstudy PAI-1 levels were not correlated with mortality ordevelopment of ARDS in critically ill patients undermechan-ical ventilation but low baseline plasma levels of the solubleurokinase plasminogen activator receptor (suPAR) were pre-dictive of survival [181] In a secondary analysis of two largerandomized controlled trials PAI-1 was associated with lunginjury (as defined as decreased oxygenation index) but notwithmortality [28] Nevertheless in another study of patientsfrom the ARDSNet ARMA study higher levels of PAI-1were independently associated with higher mortality andclinical outcomes including organ failure [182] Howeverthis association between PAI-1 levels and the development ofmultiorgan failure was not confirmed in a recent study of 100ARDS patients [32]

(2) Protein C Protein C system is an important endogenousregulator of coagulation and fibrinolysis Protein C is synthe-sized by the liver and circulates as an inactive compoundIt is transformed to its active form on cell surface by thethrombomodulin- (TM-) thrombin complex [75 76] Theendothelial cell protein C receptor (EPCR) is another cellsurface protein that can further enhance protein activationby binding the TM-thrombin complex [183] In additionto suppressing thrombin formation activated protein C hasanti-inflammatory properties such as decreasing the levelsof proinflammatory cytokines [184] Protein C can improveendothelial permeability and exert antiapoptotic effects via

10 Disease Markers

p53 pathways [185] Activated protein C can also inactivatePAI-1 thus promoting fibrinolysis [186] Plasma protein Cwas significantly lower in patients with ARDS as comparedto controls and it was associated with worse clinical out-comes including higher hospital mortality shorter durationof unassisted ventilation and increased risk ofmultiple organfailure [73] In a larger cohort of patients with early ARDSlow plasma levels of protein C were again associated withmortality and adverse clinical outcomes [182] Decreasedlevels of protein C during ARDS suggest a link betweenhypercoagulability and mortality

(3) Thrombomodulin Thrombomodulin (TM) is a mul-tidomain transmembrane-bound glycoprotein found on thesurface of endothelial cell Its main role is to neutralize theprocoagulant effects of thrombin and accelerate activationof protein C In addition to its membrane-bound form TMalso exists as a circulating soluble isoform in the plasmaIn patients with ARDS levels of soluble thrombomodulin(sTM) are higher in the pulmonary edema fluid than inplasma [73] suggesting an alveolar source but no correlationwas found between plasma sTM and the development ofARDS yet higher levels of sTM were observed in patientsat high risk for ARDS In patients with established ARDShigher plasma and alveolar levels of sTM were correlatedwith severity of illness and multiple organ failure [73] Ina larger analysis of 449 patients elevated levels of plasmasTM were associated with increased mortality thus possiblyreflecting an increased degree of inflammation and both lungand systemic endothelial damage [74]

(4) Tissue Factor (TF) Tissue factor (TF) is a 47 kDa trans-membrane glycoprotein that is the most potent stimulator ofthe extrinsic coagulation cascade TF initiates the coagulationcascade by binding and allosterically activating coagulationfactor VIIa The resulting TF-VIIa complex binds the sub-strate coagulation factor X via multiple interactions alongan extended interface to produce the TF-VIIa-X complexThis complex leads eventually to thrombin formation andfibrin deposition [77] Levels of TF in lung edema fluid arehigher than plasma levels in patients with ARDS supportinga lung origin for TF in this setting and both plasma andalveolar levels of TF are higher in ARDS patients as comparedto patients with hydrostatic edema [187] Notably patientswith sepsis-induced ARDS may have higher levels of TF ascompared to patients without ARDS [78]

(5) Cell-Free Hb Levels of cell-free hemoglobin (Hb) arehigher in the air space of ARDS patients as comparedto critically ill patients with hydrostatic lung edema [79]Instillation of red blood cells or cell-free hemoglobin causeslung injury in rats [188] and intra-alveolar hemorrhage isassociated with high levels of intra-alveolar cell-free Hbmore severe lung injury and increased lipid peroxidationin the lung from mice with tissue factor deficiency [79]Precise cellular and molecular mechanisms by which cell-free hemoglobin in the air space could mediate or potenti-ate ARDS are currently under investigation [189] Cell-freeHb could activate chemokine release within the lung and

decompartmentalization of hemoglobin is likely to provide asignificant proinflammatory stimulus in the setting of diffusealveolar damage and hemorrhage during ARDS [80]

314 EFPL Protein Ratio The pathophysiology of ARDSincludes disruption of several physical barriers includingendothelial and epithelial cell layers the basement mem-brane and the extracellularmatrix resulting in increased pul-monary microvascular permeability The pulmonary edemafluid-to-plasma protein (EFPL) ratio is a rapid safe andnoninvasive measure of alveolar-capillary membrane per-meability The EFPL ratio was first proposed as a tool todetermine the etiology of acute pulmonary edema [81] Morerecently in a large study of 390 critically ill patientsWare et aldemonstrated that the EFPL ratio had an excellent discrimi-native value in distinguishing ARDS from hydrostatic edemaand was strongly associated with clinical outcomes Using acutoff of 065 the EFPL ratio had a sensitivity of 81 and aspecificity of 81 for the diagnosis of ARDS [82]

32 Fibroproliferative Phase of ARDS In some patientsimportant and persistent accumulation of macrophagesfibrocytes fibroblasts and myofibroblasts in the alveolarcompartment leads to excessive deposition of ECM com-ponents including fibronectin and collagen types I and IIIamong other proteins An imbalance between profibrotic andantifibrotic mediators may subsequently drive this fibropro-liferative response [190] Growth factors play a major rolein the resolution of ARDS [17] Lung endothelial repair ispromoted by vascular endothelial growth factor (VEGF)A variety of growth factors promote repair of the alveo-lar epithelium including keratinocyte growth factor (KGF)hepatocyte growth factor (HGF) fibroblast growth factor(FGF) and transforming growth factor-120572 (TGF-120572) [17] Twomajor pathways with opposite effects involve growth factorsduring ARDS tyrosine kinase receptor mediation (eg KGFHGF FGF and VEGF) and serine-threonine kinase receptorssuch as TGF-1205731 which tend to have opposed effect on theupregulation that occurs when the tyrosine kinase receptorpathway is involved [85 191 192]

321 Endothelial Proliferation Novel evidence points to apotential role of VEGF in promoting repair of the alveolar-capillarymembrane during recovery fromARDS and under-standing the role of VEGF in this disease process couldbe crucial for developing new therapeutic strategies [85193] In the lung VEGF is produced primarily by epithelialcells it increases microvascular permeability [83] but has animportant role also during the repair phase by stimulatingendothelial cell proliferation and survival [86 149] Thelevels of VEGF are increased in plasma from patients withARDS but are decreased in BAL fluid compared to healthycontrols subsequently BAL levels of VEGF increase duringthe resolution of lung injury [39 84 149]

322 Epithelial Proliferation and Apoptosis KGF also knownas FGF-7 is a potent mitogenic factor for alveolar epithelialcells that is primarily produced by fibroblasts and other

Disease Markers 11

cells such as T lymphocytes KGF regulates transepithelialtransport of sodium by stimulating the epithelial channelNa+-K+-ATPase in alveolar epithelial cells [87]

HGF is a nonspecific mitogen secreted by fibroblastsalveolar macrophages endothelial cells and epithelial cellsSeveral animal and human studies suggest that KGF andHGFcould protect the alveolar space against injury and couldfacilitate the repair of alveolar structures after injury [88 194195] KGF levels could be measured in the BAL from patientswith ARDS but not in the BAL from those without ARDS inaddition BALKGFwas associated with poor prognosis [196]Elevated HGF levels were also associated with outcome [196]In 36 patients with ARDS and 11 patients with hydrostaticlung edema HGF and KGF were proven biologically activein the edema fluid of patients with ARDS and higher levelsof HGFwere associated withmortality in these patients [197]

Apoptosis of alveolar epithelial cells is a major phe-nomenon in the initiation and perpetuation of lung injury[89] The FasFasL system plays an important role in theregulation of cell life and death through its ability to initiateapoptosis [198] This system combines the cell membranesurface receptor Fas (CD95) and its natural ligand FasL(CD95L) Membrane-bound FasL mediates lymphocyte-dependent cytotoxicity clonal deletion of alloreactive T cellsand activation-induced suicide of T cells [199] Its solubleform (sFasL) results from cleavage of membrane FasL byMMPs and induces apoptosis in susceptible cells [200]Apoptosis is inducedwhenmembrane-bound or soluble FasLbinds to Fas-bearing cells By contrast apoptosis is inhibitedwhen soluble Fas binds to either membrane-bound FasL orsFasL thus preventing FasL from interacting withmembrane-bound Fas receptors [201] In patients with ARDS sFasL wasdetectable in the lung before and after the onset of clinicallydefined ARDS and nonsurvivors had significantly higherBAL levels of sFasL on day 1 as compared with survivors[200] Both soluble Fas and soluble FasL were associated withoutcome and higher in the lung edema fluid from patientswith ARDS compared to control patients with hydrostaticpulmonary edema [202] Nevertheless recent findings sug-gested limited role for FasFasL system and apoptosis inairway epithelial cell death during ARDS [90]

323 Fibroblast Proliferation Pulmonary fibroblasts pro-duce procollagen III peptide (PCP-III) that is a precursorof collagen The NT part of procollagen III resulting fromthe enzymatic cleavage of procollagen by specific proteases inthe extracellular space is considered as a marker of collagensynthesis Alveolar levels of N-PCP-III are higher in ARDSpatient as compared with controls [203] The elevation ofN-PCP-III in pulmonary edema fluid begins within the first24 h of ARDS that is during the acute phase of increasedendothelial and epithelial permeability to protein suggestingthat fibrosing alveolitis could begin very early in the course ofclinical ARDS [203] In another study high levels of N-PCP-III were early predictors of poor outcome [204 205] Morerecently Forel et al measured alveolar N-PCP-III in patientswith nonresolving ARDS thus identifying patients who haddeveloped lung fibroproliferation [206] Unfortunately it

is still unknown whether N-PCP-III measurements couldbe useful in selecting patients who would benefit fromglucocorticoid therapy among others to reduce the ARDS-associated lung fibrosis [207]

4 Perspectives

41 Combining Biomarkers Despite advances in the identi-fication of biomarker candidate and better understanding ofARDS pathogenesis no single clinical or biological markerreliably predicts clinical outcomes inARDSThe combinationof clinical and biological marker is attractive in order toimprove the sensitivity andor the specificity of the testespecially through a recent approach aimed at measuring8 biological markers that reflect endothelial and epithelialinjury inflammation and coagulation vWF SP-D TNF-R1IL-6 IL-8 ICAM-1 protein C and PAI-1 in 549 patientsenrolled in the the ARDSNet trial of low versus high positiveend-expiratory pressure [208] Clinical predictors predictedmortality with an area under the ROC curve (AUC) of082 whereas a combination of these 8 biomarkers and theclinical predictors had an AUC of 085 The best performingbiomarkers were the neutrophil chemotactic factor IL-8 andSP-D a product of AT2 cells [208] supporting the conceptthat acute inflammation and alveolar epithelial injury areimportant pathogenetic pathways in human ARDS Morerecently a panel of biomarkers of lung epithelial injuryand inflammation (SP-D sRAGE IL-8 CC16 and IL-6)provided excellent discrimination for diagnosis of ARDSin patients with severe sepsis [20] Therefore and beyondtheir better diagnostic and prognostic values the use of suchbiomarker panels may be useful for selecting patients forclinical trials that are designed to reduce lung epithelial injury[113] Nevertheless whether a therapeutic strategy based onbiomarker measurements would benefit patient outcome hasnever been investigated

42 Lung Imaging as an ARDS Biomarker Studies of lungimaging during ARDS have revealed that adequate ventilatorsettings may vary among patients with the same syndromeIn a large study gas and tissue distribution in the lungs ofARDS patients were assessed using computed tomography(CT) and compared to those of healthy volunteers [11] Lungmorphology in ARDS is characterized by marked excess oflung tissue associated with a major decrease in aerated lungregions and in functional residual capacity Some patientswith ARDS exhibit preserved aeration of the upper lobesdespite the presence of an overall excess of lung tissue (ldquofocalrdquoARDS) as opposed to other patients with more diffuse lossof aeration and excessive lung tissue (ldquodiffuserdquo or ldquononfocalrdquoARDS) [209]

Lung morphology may influence the response to pos-itive end-expiratory pressure (PEEP) recruitment maneu-vers (RM) prone position and patient outcome [12 210]In a prospective study of nineteen patients with ARDSConstantin et al found that lung morphology at zero end-expiratory pressure could predict the response to a RM withcontinuous positive airway pressure of 40 cm H

2O for 40

12 Disease Markers

seconds Nonfocal morphology was associated with higherlung recruitability and PaO

2FiO2was significantly increased

by the RM [12 211] In contrast patients with focal lungmorphology were at risk of significant hyperinflation duringthe RM with no improvement of arterial oxygenation

It has also been hypothesized that the effects of PEEPmay depend on lung morphology Puybasset et al assessedthe responses to PEEP among patients with focal or nonfocalARDS [210] The regional distribution of intrapulmonarygas and lung tissue influences the effects of PEEP in ARDSpatients maximal alveolar recruitment without evidenceof overdistension was observed in patients with nonfocalARDS Nevertheless PEEP induced mild alveolar recruit-ment in patients with focal ARDS along with overdistensionof previously aerated lung regions

Interestingly phenotyping patients with ARDS basedon their lung morphology might be possible by measuringplasma sRAGEwith commercially available kits even thoughthese findings need further validation [100 112] HoweverRAGE pathway is a promising candidate for subphenotypingpatients with ARDS as it is believed to play a major rolein the mechanisms leading to AFC and their regulation[110] Recent findings that support a relationship betweenimpaired AFC and lung morphology may therefore fill a gapin the full recognition of an ARDS phenotype based on lungmorphology that could be linked to an endotype of impairedAFC and activated RAGE pathway [12 100 101 112 113 212]

43 Biomarkers in ARDS Can They Improve Patient CareBiomarkers are broadly used in critically ill patientsespecially during inflammatory andor infectious diseasesBiomarkers have been commonly defined as characteristicsthat are objectively measured and evaluated as indicatorsof normal biological processes pathogenic processes orpharmacologic responses to therapeutic interventions [213214] Biomarkers provide a powerful approach to understanda disease with multiple applications in observational andanalytic epidemiology randomized clinical trials screeningand diagnosis or prognosis [215]

Nevertheless there are important technical attributes fora relevant biomarker First the marker must be present inperipheral body tissue andor fluid (eg blood urine salivabreath or cerebrospinal fluid) second it must be easy todetect or quantify in assays that are both affordable androbust and third its regulation should be associated asspecifically as possible with damage of a particular tissuepreferably in a quantifiable manner Prior to the widespreaduse of a marker of interest it is essential that validation andconfirmation of candidate biomarkers by robust statisticalmethods are performed during biomarker discovery [215]Sensitivity and specificity are common quality parametersfor biomarkers Sensitivity describes the probability of apositive test in cases and specificity describes probability ofnegative test in controls An association between sensitivityand specificity is represented in the ROC curve by graphingsensitivity versus 100 minus specificity Area under the ROC curve(AUROC) is therefore a measure of performance of a markerThere is no absolute cutoff value of AUROC for robustness of

a marker but aminimum of 07 is required and values greaterthan 08 are good particularly in a heterogeneous critically illpatient population [216 217]

To summarize an ideal biomarker should indicate aclear relationship with the pathophysiologic event needsto be reliable reproducible disease specific and sensitiveand should be sampled by simple methods and relativelyinexpensive with little or no diurnal variation DuringARDS no single marker has been validated with all thesecriteria to date yet we believe that sRAGE may fulfill allprerequisites of a biomarker of ARDS First plasma sRAGEhas good diagnostic and prognostic values [96 99 100109 112] Second it is very well correlated with lung injuryseverity and specific pathophysiologic features of ARDS forexample alveolar fluid clearance and lung morphology [9699ndash101 109 112] Previous studies of the predictive value ofearly levels of sRAGE for the development of ARDS in ageneral population of patients admitted to the emergencydepartment were negative [130] but current research focuseson both the kinetics of sRAGE and esRAGE and RAGE genepolymorphisms as predictors of the development of ARDSin at-risk critically ill patients [114] Finally there is someevidence suggesting that monitoring sRAGE could informat least partially on therapeutic responses in patients with orwithout ARDS [24 99 113] If these data are confirmed byfuture studies such findingswould definitely help to reinforcesRAGE a real biomarker of ARDS

5 Conclusion

Biomarker research provides an important translational linkto our understanding of lung pathobiology Through theidentification and testing of candidate biomarkers we havegained insight into the pathogenic importance of endothelialand epithelial injury and have started to unravel the complexpathways that contribute to endothelial and epithelial celldysfunction inflammation fibrosis and apoptosis in ARDSIn addition biomarker studies may help us to explore thecellular and molecular mechanisms of various therapeuticstrategies for ARDS and to better understand the potentialproinflammatory effects of mechanical ventilation Giventhe clinical heterogeneity of patients with ARDS and thecomplexity of the underlying pathobiology it is unlikely thata single biomarker will emerge for ARDS as cardiac-specifictroponin did for myocardial infarction but the develop-ment of small biomarker panels reflecting each importantlung injury pathway would provide valuable predictive andprognostic information for both clinicians and investigatorsWhile biomarkers are currently not recommended for usein clinical practice in ARDS biomarker discovery mayhold significant promise in order to develop and applytargeted therapies and to identify candidates for enrollmentin patient-tailored clinical trials of novel therapies for ARDS

Disclosure

The funders had no influence on the study design conductand analysis or on the preparation of this paper

Disease Markers 13

Conflict of Interests

No conflict of interests other sources of financial supportcorporate involvement patent holdings and so forth are tobe declared for all authors

Authorsrsquo Contribution

Raiko Blondonnet was involved in the conception and designof the review in writing the paper and in its revision priorto submission Jean-Michel Constantin was involved in theconception and design of the review in writing the paperand in its revision prior to submission Vincent Sapin wasinvolved in the conception and design of the review inwriting the paper and in its revision prior to submissionMatthieu Jabaudon takes responsibility for the content ofthe paper and was involved in the conception and design ofthe review in writing the paper and in its revision prior tosubmission

Acknowledgments

This work was supported by grants from the AuvergneRegional Council (ldquoProgramme Nouveau Chercheur de laRegion Auvergnerdquo 2013) the french Agence Nationale de laRecherche and the Direction Generale de lrsquoOffre de Soins(ldquoProgramme de Recherche Translationnelle en Santerdquo ANR-13-PRTS-0010)

References

[1] VM Ranieri G D Rubenfeld P TThompson et al ldquoAcute res-piratory distress syndrome the Berlin definitionrdquo The Journalof the American Medical Association vol 307 no 23 pp 2526ndash2533 2012

[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000

[3] C Brun-Buisson C Minelli G Bertolini et al ldquoEpidemiologyand outcome of acute lung injury in European intensive careunitsrdquo Intensive Care Medicine vol 30 no 1 pp 51ndash61 2004

[4] G D Rubenfeld E Caldwell E Peabody et al ldquoIncidence andoutcomes of acute lung injuryrdquo The New England Journal ofMedicine vol 353 no 16 pp 1685ndash1693 2005

[5] D W Dowdy M P Eid C R Dennison et al ldquoQuality oflife after acute respiratory distress syndrome a meta-analysisrdquoIntensive Care Medicine vol 32 no 8 pp 1115ndash1124 2006

[6] C S Calfee M D Eisner L B Ware et al ldquoTrauma-associatedlung injury differs clinically and biologically from acute lunginjury due to other clinical disordersrdquo Critical Care Medicinevol 35 no 10 pp 2243ndash2250 2007

[7] C S Calfee D R Janz G R Bernard et al ldquoDistinct molecularphenotypes of direct versus indirect ARDS in single and multi-center studiesrdquo Chest vol 147 no 6 pp 1539ndash1548 2015

[8] P Tejera N J Meyer F Chen et al ldquoDistinct and replicablegenetic risk factors for acute respiratory distress syndromeof pulmonary or extrapulmonary originrdquo Journal of MedicalGenetics vol 49 no 11 pp 671ndash680 2012

[9] M A Matthay G A Zimmerman C Esmon et al ldquoFutureresearch directions in acute lung injury summary of a National

Heart Lung and Blood Institute Working Grouprdquo AmericanJournal of Respiratory and Critical Care Medicine vol 167 no7 pp 1027ndash1035 2003

[10] J P Reilly S Bellamy M G S Shashaty et al ldquoHeterogeneousphenotypes of acute respiratory distress syndrome after majortraumardquo Annals of the American Thoracic Society vol 11 no 5pp 728ndash736 2014

[11] L Puybasset P Cluzel N Chao et al ldquoA computed tomographyscan assessment of regional lung volume in acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol158 no 5 pp 1644ndash1655 1998

[12] J-M Constantin S Grasso G Chanques et al ldquoLungmorphol-ogy predicts response to recruitment maneuver in patients withacute respiratory distress syndromerdquo Critical Care Medicinevol 38 no 4 pp 1108ndash1117 2010

[13] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoSubphenotypes in acute respiratorydistress syndrome latent class analysis of data from tworandomised controlled trialsrdquoThe Lancet Respiratory Medicinevol 2 no 8 pp 611ndash620 2014

[14] R Marshall G Bellingan and G Laurent ldquoThe acute respira-tory distress syndrome fibrosis in the fast lanerdquoThorax vol 53no 10 pp 815ndash817 1998

[15] R B Henderson J A R Hobbs M Mathies and N HoggldquoRapid recruitment of inflammatory monocytes is independentof neutrophil migrationrdquo Blood vol 102 no 1 pp 328ndash3352003

[16] HMMarriott andDH Dockrell ldquoThe role of themacrophagein lung disease mediated by bacteriardquo Experimental LungResearch vol 33 no 10 pp 493ndash505 2007

[17] L J M Cross and M A Matthay ldquoBiomarkers in acute lunginjury insights into the pathogenesis of acute lung injuryrdquoCritical Care Clinics vol 27 no 2 pp 355ndash377 2011

[18] H K Gaggin and J L Januzzi ldquoBiomarkers and diagnostics inheart failurerdquo Biochimica et Biophysica Acta (BBA)mdashMolecularBasis of Disease vol 1832 no 12 pp 2442ndash2450 2013

[19] E Christenson and R H Christenson ldquoThe role of cardiacbiomarkers in the diagnosis and management of patientspresenting with suspected acute coronary syndromerdquo Annals ofLaboratory Medicine vol 33 no 5 pp 309ndash318 2013

[20] L B Ware T Koyama Z Zhao et al ldquoBiomarkers of lungepithelial injury and inflammation distinguish severe sepsispatientswith acute respiratory distress syndromerdquoCritical Carevol 17 no 5 article R253 2013

[21] M A Matthay L B Ware and G A Zimmerman ldquoTheacute respiratory distress syndromerdquo The Journal of ClinicalInvestigation vol 122 no 8 pp 2731ndash2740 2012

[22] M Shirasawa N Fujiwara S Hirabayashi et al ldquoReceptor foradvanced glycation end-products is a marker of type I lungalveolar cellsrdquo Genes to Cells vol 9 no 2 pp 165ndash174 2004

[23] M Neeper A M Schmidt J Brett et al ldquoCloning andexpression of a cell surface receptor for advanced glycosylationend products of proteinsrdquo The Journal of Biological Chemistryvol 267 no 21 pp 14998ndash15004 1992

[24] M Jabaudon E Futier L Roszyk V Sapin B Pereira andJ Constantin ldquoAssociation between intraoperative ventilatorsettings and plasma levels of soluble receptor for advancedglycation end-products in patients without pre-existing lunginjuryrdquo Respirology vol 20 no 7 pp 1131ndash1138 2015

[25] L G Dobbs R F Gonzalez L Allen and D K Froh ldquoHTI56an integral membrane protein specific to human alveolar type

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ObesityJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

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Research and TreatmentAIDS

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

10 Disease Markers

p53 pathways [185] Activated protein C can also inactivatePAI-1 thus promoting fibrinolysis [186] Plasma protein Cwas significantly lower in patients with ARDS as comparedto controls and it was associated with worse clinical out-comes including higher hospital mortality shorter durationof unassisted ventilation and increased risk ofmultiple organfailure [73] In a larger cohort of patients with early ARDSlow plasma levels of protein C were again associated withmortality and adverse clinical outcomes [182] Decreasedlevels of protein C during ARDS suggest a link betweenhypercoagulability and mortality

(3) Thrombomodulin Thrombomodulin (TM) is a mul-tidomain transmembrane-bound glycoprotein found on thesurface of endothelial cell Its main role is to neutralize theprocoagulant effects of thrombin and accelerate activationof protein C In addition to its membrane-bound form TMalso exists as a circulating soluble isoform in the plasmaIn patients with ARDS levels of soluble thrombomodulin(sTM) are higher in the pulmonary edema fluid than inplasma [73] suggesting an alveolar source but no correlationwas found between plasma sTM and the development ofARDS yet higher levels of sTM were observed in patientsat high risk for ARDS In patients with established ARDShigher plasma and alveolar levels of sTM were correlatedwith severity of illness and multiple organ failure [73] Ina larger analysis of 449 patients elevated levels of plasmasTM were associated with increased mortality thus possiblyreflecting an increased degree of inflammation and both lungand systemic endothelial damage [74]

(4) Tissue Factor (TF) Tissue factor (TF) is a 47 kDa trans-membrane glycoprotein that is the most potent stimulator ofthe extrinsic coagulation cascade TF initiates the coagulationcascade by binding and allosterically activating coagulationfactor VIIa The resulting TF-VIIa complex binds the sub-strate coagulation factor X via multiple interactions alongan extended interface to produce the TF-VIIa-X complexThis complex leads eventually to thrombin formation andfibrin deposition [77] Levels of TF in lung edema fluid arehigher than plasma levels in patients with ARDS supportinga lung origin for TF in this setting and both plasma andalveolar levels of TF are higher in ARDS patients as comparedto patients with hydrostatic edema [187] Notably patientswith sepsis-induced ARDS may have higher levels of TF ascompared to patients without ARDS [78]

(5) Cell-Free Hb Levels of cell-free hemoglobin (Hb) arehigher in the air space of ARDS patients as comparedto critically ill patients with hydrostatic lung edema [79]Instillation of red blood cells or cell-free hemoglobin causeslung injury in rats [188] and intra-alveolar hemorrhage isassociated with high levels of intra-alveolar cell-free Hbmore severe lung injury and increased lipid peroxidationin the lung from mice with tissue factor deficiency [79]Precise cellular and molecular mechanisms by which cell-free hemoglobin in the air space could mediate or potenti-ate ARDS are currently under investigation [189] Cell-freeHb could activate chemokine release within the lung and

decompartmentalization of hemoglobin is likely to provide asignificant proinflammatory stimulus in the setting of diffusealveolar damage and hemorrhage during ARDS [80]

314 EFPL Protein Ratio The pathophysiology of ARDSincludes disruption of several physical barriers includingendothelial and epithelial cell layers the basement mem-brane and the extracellularmatrix resulting in increased pul-monary microvascular permeability The pulmonary edemafluid-to-plasma protein (EFPL) ratio is a rapid safe andnoninvasive measure of alveolar-capillary membrane per-meability The EFPL ratio was first proposed as a tool todetermine the etiology of acute pulmonary edema [81] Morerecently in a large study of 390 critically ill patientsWare et aldemonstrated that the EFPL ratio had an excellent discrimi-native value in distinguishing ARDS from hydrostatic edemaand was strongly associated with clinical outcomes Using acutoff of 065 the EFPL ratio had a sensitivity of 81 and aspecificity of 81 for the diagnosis of ARDS [82]

32 Fibroproliferative Phase of ARDS In some patientsimportant and persistent accumulation of macrophagesfibrocytes fibroblasts and myofibroblasts in the alveolarcompartment leads to excessive deposition of ECM com-ponents including fibronectin and collagen types I and IIIamong other proteins An imbalance between profibrotic andantifibrotic mediators may subsequently drive this fibropro-liferative response [190] Growth factors play a major rolein the resolution of ARDS [17] Lung endothelial repair ispromoted by vascular endothelial growth factor (VEGF)A variety of growth factors promote repair of the alveo-lar epithelium including keratinocyte growth factor (KGF)hepatocyte growth factor (HGF) fibroblast growth factor(FGF) and transforming growth factor-120572 (TGF-120572) [17] Twomajor pathways with opposite effects involve growth factorsduring ARDS tyrosine kinase receptor mediation (eg KGFHGF FGF and VEGF) and serine-threonine kinase receptorssuch as TGF-1205731 which tend to have opposed effect on theupregulation that occurs when the tyrosine kinase receptorpathway is involved [85 191 192]

321 Endothelial Proliferation Novel evidence points to apotential role of VEGF in promoting repair of the alveolar-capillarymembrane during recovery fromARDS and under-standing the role of VEGF in this disease process couldbe crucial for developing new therapeutic strategies [85193] In the lung VEGF is produced primarily by epithelialcells it increases microvascular permeability [83] but has animportant role also during the repair phase by stimulatingendothelial cell proliferation and survival [86 149] Thelevels of VEGF are increased in plasma from patients withARDS but are decreased in BAL fluid compared to healthycontrols subsequently BAL levels of VEGF increase duringthe resolution of lung injury [39 84 149]

322 Epithelial Proliferation and Apoptosis KGF also knownas FGF-7 is a potent mitogenic factor for alveolar epithelialcells that is primarily produced by fibroblasts and other

Disease Markers 11

cells such as T lymphocytes KGF regulates transepithelialtransport of sodium by stimulating the epithelial channelNa+-K+-ATPase in alveolar epithelial cells [87]

HGF is a nonspecific mitogen secreted by fibroblastsalveolar macrophages endothelial cells and epithelial cellsSeveral animal and human studies suggest that KGF andHGFcould protect the alveolar space against injury and couldfacilitate the repair of alveolar structures after injury [88 194195] KGF levels could be measured in the BAL from patientswith ARDS but not in the BAL from those without ARDS inaddition BALKGFwas associated with poor prognosis [196]Elevated HGF levels were also associated with outcome [196]In 36 patients with ARDS and 11 patients with hydrostaticlung edema HGF and KGF were proven biologically activein the edema fluid of patients with ARDS and higher levelsof HGFwere associated withmortality in these patients [197]

Apoptosis of alveolar epithelial cells is a major phe-nomenon in the initiation and perpetuation of lung injury[89] The FasFasL system plays an important role in theregulation of cell life and death through its ability to initiateapoptosis [198] This system combines the cell membranesurface receptor Fas (CD95) and its natural ligand FasL(CD95L) Membrane-bound FasL mediates lymphocyte-dependent cytotoxicity clonal deletion of alloreactive T cellsand activation-induced suicide of T cells [199] Its solubleform (sFasL) results from cleavage of membrane FasL byMMPs and induces apoptosis in susceptible cells [200]Apoptosis is inducedwhenmembrane-bound or soluble FasLbinds to Fas-bearing cells By contrast apoptosis is inhibitedwhen soluble Fas binds to either membrane-bound FasL orsFasL thus preventing FasL from interacting withmembrane-bound Fas receptors [201] In patients with ARDS sFasL wasdetectable in the lung before and after the onset of clinicallydefined ARDS and nonsurvivors had significantly higherBAL levels of sFasL on day 1 as compared with survivors[200] Both soluble Fas and soluble FasL were associated withoutcome and higher in the lung edema fluid from patientswith ARDS compared to control patients with hydrostaticpulmonary edema [202] Nevertheless recent findings sug-gested limited role for FasFasL system and apoptosis inairway epithelial cell death during ARDS [90]

323 Fibroblast Proliferation Pulmonary fibroblasts pro-duce procollagen III peptide (PCP-III) that is a precursorof collagen The NT part of procollagen III resulting fromthe enzymatic cleavage of procollagen by specific proteases inthe extracellular space is considered as a marker of collagensynthesis Alveolar levels of N-PCP-III are higher in ARDSpatient as compared with controls [203] The elevation ofN-PCP-III in pulmonary edema fluid begins within the first24 h of ARDS that is during the acute phase of increasedendothelial and epithelial permeability to protein suggestingthat fibrosing alveolitis could begin very early in the course ofclinical ARDS [203] In another study high levels of N-PCP-III were early predictors of poor outcome [204 205] Morerecently Forel et al measured alveolar N-PCP-III in patientswith nonresolving ARDS thus identifying patients who haddeveloped lung fibroproliferation [206] Unfortunately it

is still unknown whether N-PCP-III measurements couldbe useful in selecting patients who would benefit fromglucocorticoid therapy among others to reduce the ARDS-associated lung fibrosis [207]

4 Perspectives

41 Combining Biomarkers Despite advances in the identi-fication of biomarker candidate and better understanding ofARDS pathogenesis no single clinical or biological markerreliably predicts clinical outcomes inARDSThe combinationof clinical and biological marker is attractive in order toimprove the sensitivity andor the specificity of the testespecially through a recent approach aimed at measuring8 biological markers that reflect endothelial and epithelialinjury inflammation and coagulation vWF SP-D TNF-R1IL-6 IL-8 ICAM-1 protein C and PAI-1 in 549 patientsenrolled in the the ARDSNet trial of low versus high positiveend-expiratory pressure [208] Clinical predictors predictedmortality with an area under the ROC curve (AUC) of082 whereas a combination of these 8 biomarkers and theclinical predictors had an AUC of 085 The best performingbiomarkers were the neutrophil chemotactic factor IL-8 andSP-D a product of AT2 cells [208] supporting the conceptthat acute inflammation and alveolar epithelial injury areimportant pathogenetic pathways in human ARDS Morerecently a panel of biomarkers of lung epithelial injuryand inflammation (SP-D sRAGE IL-8 CC16 and IL-6)provided excellent discrimination for diagnosis of ARDSin patients with severe sepsis [20] Therefore and beyondtheir better diagnostic and prognostic values the use of suchbiomarker panels may be useful for selecting patients forclinical trials that are designed to reduce lung epithelial injury[113] Nevertheless whether a therapeutic strategy based onbiomarker measurements would benefit patient outcome hasnever been investigated

42 Lung Imaging as an ARDS Biomarker Studies of lungimaging during ARDS have revealed that adequate ventilatorsettings may vary among patients with the same syndromeIn a large study gas and tissue distribution in the lungs ofARDS patients were assessed using computed tomography(CT) and compared to those of healthy volunteers [11] Lungmorphology in ARDS is characterized by marked excess oflung tissue associated with a major decrease in aerated lungregions and in functional residual capacity Some patientswith ARDS exhibit preserved aeration of the upper lobesdespite the presence of an overall excess of lung tissue (ldquofocalrdquoARDS) as opposed to other patients with more diffuse lossof aeration and excessive lung tissue (ldquodiffuserdquo or ldquononfocalrdquoARDS) [209]

Lung morphology may influence the response to pos-itive end-expiratory pressure (PEEP) recruitment maneu-vers (RM) prone position and patient outcome [12 210]In a prospective study of nineteen patients with ARDSConstantin et al found that lung morphology at zero end-expiratory pressure could predict the response to a RM withcontinuous positive airway pressure of 40 cm H

2O for 40

12 Disease Markers

seconds Nonfocal morphology was associated with higherlung recruitability and PaO

2FiO2was significantly increased

by the RM [12 211] In contrast patients with focal lungmorphology were at risk of significant hyperinflation duringthe RM with no improvement of arterial oxygenation

It has also been hypothesized that the effects of PEEPmay depend on lung morphology Puybasset et al assessedthe responses to PEEP among patients with focal or nonfocalARDS [210] The regional distribution of intrapulmonarygas and lung tissue influences the effects of PEEP in ARDSpatients maximal alveolar recruitment without evidenceof overdistension was observed in patients with nonfocalARDS Nevertheless PEEP induced mild alveolar recruit-ment in patients with focal ARDS along with overdistensionof previously aerated lung regions

Interestingly phenotyping patients with ARDS basedon their lung morphology might be possible by measuringplasma sRAGEwith commercially available kits even thoughthese findings need further validation [100 112] HoweverRAGE pathway is a promising candidate for subphenotypingpatients with ARDS as it is believed to play a major rolein the mechanisms leading to AFC and their regulation[110] Recent findings that support a relationship betweenimpaired AFC and lung morphology may therefore fill a gapin the full recognition of an ARDS phenotype based on lungmorphology that could be linked to an endotype of impairedAFC and activated RAGE pathway [12 100 101 112 113 212]

43 Biomarkers in ARDS Can They Improve Patient CareBiomarkers are broadly used in critically ill patientsespecially during inflammatory andor infectious diseasesBiomarkers have been commonly defined as characteristicsthat are objectively measured and evaluated as indicatorsof normal biological processes pathogenic processes orpharmacologic responses to therapeutic interventions [213214] Biomarkers provide a powerful approach to understanda disease with multiple applications in observational andanalytic epidemiology randomized clinical trials screeningand diagnosis or prognosis [215]

Nevertheless there are important technical attributes fora relevant biomarker First the marker must be present inperipheral body tissue andor fluid (eg blood urine salivabreath or cerebrospinal fluid) second it must be easy todetect or quantify in assays that are both affordable androbust and third its regulation should be associated asspecifically as possible with damage of a particular tissuepreferably in a quantifiable manner Prior to the widespreaduse of a marker of interest it is essential that validation andconfirmation of candidate biomarkers by robust statisticalmethods are performed during biomarker discovery [215]Sensitivity and specificity are common quality parametersfor biomarkers Sensitivity describes the probability of apositive test in cases and specificity describes probability ofnegative test in controls An association between sensitivityand specificity is represented in the ROC curve by graphingsensitivity versus 100 minus specificity Area under the ROC curve(AUROC) is therefore a measure of performance of a markerThere is no absolute cutoff value of AUROC for robustness of

a marker but aminimum of 07 is required and values greaterthan 08 are good particularly in a heterogeneous critically illpatient population [216 217]

To summarize an ideal biomarker should indicate aclear relationship with the pathophysiologic event needsto be reliable reproducible disease specific and sensitiveand should be sampled by simple methods and relativelyinexpensive with little or no diurnal variation DuringARDS no single marker has been validated with all thesecriteria to date yet we believe that sRAGE may fulfill allprerequisites of a biomarker of ARDS First plasma sRAGEhas good diagnostic and prognostic values [96 99 100109 112] Second it is very well correlated with lung injuryseverity and specific pathophysiologic features of ARDS forexample alveolar fluid clearance and lung morphology [9699ndash101 109 112] Previous studies of the predictive value ofearly levels of sRAGE for the development of ARDS in ageneral population of patients admitted to the emergencydepartment were negative [130] but current research focuseson both the kinetics of sRAGE and esRAGE and RAGE genepolymorphisms as predictors of the development of ARDSin at-risk critically ill patients [114] Finally there is someevidence suggesting that monitoring sRAGE could informat least partially on therapeutic responses in patients with orwithout ARDS [24 99 113] If these data are confirmed byfuture studies such findingswould definitely help to reinforcesRAGE a real biomarker of ARDS

5 Conclusion

Biomarker research provides an important translational linkto our understanding of lung pathobiology Through theidentification and testing of candidate biomarkers we havegained insight into the pathogenic importance of endothelialand epithelial injury and have started to unravel the complexpathways that contribute to endothelial and epithelial celldysfunction inflammation fibrosis and apoptosis in ARDSIn addition biomarker studies may help us to explore thecellular and molecular mechanisms of various therapeuticstrategies for ARDS and to better understand the potentialproinflammatory effects of mechanical ventilation Giventhe clinical heterogeneity of patients with ARDS and thecomplexity of the underlying pathobiology it is unlikely thata single biomarker will emerge for ARDS as cardiac-specifictroponin did for myocardial infarction but the develop-ment of small biomarker panels reflecting each importantlung injury pathway would provide valuable predictive andprognostic information for both clinicians and investigatorsWhile biomarkers are currently not recommended for usein clinical practice in ARDS biomarker discovery mayhold significant promise in order to develop and applytargeted therapies and to identify candidates for enrollmentin patient-tailored clinical trials of novel therapies for ARDS

Disclosure

The funders had no influence on the study design conductand analysis or on the preparation of this paper

Disease Markers 13

Conflict of Interests

No conflict of interests other sources of financial supportcorporate involvement patent holdings and so forth are tobe declared for all authors

Authorsrsquo Contribution

Raiko Blondonnet was involved in the conception and designof the review in writing the paper and in its revision priorto submission Jean-Michel Constantin was involved in theconception and design of the review in writing the paperand in its revision prior to submission Vincent Sapin wasinvolved in the conception and design of the review inwriting the paper and in its revision prior to submissionMatthieu Jabaudon takes responsibility for the content ofthe paper and was involved in the conception and design ofthe review in writing the paper and in its revision prior tosubmission

Acknowledgments

This work was supported by grants from the AuvergneRegional Council (ldquoProgramme Nouveau Chercheur de laRegion Auvergnerdquo 2013) the french Agence Nationale de laRecherche and the Direction Generale de lrsquoOffre de Soins(ldquoProgramme de Recherche Translationnelle en Santerdquo ANR-13-PRTS-0010)

References

[1] VM Ranieri G D Rubenfeld P TThompson et al ldquoAcute res-piratory distress syndrome the Berlin definitionrdquo The Journalof the American Medical Association vol 307 no 23 pp 2526ndash2533 2012

[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000

[3] C Brun-Buisson C Minelli G Bertolini et al ldquoEpidemiologyand outcome of acute lung injury in European intensive careunitsrdquo Intensive Care Medicine vol 30 no 1 pp 51ndash61 2004

[4] G D Rubenfeld E Caldwell E Peabody et al ldquoIncidence andoutcomes of acute lung injuryrdquo The New England Journal ofMedicine vol 353 no 16 pp 1685ndash1693 2005

[5] D W Dowdy M P Eid C R Dennison et al ldquoQuality oflife after acute respiratory distress syndrome a meta-analysisrdquoIntensive Care Medicine vol 32 no 8 pp 1115ndash1124 2006

[6] C S Calfee M D Eisner L B Ware et al ldquoTrauma-associatedlung injury differs clinically and biologically from acute lunginjury due to other clinical disordersrdquo Critical Care Medicinevol 35 no 10 pp 2243ndash2250 2007

[7] C S Calfee D R Janz G R Bernard et al ldquoDistinct molecularphenotypes of direct versus indirect ARDS in single and multi-center studiesrdquo Chest vol 147 no 6 pp 1539ndash1548 2015

[8] P Tejera N J Meyer F Chen et al ldquoDistinct and replicablegenetic risk factors for acute respiratory distress syndromeof pulmonary or extrapulmonary originrdquo Journal of MedicalGenetics vol 49 no 11 pp 671ndash680 2012

[9] M A Matthay G A Zimmerman C Esmon et al ldquoFutureresearch directions in acute lung injury summary of a National

Heart Lung and Blood Institute Working Grouprdquo AmericanJournal of Respiratory and Critical Care Medicine vol 167 no7 pp 1027ndash1035 2003

[10] J P Reilly S Bellamy M G S Shashaty et al ldquoHeterogeneousphenotypes of acute respiratory distress syndrome after majortraumardquo Annals of the American Thoracic Society vol 11 no 5pp 728ndash736 2014

[11] L Puybasset P Cluzel N Chao et al ldquoA computed tomographyscan assessment of regional lung volume in acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol158 no 5 pp 1644ndash1655 1998

[12] J-M Constantin S Grasso G Chanques et al ldquoLungmorphol-ogy predicts response to recruitment maneuver in patients withacute respiratory distress syndromerdquo Critical Care Medicinevol 38 no 4 pp 1108ndash1117 2010

[13] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoSubphenotypes in acute respiratorydistress syndrome latent class analysis of data from tworandomised controlled trialsrdquoThe Lancet Respiratory Medicinevol 2 no 8 pp 611ndash620 2014

[14] R Marshall G Bellingan and G Laurent ldquoThe acute respira-tory distress syndrome fibrosis in the fast lanerdquoThorax vol 53no 10 pp 815ndash817 1998

[15] R B Henderson J A R Hobbs M Mathies and N HoggldquoRapid recruitment of inflammatory monocytes is independentof neutrophil migrationrdquo Blood vol 102 no 1 pp 328ndash3352003

[16] HMMarriott andDH Dockrell ldquoThe role of themacrophagein lung disease mediated by bacteriardquo Experimental LungResearch vol 33 no 10 pp 493ndash505 2007

[17] L J M Cross and M A Matthay ldquoBiomarkers in acute lunginjury insights into the pathogenesis of acute lung injuryrdquoCritical Care Clinics vol 27 no 2 pp 355ndash377 2011

[18] H K Gaggin and J L Januzzi ldquoBiomarkers and diagnostics inheart failurerdquo Biochimica et Biophysica Acta (BBA)mdashMolecularBasis of Disease vol 1832 no 12 pp 2442ndash2450 2013

[19] E Christenson and R H Christenson ldquoThe role of cardiacbiomarkers in the diagnosis and management of patientspresenting with suspected acute coronary syndromerdquo Annals ofLaboratory Medicine vol 33 no 5 pp 309ndash318 2013

[20] L B Ware T Koyama Z Zhao et al ldquoBiomarkers of lungepithelial injury and inflammation distinguish severe sepsispatientswith acute respiratory distress syndromerdquoCritical Carevol 17 no 5 article R253 2013

[21] M A Matthay L B Ware and G A Zimmerman ldquoTheacute respiratory distress syndromerdquo The Journal of ClinicalInvestigation vol 122 no 8 pp 2731ndash2740 2012

[22] M Shirasawa N Fujiwara S Hirabayashi et al ldquoReceptor foradvanced glycation end-products is a marker of type I lungalveolar cellsrdquo Genes to Cells vol 9 no 2 pp 165ndash174 2004

[23] M Neeper A M Schmidt J Brett et al ldquoCloning andexpression of a cell surface receptor for advanced glycosylationend products of proteinsrdquo The Journal of Biological Chemistryvol 267 no 21 pp 14998ndash15004 1992

[24] M Jabaudon E Futier L Roszyk V Sapin B Pereira andJ Constantin ldquoAssociation between intraoperative ventilatorsettings and plasma levels of soluble receptor for advancedglycation end-products in patients without pre-existing lunginjuryrdquo Respirology vol 20 no 7 pp 1131ndash1138 2015

[25] L G Dobbs R F Gonzalez L Allen and D K Froh ldquoHTI56an integral membrane protein specific to human alveolar type

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Disease Markers 11

cells such as T lymphocytes KGF regulates transepithelialtransport of sodium by stimulating the epithelial channelNa+-K+-ATPase in alveolar epithelial cells [87]

HGF is a nonspecific mitogen secreted by fibroblastsalveolar macrophages endothelial cells and epithelial cellsSeveral animal and human studies suggest that KGF andHGFcould protect the alveolar space against injury and couldfacilitate the repair of alveolar structures after injury [88 194195] KGF levels could be measured in the BAL from patientswith ARDS but not in the BAL from those without ARDS inaddition BALKGFwas associated with poor prognosis [196]Elevated HGF levels were also associated with outcome [196]In 36 patients with ARDS and 11 patients with hydrostaticlung edema HGF and KGF were proven biologically activein the edema fluid of patients with ARDS and higher levelsof HGFwere associated withmortality in these patients [197]

Apoptosis of alveolar epithelial cells is a major phe-nomenon in the initiation and perpetuation of lung injury[89] The FasFasL system plays an important role in theregulation of cell life and death through its ability to initiateapoptosis [198] This system combines the cell membranesurface receptor Fas (CD95) and its natural ligand FasL(CD95L) Membrane-bound FasL mediates lymphocyte-dependent cytotoxicity clonal deletion of alloreactive T cellsand activation-induced suicide of T cells [199] Its solubleform (sFasL) results from cleavage of membrane FasL byMMPs and induces apoptosis in susceptible cells [200]Apoptosis is inducedwhenmembrane-bound or soluble FasLbinds to Fas-bearing cells By contrast apoptosis is inhibitedwhen soluble Fas binds to either membrane-bound FasL orsFasL thus preventing FasL from interacting withmembrane-bound Fas receptors [201] In patients with ARDS sFasL wasdetectable in the lung before and after the onset of clinicallydefined ARDS and nonsurvivors had significantly higherBAL levels of sFasL on day 1 as compared with survivors[200] Both soluble Fas and soluble FasL were associated withoutcome and higher in the lung edema fluid from patientswith ARDS compared to control patients with hydrostaticpulmonary edema [202] Nevertheless recent findings sug-gested limited role for FasFasL system and apoptosis inairway epithelial cell death during ARDS [90]

323 Fibroblast Proliferation Pulmonary fibroblasts pro-duce procollagen III peptide (PCP-III) that is a precursorof collagen The NT part of procollagen III resulting fromthe enzymatic cleavage of procollagen by specific proteases inthe extracellular space is considered as a marker of collagensynthesis Alveolar levels of N-PCP-III are higher in ARDSpatient as compared with controls [203] The elevation ofN-PCP-III in pulmonary edema fluid begins within the first24 h of ARDS that is during the acute phase of increasedendothelial and epithelial permeability to protein suggestingthat fibrosing alveolitis could begin very early in the course ofclinical ARDS [203] In another study high levels of N-PCP-III were early predictors of poor outcome [204 205] Morerecently Forel et al measured alveolar N-PCP-III in patientswith nonresolving ARDS thus identifying patients who haddeveloped lung fibroproliferation [206] Unfortunately it

is still unknown whether N-PCP-III measurements couldbe useful in selecting patients who would benefit fromglucocorticoid therapy among others to reduce the ARDS-associated lung fibrosis [207]

4 Perspectives

41 Combining Biomarkers Despite advances in the identi-fication of biomarker candidate and better understanding ofARDS pathogenesis no single clinical or biological markerreliably predicts clinical outcomes inARDSThe combinationof clinical and biological marker is attractive in order toimprove the sensitivity andor the specificity of the testespecially through a recent approach aimed at measuring8 biological markers that reflect endothelial and epithelialinjury inflammation and coagulation vWF SP-D TNF-R1IL-6 IL-8 ICAM-1 protein C and PAI-1 in 549 patientsenrolled in the the ARDSNet trial of low versus high positiveend-expiratory pressure [208] Clinical predictors predictedmortality with an area under the ROC curve (AUC) of082 whereas a combination of these 8 biomarkers and theclinical predictors had an AUC of 085 The best performingbiomarkers were the neutrophil chemotactic factor IL-8 andSP-D a product of AT2 cells [208] supporting the conceptthat acute inflammation and alveolar epithelial injury areimportant pathogenetic pathways in human ARDS Morerecently a panel of biomarkers of lung epithelial injuryand inflammation (SP-D sRAGE IL-8 CC16 and IL-6)provided excellent discrimination for diagnosis of ARDSin patients with severe sepsis [20] Therefore and beyondtheir better diagnostic and prognostic values the use of suchbiomarker panels may be useful for selecting patients forclinical trials that are designed to reduce lung epithelial injury[113] Nevertheless whether a therapeutic strategy based onbiomarker measurements would benefit patient outcome hasnever been investigated

42 Lung Imaging as an ARDS Biomarker Studies of lungimaging during ARDS have revealed that adequate ventilatorsettings may vary among patients with the same syndromeIn a large study gas and tissue distribution in the lungs ofARDS patients were assessed using computed tomography(CT) and compared to those of healthy volunteers [11] Lungmorphology in ARDS is characterized by marked excess oflung tissue associated with a major decrease in aerated lungregions and in functional residual capacity Some patientswith ARDS exhibit preserved aeration of the upper lobesdespite the presence of an overall excess of lung tissue (ldquofocalrdquoARDS) as opposed to other patients with more diffuse lossof aeration and excessive lung tissue (ldquodiffuserdquo or ldquononfocalrdquoARDS) [209]

Lung morphology may influence the response to pos-itive end-expiratory pressure (PEEP) recruitment maneu-vers (RM) prone position and patient outcome [12 210]In a prospective study of nineteen patients with ARDSConstantin et al found that lung morphology at zero end-expiratory pressure could predict the response to a RM withcontinuous positive airway pressure of 40 cm H

2O for 40

12 Disease Markers

seconds Nonfocal morphology was associated with higherlung recruitability and PaO

2FiO2was significantly increased

by the RM [12 211] In contrast patients with focal lungmorphology were at risk of significant hyperinflation duringthe RM with no improvement of arterial oxygenation

It has also been hypothesized that the effects of PEEPmay depend on lung morphology Puybasset et al assessedthe responses to PEEP among patients with focal or nonfocalARDS [210] The regional distribution of intrapulmonarygas and lung tissue influences the effects of PEEP in ARDSpatients maximal alveolar recruitment without evidenceof overdistension was observed in patients with nonfocalARDS Nevertheless PEEP induced mild alveolar recruit-ment in patients with focal ARDS along with overdistensionof previously aerated lung regions

Interestingly phenotyping patients with ARDS basedon their lung morphology might be possible by measuringplasma sRAGEwith commercially available kits even thoughthese findings need further validation [100 112] HoweverRAGE pathway is a promising candidate for subphenotypingpatients with ARDS as it is believed to play a major rolein the mechanisms leading to AFC and their regulation[110] Recent findings that support a relationship betweenimpaired AFC and lung morphology may therefore fill a gapin the full recognition of an ARDS phenotype based on lungmorphology that could be linked to an endotype of impairedAFC and activated RAGE pathway [12 100 101 112 113 212]

43 Biomarkers in ARDS Can They Improve Patient CareBiomarkers are broadly used in critically ill patientsespecially during inflammatory andor infectious diseasesBiomarkers have been commonly defined as characteristicsthat are objectively measured and evaluated as indicatorsof normal biological processes pathogenic processes orpharmacologic responses to therapeutic interventions [213214] Biomarkers provide a powerful approach to understanda disease with multiple applications in observational andanalytic epidemiology randomized clinical trials screeningand diagnosis or prognosis [215]

Nevertheless there are important technical attributes fora relevant biomarker First the marker must be present inperipheral body tissue andor fluid (eg blood urine salivabreath or cerebrospinal fluid) second it must be easy todetect or quantify in assays that are both affordable androbust and third its regulation should be associated asspecifically as possible with damage of a particular tissuepreferably in a quantifiable manner Prior to the widespreaduse of a marker of interest it is essential that validation andconfirmation of candidate biomarkers by robust statisticalmethods are performed during biomarker discovery [215]Sensitivity and specificity are common quality parametersfor biomarkers Sensitivity describes the probability of apositive test in cases and specificity describes probability ofnegative test in controls An association between sensitivityand specificity is represented in the ROC curve by graphingsensitivity versus 100 minus specificity Area under the ROC curve(AUROC) is therefore a measure of performance of a markerThere is no absolute cutoff value of AUROC for robustness of

a marker but aminimum of 07 is required and values greaterthan 08 are good particularly in a heterogeneous critically illpatient population [216 217]

To summarize an ideal biomarker should indicate aclear relationship with the pathophysiologic event needsto be reliable reproducible disease specific and sensitiveand should be sampled by simple methods and relativelyinexpensive with little or no diurnal variation DuringARDS no single marker has been validated with all thesecriteria to date yet we believe that sRAGE may fulfill allprerequisites of a biomarker of ARDS First plasma sRAGEhas good diagnostic and prognostic values [96 99 100109 112] Second it is very well correlated with lung injuryseverity and specific pathophysiologic features of ARDS forexample alveolar fluid clearance and lung morphology [9699ndash101 109 112] Previous studies of the predictive value ofearly levels of sRAGE for the development of ARDS in ageneral population of patients admitted to the emergencydepartment were negative [130] but current research focuseson both the kinetics of sRAGE and esRAGE and RAGE genepolymorphisms as predictors of the development of ARDSin at-risk critically ill patients [114] Finally there is someevidence suggesting that monitoring sRAGE could informat least partially on therapeutic responses in patients with orwithout ARDS [24 99 113] If these data are confirmed byfuture studies such findingswould definitely help to reinforcesRAGE a real biomarker of ARDS

5 Conclusion

Biomarker research provides an important translational linkto our understanding of lung pathobiology Through theidentification and testing of candidate biomarkers we havegained insight into the pathogenic importance of endothelialand epithelial injury and have started to unravel the complexpathways that contribute to endothelial and epithelial celldysfunction inflammation fibrosis and apoptosis in ARDSIn addition biomarker studies may help us to explore thecellular and molecular mechanisms of various therapeuticstrategies for ARDS and to better understand the potentialproinflammatory effects of mechanical ventilation Giventhe clinical heterogeneity of patients with ARDS and thecomplexity of the underlying pathobiology it is unlikely thata single biomarker will emerge for ARDS as cardiac-specifictroponin did for myocardial infarction but the develop-ment of small biomarker panels reflecting each importantlung injury pathway would provide valuable predictive andprognostic information for both clinicians and investigatorsWhile biomarkers are currently not recommended for usein clinical practice in ARDS biomarker discovery mayhold significant promise in order to develop and applytargeted therapies and to identify candidates for enrollmentin patient-tailored clinical trials of novel therapies for ARDS

Disclosure

The funders had no influence on the study design conductand analysis or on the preparation of this paper

Disease Markers 13

Conflict of Interests

No conflict of interests other sources of financial supportcorporate involvement patent holdings and so forth are tobe declared for all authors

Authorsrsquo Contribution

Raiko Blondonnet was involved in the conception and designof the review in writing the paper and in its revision priorto submission Jean-Michel Constantin was involved in theconception and design of the review in writing the paperand in its revision prior to submission Vincent Sapin wasinvolved in the conception and design of the review inwriting the paper and in its revision prior to submissionMatthieu Jabaudon takes responsibility for the content ofthe paper and was involved in the conception and design ofthe review in writing the paper and in its revision prior tosubmission

Acknowledgments

This work was supported by grants from the AuvergneRegional Council (ldquoProgramme Nouveau Chercheur de laRegion Auvergnerdquo 2013) the french Agence Nationale de laRecherche and the Direction Generale de lrsquoOffre de Soins(ldquoProgramme de Recherche Translationnelle en Santerdquo ANR-13-PRTS-0010)

References

[1] VM Ranieri G D Rubenfeld P TThompson et al ldquoAcute res-piratory distress syndrome the Berlin definitionrdquo The Journalof the American Medical Association vol 307 no 23 pp 2526ndash2533 2012

[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000

[3] C Brun-Buisson C Minelli G Bertolini et al ldquoEpidemiologyand outcome of acute lung injury in European intensive careunitsrdquo Intensive Care Medicine vol 30 no 1 pp 51ndash61 2004

[4] G D Rubenfeld E Caldwell E Peabody et al ldquoIncidence andoutcomes of acute lung injuryrdquo The New England Journal ofMedicine vol 353 no 16 pp 1685ndash1693 2005

[5] D W Dowdy M P Eid C R Dennison et al ldquoQuality oflife after acute respiratory distress syndrome a meta-analysisrdquoIntensive Care Medicine vol 32 no 8 pp 1115ndash1124 2006

[6] C S Calfee M D Eisner L B Ware et al ldquoTrauma-associatedlung injury differs clinically and biologically from acute lunginjury due to other clinical disordersrdquo Critical Care Medicinevol 35 no 10 pp 2243ndash2250 2007

[7] C S Calfee D R Janz G R Bernard et al ldquoDistinct molecularphenotypes of direct versus indirect ARDS in single and multi-center studiesrdquo Chest vol 147 no 6 pp 1539ndash1548 2015

[8] P Tejera N J Meyer F Chen et al ldquoDistinct and replicablegenetic risk factors for acute respiratory distress syndromeof pulmonary or extrapulmonary originrdquo Journal of MedicalGenetics vol 49 no 11 pp 671ndash680 2012

[9] M A Matthay G A Zimmerman C Esmon et al ldquoFutureresearch directions in acute lung injury summary of a National

Heart Lung and Blood Institute Working Grouprdquo AmericanJournal of Respiratory and Critical Care Medicine vol 167 no7 pp 1027ndash1035 2003

[10] J P Reilly S Bellamy M G S Shashaty et al ldquoHeterogeneousphenotypes of acute respiratory distress syndrome after majortraumardquo Annals of the American Thoracic Society vol 11 no 5pp 728ndash736 2014

[11] L Puybasset P Cluzel N Chao et al ldquoA computed tomographyscan assessment of regional lung volume in acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol158 no 5 pp 1644ndash1655 1998

[12] J-M Constantin S Grasso G Chanques et al ldquoLungmorphol-ogy predicts response to recruitment maneuver in patients withacute respiratory distress syndromerdquo Critical Care Medicinevol 38 no 4 pp 1108ndash1117 2010

[13] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoSubphenotypes in acute respiratorydistress syndrome latent class analysis of data from tworandomised controlled trialsrdquoThe Lancet Respiratory Medicinevol 2 no 8 pp 611ndash620 2014

[14] R Marshall G Bellingan and G Laurent ldquoThe acute respira-tory distress syndrome fibrosis in the fast lanerdquoThorax vol 53no 10 pp 815ndash817 1998

[15] R B Henderson J A R Hobbs M Mathies and N HoggldquoRapid recruitment of inflammatory monocytes is independentof neutrophil migrationrdquo Blood vol 102 no 1 pp 328ndash3352003

[16] HMMarriott andDH Dockrell ldquoThe role of themacrophagein lung disease mediated by bacteriardquo Experimental LungResearch vol 33 no 10 pp 493ndash505 2007

[17] L J M Cross and M A Matthay ldquoBiomarkers in acute lunginjury insights into the pathogenesis of acute lung injuryrdquoCritical Care Clinics vol 27 no 2 pp 355ndash377 2011

[18] H K Gaggin and J L Januzzi ldquoBiomarkers and diagnostics inheart failurerdquo Biochimica et Biophysica Acta (BBA)mdashMolecularBasis of Disease vol 1832 no 12 pp 2442ndash2450 2013

[19] E Christenson and R H Christenson ldquoThe role of cardiacbiomarkers in the diagnosis and management of patientspresenting with suspected acute coronary syndromerdquo Annals ofLaboratory Medicine vol 33 no 5 pp 309ndash318 2013

[20] L B Ware T Koyama Z Zhao et al ldquoBiomarkers of lungepithelial injury and inflammation distinguish severe sepsispatientswith acute respiratory distress syndromerdquoCritical Carevol 17 no 5 article R253 2013

[21] M A Matthay L B Ware and G A Zimmerman ldquoTheacute respiratory distress syndromerdquo The Journal of ClinicalInvestigation vol 122 no 8 pp 2731ndash2740 2012

[22] M Shirasawa N Fujiwara S Hirabayashi et al ldquoReceptor foradvanced glycation end-products is a marker of type I lungalveolar cellsrdquo Genes to Cells vol 9 no 2 pp 165ndash174 2004

[23] M Neeper A M Schmidt J Brett et al ldquoCloning andexpression of a cell surface receptor for advanced glycosylationend products of proteinsrdquo The Journal of Biological Chemistryvol 267 no 21 pp 14998ndash15004 1992

[24] M Jabaudon E Futier L Roszyk V Sapin B Pereira andJ Constantin ldquoAssociation between intraoperative ventilatorsettings and plasma levels of soluble receptor for advancedglycation end-products in patients without pre-existing lunginjuryrdquo Respirology vol 20 no 7 pp 1131ndash1138 2015

[25] L G Dobbs R F Gonzalez L Allen and D K Froh ldquoHTI56an integral membrane protein specific to human alveolar type

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

12 Disease Markers

seconds Nonfocal morphology was associated with higherlung recruitability and PaO

2FiO2was significantly increased

by the RM [12 211] In contrast patients with focal lungmorphology were at risk of significant hyperinflation duringthe RM with no improvement of arterial oxygenation

It has also been hypothesized that the effects of PEEPmay depend on lung morphology Puybasset et al assessedthe responses to PEEP among patients with focal or nonfocalARDS [210] The regional distribution of intrapulmonarygas and lung tissue influences the effects of PEEP in ARDSpatients maximal alveolar recruitment without evidenceof overdistension was observed in patients with nonfocalARDS Nevertheless PEEP induced mild alveolar recruit-ment in patients with focal ARDS along with overdistensionof previously aerated lung regions

Interestingly phenotyping patients with ARDS basedon their lung morphology might be possible by measuringplasma sRAGEwith commercially available kits even thoughthese findings need further validation [100 112] HoweverRAGE pathway is a promising candidate for subphenotypingpatients with ARDS as it is believed to play a major rolein the mechanisms leading to AFC and their regulation[110] Recent findings that support a relationship betweenimpaired AFC and lung morphology may therefore fill a gapin the full recognition of an ARDS phenotype based on lungmorphology that could be linked to an endotype of impairedAFC and activated RAGE pathway [12 100 101 112 113 212]

43 Biomarkers in ARDS Can They Improve Patient CareBiomarkers are broadly used in critically ill patientsespecially during inflammatory andor infectious diseasesBiomarkers have been commonly defined as characteristicsthat are objectively measured and evaluated as indicatorsof normal biological processes pathogenic processes orpharmacologic responses to therapeutic interventions [213214] Biomarkers provide a powerful approach to understanda disease with multiple applications in observational andanalytic epidemiology randomized clinical trials screeningand diagnosis or prognosis [215]

Nevertheless there are important technical attributes fora relevant biomarker First the marker must be present inperipheral body tissue andor fluid (eg blood urine salivabreath or cerebrospinal fluid) second it must be easy todetect or quantify in assays that are both affordable androbust and third its regulation should be associated asspecifically as possible with damage of a particular tissuepreferably in a quantifiable manner Prior to the widespreaduse of a marker of interest it is essential that validation andconfirmation of candidate biomarkers by robust statisticalmethods are performed during biomarker discovery [215]Sensitivity and specificity are common quality parametersfor biomarkers Sensitivity describes the probability of apositive test in cases and specificity describes probability ofnegative test in controls An association between sensitivityand specificity is represented in the ROC curve by graphingsensitivity versus 100 minus specificity Area under the ROC curve(AUROC) is therefore a measure of performance of a markerThere is no absolute cutoff value of AUROC for robustness of

a marker but aminimum of 07 is required and values greaterthan 08 are good particularly in a heterogeneous critically illpatient population [216 217]

To summarize an ideal biomarker should indicate aclear relationship with the pathophysiologic event needsto be reliable reproducible disease specific and sensitiveand should be sampled by simple methods and relativelyinexpensive with little or no diurnal variation DuringARDS no single marker has been validated with all thesecriteria to date yet we believe that sRAGE may fulfill allprerequisites of a biomarker of ARDS First plasma sRAGEhas good diagnostic and prognostic values [96 99 100109 112] Second it is very well correlated with lung injuryseverity and specific pathophysiologic features of ARDS forexample alveolar fluid clearance and lung morphology [9699ndash101 109 112] Previous studies of the predictive value ofearly levels of sRAGE for the development of ARDS in ageneral population of patients admitted to the emergencydepartment were negative [130] but current research focuseson both the kinetics of sRAGE and esRAGE and RAGE genepolymorphisms as predictors of the development of ARDSin at-risk critically ill patients [114] Finally there is someevidence suggesting that monitoring sRAGE could informat least partially on therapeutic responses in patients with orwithout ARDS [24 99 113] If these data are confirmed byfuture studies such findingswould definitely help to reinforcesRAGE a real biomarker of ARDS

5 Conclusion

Biomarker research provides an important translational linkto our understanding of lung pathobiology Through theidentification and testing of candidate biomarkers we havegained insight into the pathogenic importance of endothelialand epithelial injury and have started to unravel the complexpathways that contribute to endothelial and epithelial celldysfunction inflammation fibrosis and apoptosis in ARDSIn addition biomarker studies may help us to explore thecellular and molecular mechanisms of various therapeuticstrategies for ARDS and to better understand the potentialproinflammatory effects of mechanical ventilation Giventhe clinical heterogeneity of patients with ARDS and thecomplexity of the underlying pathobiology it is unlikely thata single biomarker will emerge for ARDS as cardiac-specifictroponin did for myocardial infarction but the develop-ment of small biomarker panels reflecting each importantlung injury pathway would provide valuable predictive andprognostic information for both clinicians and investigatorsWhile biomarkers are currently not recommended for usein clinical practice in ARDS biomarker discovery mayhold significant promise in order to develop and applytargeted therapies and to identify candidates for enrollmentin patient-tailored clinical trials of novel therapies for ARDS

Disclosure

The funders had no influence on the study design conductand analysis or on the preparation of this paper

Disease Markers 13

Conflict of Interests

No conflict of interests other sources of financial supportcorporate involvement patent holdings and so forth are tobe declared for all authors

Authorsrsquo Contribution

Raiko Blondonnet was involved in the conception and designof the review in writing the paper and in its revision priorto submission Jean-Michel Constantin was involved in theconception and design of the review in writing the paperand in its revision prior to submission Vincent Sapin wasinvolved in the conception and design of the review inwriting the paper and in its revision prior to submissionMatthieu Jabaudon takes responsibility for the content ofthe paper and was involved in the conception and design ofthe review in writing the paper and in its revision prior tosubmission

Acknowledgments

This work was supported by grants from the AuvergneRegional Council (ldquoProgramme Nouveau Chercheur de laRegion Auvergnerdquo 2013) the french Agence Nationale de laRecherche and the Direction Generale de lrsquoOffre de Soins(ldquoProgramme de Recherche Translationnelle en Santerdquo ANR-13-PRTS-0010)

References

[1] VM Ranieri G D Rubenfeld P TThompson et al ldquoAcute res-piratory distress syndrome the Berlin definitionrdquo The Journalof the American Medical Association vol 307 no 23 pp 2526ndash2533 2012

[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000

[3] C Brun-Buisson C Minelli G Bertolini et al ldquoEpidemiologyand outcome of acute lung injury in European intensive careunitsrdquo Intensive Care Medicine vol 30 no 1 pp 51ndash61 2004

[4] G D Rubenfeld E Caldwell E Peabody et al ldquoIncidence andoutcomes of acute lung injuryrdquo The New England Journal ofMedicine vol 353 no 16 pp 1685ndash1693 2005

[5] D W Dowdy M P Eid C R Dennison et al ldquoQuality oflife after acute respiratory distress syndrome a meta-analysisrdquoIntensive Care Medicine vol 32 no 8 pp 1115ndash1124 2006

[6] C S Calfee M D Eisner L B Ware et al ldquoTrauma-associatedlung injury differs clinically and biologically from acute lunginjury due to other clinical disordersrdquo Critical Care Medicinevol 35 no 10 pp 2243ndash2250 2007

[7] C S Calfee D R Janz G R Bernard et al ldquoDistinct molecularphenotypes of direct versus indirect ARDS in single and multi-center studiesrdquo Chest vol 147 no 6 pp 1539ndash1548 2015

[8] P Tejera N J Meyer F Chen et al ldquoDistinct and replicablegenetic risk factors for acute respiratory distress syndromeof pulmonary or extrapulmonary originrdquo Journal of MedicalGenetics vol 49 no 11 pp 671ndash680 2012

[9] M A Matthay G A Zimmerman C Esmon et al ldquoFutureresearch directions in acute lung injury summary of a National

Heart Lung and Blood Institute Working Grouprdquo AmericanJournal of Respiratory and Critical Care Medicine vol 167 no7 pp 1027ndash1035 2003

[10] J P Reilly S Bellamy M G S Shashaty et al ldquoHeterogeneousphenotypes of acute respiratory distress syndrome after majortraumardquo Annals of the American Thoracic Society vol 11 no 5pp 728ndash736 2014

[11] L Puybasset P Cluzel N Chao et al ldquoA computed tomographyscan assessment of regional lung volume in acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol158 no 5 pp 1644ndash1655 1998

[12] J-M Constantin S Grasso G Chanques et al ldquoLungmorphol-ogy predicts response to recruitment maneuver in patients withacute respiratory distress syndromerdquo Critical Care Medicinevol 38 no 4 pp 1108ndash1117 2010

[13] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoSubphenotypes in acute respiratorydistress syndrome latent class analysis of data from tworandomised controlled trialsrdquoThe Lancet Respiratory Medicinevol 2 no 8 pp 611ndash620 2014

[14] R Marshall G Bellingan and G Laurent ldquoThe acute respira-tory distress syndrome fibrosis in the fast lanerdquoThorax vol 53no 10 pp 815ndash817 1998

[15] R B Henderson J A R Hobbs M Mathies and N HoggldquoRapid recruitment of inflammatory monocytes is independentof neutrophil migrationrdquo Blood vol 102 no 1 pp 328ndash3352003

[16] HMMarriott andDH Dockrell ldquoThe role of themacrophagein lung disease mediated by bacteriardquo Experimental LungResearch vol 33 no 10 pp 493ndash505 2007

[17] L J M Cross and M A Matthay ldquoBiomarkers in acute lunginjury insights into the pathogenesis of acute lung injuryrdquoCritical Care Clinics vol 27 no 2 pp 355ndash377 2011

[18] H K Gaggin and J L Januzzi ldquoBiomarkers and diagnostics inheart failurerdquo Biochimica et Biophysica Acta (BBA)mdashMolecularBasis of Disease vol 1832 no 12 pp 2442ndash2450 2013

[19] E Christenson and R H Christenson ldquoThe role of cardiacbiomarkers in the diagnosis and management of patientspresenting with suspected acute coronary syndromerdquo Annals ofLaboratory Medicine vol 33 no 5 pp 309ndash318 2013

[20] L B Ware T Koyama Z Zhao et al ldquoBiomarkers of lungepithelial injury and inflammation distinguish severe sepsispatientswith acute respiratory distress syndromerdquoCritical Carevol 17 no 5 article R253 2013

[21] M A Matthay L B Ware and G A Zimmerman ldquoTheacute respiratory distress syndromerdquo The Journal of ClinicalInvestigation vol 122 no 8 pp 2731ndash2740 2012

[22] M Shirasawa N Fujiwara S Hirabayashi et al ldquoReceptor foradvanced glycation end-products is a marker of type I lungalveolar cellsrdquo Genes to Cells vol 9 no 2 pp 165ndash174 2004

[23] M Neeper A M Schmidt J Brett et al ldquoCloning andexpression of a cell surface receptor for advanced glycosylationend products of proteinsrdquo The Journal of Biological Chemistryvol 267 no 21 pp 14998ndash15004 1992

[24] M Jabaudon E Futier L Roszyk V Sapin B Pereira andJ Constantin ldquoAssociation between intraoperative ventilatorsettings and plasma levels of soluble receptor for advancedglycation end-products in patients without pre-existing lunginjuryrdquo Respirology vol 20 no 7 pp 1131ndash1138 2015

[25] L G Dobbs R F Gonzalez L Allen and D K Froh ldquoHTI56an integral membrane protein specific to human alveolar type

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Research and TreatmentAIDS

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Disease Markers 13

Conflict of Interests

No conflict of interests other sources of financial supportcorporate involvement patent holdings and so forth are tobe declared for all authors

Authorsrsquo Contribution

Raiko Blondonnet was involved in the conception and designof the review in writing the paper and in its revision priorto submission Jean-Michel Constantin was involved in theconception and design of the review in writing the paperand in its revision prior to submission Vincent Sapin wasinvolved in the conception and design of the review inwriting the paper and in its revision prior to submissionMatthieu Jabaudon takes responsibility for the content ofthe paper and was involved in the conception and design ofthe review in writing the paper and in its revision prior tosubmission

Acknowledgments

This work was supported by grants from the AuvergneRegional Council (ldquoProgramme Nouveau Chercheur de laRegion Auvergnerdquo 2013) the french Agence Nationale de laRecherche and the Direction Generale de lrsquoOffre de Soins(ldquoProgramme de Recherche Translationnelle en Santerdquo ANR-13-PRTS-0010)

References

[1] VM Ranieri G D Rubenfeld P TThompson et al ldquoAcute res-piratory distress syndrome the Berlin definitionrdquo The Journalof the American Medical Association vol 307 no 23 pp 2526ndash2533 2012

[2] L B Ware and M A Matthay ldquoThe acute respiratory distresssyndromerdquo The New England Journal of Medicine vol 342 no18 pp 1334ndash1349 2000

[3] C Brun-Buisson C Minelli G Bertolini et al ldquoEpidemiologyand outcome of acute lung injury in European intensive careunitsrdquo Intensive Care Medicine vol 30 no 1 pp 51ndash61 2004

[4] G D Rubenfeld E Caldwell E Peabody et al ldquoIncidence andoutcomes of acute lung injuryrdquo The New England Journal ofMedicine vol 353 no 16 pp 1685ndash1693 2005

[5] D W Dowdy M P Eid C R Dennison et al ldquoQuality oflife after acute respiratory distress syndrome a meta-analysisrdquoIntensive Care Medicine vol 32 no 8 pp 1115ndash1124 2006

[6] C S Calfee M D Eisner L B Ware et al ldquoTrauma-associatedlung injury differs clinically and biologically from acute lunginjury due to other clinical disordersrdquo Critical Care Medicinevol 35 no 10 pp 2243ndash2250 2007

[7] C S Calfee D R Janz G R Bernard et al ldquoDistinct molecularphenotypes of direct versus indirect ARDS in single and multi-center studiesrdquo Chest vol 147 no 6 pp 1539ndash1548 2015

[8] P Tejera N J Meyer F Chen et al ldquoDistinct and replicablegenetic risk factors for acute respiratory distress syndromeof pulmonary or extrapulmonary originrdquo Journal of MedicalGenetics vol 49 no 11 pp 671ndash680 2012

[9] M A Matthay G A Zimmerman C Esmon et al ldquoFutureresearch directions in acute lung injury summary of a National

Heart Lung and Blood Institute Working Grouprdquo AmericanJournal of Respiratory and Critical Care Medicine vol 167 no7 pp 1027ndash1035 2003

[10] J P Reilly S Bellamy M G S Shashaty et al ldquoHeterogeneousphenotypes of acute respiratory distress syndrome after majortraumardquo Annals of the American Thoracic Society vol 11 no 5pp 728ndash736 2014

[11] L Puybasset P Cluzel N Chao et al ldquoA computed tomographyscan assessment of regional lung volume in acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol158 no 5 pp 1644ndash1655 1998

[12] J-M Constantin S Grasso G Chanques et al ldquoLungmorphol-ogy predicts response to recruitment maneuver in patients withacute respiratory distress syndromerdquo Critical Care Medicinevol 38 no 4 pp 1108ndash1117 2010

[13] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoSubphenotypes in acute respiratorydistress syndrome latent class analysis of data from tworandomised controlled trialsrdquoThe Lancet Respiratory Medicinevol 2 no 8 pp 611ndash620 2014

[14] R Marshall G Bellingan and G Laurent ldquoThe acute respira-tory distress syndrome fibrosis in the fast lanerdquoThorax vol 53no 10 pp 815ndash817 1998

[15] R B Henderson J A R Hobbs M Mathies and N HoggldquoRapid recruitment of inflammatory monocytes is independentof neutrophil migrationrdquo Blood vol 102 no 1 pp 328ndash3352003

[16] HMMarriott andDH Dockrell ldquoThe role of themacrophagein lung disease mediated by bacteriardquo Experimental LungResearch vol 33 no 10 pp 493ndash505 2007

[17] L J M Cross and M A Matthay ldquoBiomarkers in acute lunginjury insights into the pathogenesis of acute lung injuryrdquoCritical Care Clinics vol 27 no 2 pp 355ndash377 2011

[18] H K Gaggin and J L Januzzi ldquoBiomarkers and diagnostics inheart failurerdquo Biochimica et Biophysica Acta (BBA)mdashMolecularBasis of Disease vol 1832 no 12 pp 2442ndash2450 2013

[19] E Christenson and R H Christenson ldquoThe role of cardiacbiomarkers in the diagnosis and management of patientspresenting with suspected acute coronary syndromerdquo Annals ofLaboratory Medicine vol 33 no 5 pp 309ndash318 2013

[20] L B Ware T Koyama Z Zhao et al ldquoBiomarkers of lungepithelial injury and inflammation distinguish severe sepsispatientswith acute respiratory distress syndromerdquoCritical Carevol 17 no 5 article R253 2013

[21] M A Matthay L B Ware and G A Zimmerman ldquoTheacute respiratory distress syndromerdquo The Journal of ClinicalInvestigation vol 122 no 8 pp 2731ndash2740 2012

[22] M Shirasawa N Fujiwara S Hirabayashi et al ldquoReceptor foradvanced glycation end-products is a marker of type I lungalveolar cellsrdquo Genes to Cells vol 9 no 2 pp 165ndash174 2004

[23] M Neeper A M Schmidt J Brett et al ldquoCloning andexpression of a cell surface receptor for advanced glycosylationend products of proteinsrdquo The Journal of Biological Chemistryvol 267 no 21 pp 14998ndash15004 1992

[24] M Jabaudon E Futier L Roszyk V Sapin B Pereira andJ Constantin ldquoAssociation between intraoperative ventilatorsettings and plasma levels of soluble receptor for advancedglycation end-products in patients without pre-existing lunginjuryrdquo Respirology vol 20 no 7 pp 1131ndash1138 2015

[25] L G Dobbs R F Gonzalez L Allen and D K Froh ldquoHTI56an integral membrane protein specific to human alveolar type

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

14 Disease Markers

I cellsrdquo Journal of Histochemistry amp Cytochemistry vol 47 pp129ndash137 1999

[26] L G Dobbs M C Williams and R Gonzalez ldquoMonoclonalantibodies specific to apical surfaces of rat alveolar type I cellsbind to surfaces of cultured but not freshly isolated type IIcellsrdquoMolecular Cell Research vol 970 no 2 pp 146ndash156 1988

[27] I W Cheng L B Ware K E Greene T J Nuckton M DEisner and M A Matthay ldquoPrognostic value of surfactantproteins A and D in patients with acute lung injuryrdquo CriticalCare Medicine vol 31 no 1 pp 20ndash27 2003

[28] A Agrawal H Zhuo S Brady et al ldquoPathogenetic andpredictive value of biomarkers in patients with ALI and lowerseverity of illness results from two clinical trialsrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 303 no 8 pp L634ndashL639 2012

[29] H Sato M E J Callister S Mumby et al ldquoKL-6 levels areelevated in plasma from patients with acute respiratory distresssyndromerdquo European Respiratory Journal vol 23 no 1 pp 142ndash145 2004

[30] R M Determann A A N M Royakkers J J Haitsma et alldquoPlasma levels of surfactant protein D and KL-6 for evaluationof lung injury in critically ill mechanically ventilated patientsrdquoBMC Pulmonary Medicine vol 10 article 6 2010

[31] F Broeckaert and A Bernard ldquoClara cell secretory protein(CC16) characteristics and perspectives as lung peripheralbiomarkerrdquo Clinical and Experimental Allergy vol 30 no 4 pp469ndash475 2000

[32] R Cartin-Ceba R D Hubmayr R Qin et al ldquoPredictive valueof plasma biomarkers for mortality and organ failure devel-opment in patients with acute respiratory distress syndromerdquoJournal of Critical Care vol 30 no 1 pp 219e1ndash219e7 2015

[33] L Eklund and P Saharinen ldquoAngiopoietin signaling in thevasculaturerdquoExperimental Cell Research vol 319 no 9 pp 1271ndash1280 2013

[34] C S Calfee D Gallagher J Abbott B T Thompson andM A Matthay ldquoPlasma angiopoietin-2 in clinical acute lunginjury prognostic and pathogenetic significancerdquo Critical CareMedicine vol 40 no 6 pp 1731ndash1737 2012

[35] M L Dustin R Rothlein A K Bhan C A Dinarello and TA Springer ldquoInduction by IL 1 and interferon-gamma tissuedistribution biochemistry and function of a natural adherencemolecule (ICAM-1)rdquoThe Journal of Immunology vol 137 no 1pp 245ndash254 1986

[36] R P McEver ldquoSelectins lectins that initiate cell adhesion underflowrdquoCurrent Opinion in Cell Biology vol 14 no 5 pp 581ndash5862002

[37] D Osaka Y Shibata K Kanouchi et al ldquoSoluble endothelialselectin in acute lung injury complicated by severe pneumoniardquoInternational Journal of Medical Sciences vol 8 no 4 pp 302ndash308 2011

[38] M Shibuya ldquoVascular endothelial growth factor and its receptorsystem physiological functions in angiogenesis and pathologi-cal roles in various diseasesrdquo Journal of Biochemistry vol 153no 1 pp 13ndash19 2013

[39] L B Ware R J Kaner R G Crystal et al ldquoVEGF levels in thealveolar compartment do not distinguish between ARDS andhydrostatic pulmonary oedamardquo European Respiratory Journalvol 26 no 1 pp 101ndash105 2005

[40] L B Ware M D Eisner B T Thompson P E Parsons and MAMatthay ldquoSignificance of vonWillebrand factor in septic andnonseptic patients with acute lung injuryrdquo American Journal of

Respiratory and Critical Care Medicine vol 170 no 7 pp 766ndash772 2004

[41] A J Reininger ldquoFunction of von Willebrand factor inhaemostasis and thrombosisrdquoHaemophilia vol 14 supplement5 pp 11ndash26 2008

[42] M S Bajaj and S M Tricomi ldquoPlasma levels of the threeendothelial-specific proteins von Willebrand factor tissue fac-tor pathway inhibitor and thrombomodulin do not predict thedevelopment of acute respiratory distress syndromerdquo IntensiveCare Medicine vol 25 no 11 pp 1259ndash1266 1999

[43] J Tzu andMPMarinkovich ldquoBridging structurewith functionstructural regulatory and developmental role of lamininsrdquoInternational Journal of Biochemistry and Cell Biology vol 40no 2 pp 199ndash214 2008

[44] K Torii K-I Iida Y Miyazaki et al ldquoHigher concentrationsof matrix metalloproteinases in bronchoalveolar lavage fluid ofpatients with adult respiratory distress syndromerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no1 pp 43ndash46 1997

[45] E G Cleary and M A Gibson ldquoElastic tissue elastin andelastin associated microfibrilsrdquo in Extracellular Matrix vol 2pp 95ndash140 Harwood Academic Publishers Amsterdam TheNetherlands 1996

[46] D E McClintock B Starcher M D Eisner et al ldquoHigher urinedesmosine levels are associated with mortality in patients withacute lung injuryrdquo The American Journal of PhysiologymdashLungCellular andMolecular Physiology vol 291 no 4 pp L566ndashL5712006

[47] J Hastbacka R Linko T Tervahartiala et al ldquoSerum MMP-8 and TIMP-1 in critically ill patients with acute respiratoryfailure TIMP-1 is associated with increased 90-day mortalityrdquoAnesthesia amp Analgesia vol 118 no 4 pp 790ndash798 2014

[48] A H Hergrueter K Nguyen and C A Owen ldquoMatrix met-alloproteinases all the RAGE in the acute respiratory distresssyndromerdquoThe American Journal of PhysiologymdashLung Cellularand Molecular Physiology vol 300 no 4 pp L512ndashL515 2011

[49] N Yamakawa T Uchida M A Matthay and K MakitaldquoProteolytic release of the receptor for advanced glycation endproducts from in vitro and in situ alveolar epithelial cellsrdquoTheAmerican Journal of Physiologymdash Lung Cellular and MolecularPhysiology vol 300 no 4 pp L516ndashL525 2011

[50] T Strowig J Henao-Mejia E Elinav and R Flavell ldquoInflam-masomes in health and diseaserdquo Nature vol 481 no 7381 pp278ndash286 2012

[51] HMakabeM Kojika G Takahashi et al ldquoInterleukin-18 levelsreflect the long-term prognosis of acute lung injury and acuterespiratory distress syndromerdquo Journal of Anesthesia vol 26 no5 pp 658ndash663 2012

[52] J Cohen ldquoThe immunopathogenesis of sepsisrdquoNature vol 420no 6917 pp 885ndash891 2002

[53] D Bouros M G Alexandrakis K M Antoniou et al ldquoTheclinical significance of serum and bronchoalveolar lavageinflammatory cytokines in patients at risk for Acute RespiratoryDistress Syndromerdquo BMC Pulmonary Medicine vol 4 article 62004

[54] P E Parsons M A Matthay L B Ware and M D EisnerldquoElevated plasma levels of soluble TNF receptors are associatedwith morbidity and mortality in patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 288 no 3 pp L426ndashL431 2005

[55] G U Meduri S Headley G Kohler et al ldquoPersistent elevationof inflammatory cytokines predicts a poor outcome in ARDS

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

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Computational and Mathematical Methods in Medicine

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Research and TreatmentAIDS

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Disease Markers 15

plasma IL-1120573 and IL-6 levels are consistent and efficient predic-tors of outcome over timerdquo Chest vol 107 no 4 pp 1062ndash10731995

[56] P E Parsons M Moss J L Vannice E E Moore F AMoore and J E Repine ldquoCirculating IL-1ra and IL-10 levelsare increased but do not predict the development of acuterespiratory distress syndrome in at-risk patientsrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 155 no4 pp 1469ndash1473 1997

[57] M A Kovach K A Stringer R Bunting et al ldquoMicroarrayanalysis identifies IL-1 receptor type 2 as a novel candidatebiomarker in patients with acute respiratory distress syndromerdquoRespiratory Research vol 16 article 29 2015

[58] R G Brower P N Lanken N MacIntyre et al ldquoHigher versuslower positive end-expiratory pressures in patients with theacute respiratory distress syndromerdquo The New England Journalof Medicine vol 351 no 4 pp 327ndash336 2004

[59] P E Parsons M D Eisner B T Thompson et al ldquoLower tidalvolume ventilation and plasma cytokine markers of inflamma-tion in patients with acute lung injuryrdquo Critical Care Medicinevol 33 no 1 pp 1ndash6 2005

[60] D F Fiorentino A Zlotnik T R Mosmann M Howard andA OrsquoGarra ldquoIL-10 inhibits cytokine production by activatedmacrophagesrdquo Journal of Immunology vol 147 no 11 pp 3815ndash3822 1991

[61] L Armstrong and A B Millar ldquoRelative production of tumournecrosis factor and interleukin 10 in adult respiratory distresssyndromerdquoThorax vol 52 no 5 pp 442ndash446 1997

[62] M J Cohen K Brohi C S Calfee et al ldquoEarly release ofhigh mobility group box nuclear protein 1 after severe traumain humans role of injury severity and tissue hypoperfusionrdquoCritical Care vol 13 no 6 article R174 2009

[63] TNakamura E SatoN Fujiwara YKawagoe SMaeda and S-I Yamagishi ldquoIncreased levels of soluble receptor for advancedglycation end products (sRAGE) and high mobility group box1 (HMGB1) are associated with death in patients with acuterespiratory distress syndromerdquo Clinical Biochemistry vol 44no 8-9 pp 601ndash604 2011

[64] T R Martin G D Rubenfeld J T Ruzinski et al ldquoRelationshipbetween soluble CD14 lipopolysaccharide binding proteinand the alveolar inflammatory response in patients with acuterespiratory distress syndromerdquo American Journal of Respiratoryand Critical Care Medicine vol 155 no 3 pp 937ndash944 1997

[65] J Villar L Perez-Mendez E Espinosa et al ldquoSerum lipopol-ysaccharide binding protein levels predict severity of lunginjury and mortality in patients with severe sepsisrdquo PLoS ONEvol 4 no 8 Article ID e6818 2009

[66] C Sittipunt K P Steinberg J T Ruzinski et al ldquoNitric oxideand nitrotyrosine in the lungs of patients with acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 163 no 2 pp 503ndash510 2001

[67] L B Ware J A Magarik N Wickersham et al ldquoLow plasmacitrulline levels are associated with acute respiratory distresssyndrome in patients with severe sepsisrdquo Critical Care vol 17article R10 2013

[68] E K Bajwa U A Khan J L Januzzi M N Gong B TThompson and D C Christiani ldquoPlasma C-reactive proteinlevels are associated with improved outcome in ARDSrdquo Chestvol 136 no 2 pp 471ndash480 2009

[69] S H Hoeboer H M Oudemans-van Straaten and A B JGroeneveld ldquoAlbumin rather than C-reactive protein may be

valuable in predicting and monitoring the severity and courseof acute respiratory distress syndrome in critically ill patientswith or at risk for the syndrome after new onset feverrdquo BMCPulmonary Medicine vol 15 article 22 2015

[70] I R Doyle C Hermans A Bernard T E Nicholas andA D Bersten ldquoClearance of clara cell secretory protein 16(CC16) and surfactant proteins A and B from blood in acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 158 no 5 pp 1528ndash1535 1998

[71] L B Ware J A Bastarache and L Wang ldquoCoagulationand fibrinolysis in human acute lung injurymdashnew therapeutictargetsrdquo Keio Journal of Medicine vol 54 no 3 pp 142ndash1492005

[72] P Prabhakaran L B Ware K E White M T Cross M AMatthay and M A Olman ldquoElevated levels of plasminogenactivator inhibitor-1 in pulmonary edema fluid are associatedwith mortality in acute lung injuryrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 285no 1 pp L20ndashL28 2003

[73] L B Ware X Fang and M A Matthay ldquoProtein C andthrombomodulin in human acute lung injuryrdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 285 no 3 pp L514ndashL521 2003

[74] A Sapru C S Calfee K D Liu et al ldquoPlasma solublethrombomodulin levels are associated with mortality in theacute respiratory distress syndromerdquo Intensive Care Medicinevol 41 pp 470ndash478 2015

[75] AKoutsi A Papapanagiotou andAG Papavassiliou ldquoThrom-bomodulin from haemostasis to inflammation and tumouri-genesisrdquo International Journal of Biochemistry and Cell Biologyvol 40 no 9 pp 1669ndash1673 2008

[76] EMConway ldquoThrombomodulin and its role in inflammationrdquoSeminars in Immunopathology vol 34 no 1 pp 107ndash125 2012

[77] W Ruf and M Riewald ldquoTissue factor-dependent coagulationprotease signaling in acute lung injuryrdquo Critical Care Medicinevol 31 no 4 pp S231ndashS237 2003

[78] MXue Z SunM Shao et al ldquoDiagnostic andprognostic utilityof tissue factor for severe sepsis and sepsis-induced acute lunginjuryrdquo Journal of Translational Medicine vol 13 article 1722015

[79] J A Bastarache S C Sebag J K Clune et al ldquoLow levels oftissue factor lead to alveolar haemorrhage potentiating murineacute lung injury and oxidative stressrdquo Thorax vol 67 no 12pp 1032ndash1039 2012

[80] S Mumby L Ramakrishnan T W Evans M J D Griffithsand G J Quinlan ldquoMethemoglobin-induced signaling andchemokine responses in human alveolar epithelial cellsrdquo TheAmerican Journal of PhysiologymdashLung Cellular and MolecularPhysiology vol 306 no 1 pp L88ndashL100 2014

[81] A Fein R F Grossman J G Jones et al ldquoThe value of edemafluid protein measurement in patients with pulmonary edemardquoTheAmerican Journal of Medicine vol 67 no 1 pp 32ndash38 1979

[82] L B Ware R D Fremont J A Bastarache C S Calfeeand M A Matthay ldquoDetermining the aetiology of pulmonaryoedema by the oedema fluid-to-plasma protein ratiordquo EuropeanRespiratory Journal vol 35 no 2 pp 331ndash337 2010

[83] D R Thickett L Armstrong S J Christie and A B MillarldquoVascular endothelial growth factormay contribute to increasedvascular permeability in acute respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol164 no 9 pp 1601ndash1605 2001

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

16 Disease Markers

[84] Y Abadie F Bregeon L Papazian et al ldquoDecreased VEGFconcentration in lung tissue and vascular injury during ARDSrdquoEuropean Respiratory Journal vol 25 no 1 pp 139ndash146 2005

[85] T J Desai andW V Cardoso ldquoGrowth factors in lung develop-ment and disease friends or foerdquo Respiratory Research vol 3article 2 2002

[86] BMaitre S Boussat D Jean et al ldquoVascular endothelial growthfactor synthesis in the acute phase of experimental and clinicallung injuryrdquoEuropean Respiratory Journal vol 18 no 1 pp 100ndash106 2001

[87] Z Borok S I Danto L L Dimen X-L Zhang and RL Lubman ldquoNa+-K+-ATPase expression in alveolar epithelialcells upregulation of active ion transport by KGFrdquo AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 274 no 1 pp L149ndashL158 1998

[88] L B Ware and M A Matthay ldquoKeratinocyte and hepatocytegrowth factors in the lung Roles in lung development inflam-mation and repairrdquoThe American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 282 no 5 pp L924ndashL940 2002

[89] V Galani E Tatsaki M Bai et al ldquoThe role of apoptosis inthe pathophysiology of Acute Respiratory Distress Syndrome(ARDS) an up-to-date cell-specific reviewrdquo Pathology Researchand Practice vol 206 no 3 pp 145ndash150 2010

[90] R C Pires-Neto MM B Morales T Lancas et al ldquoExpressionof acute-phase cytokines surfactant proteins and epithelialapoptosis in small airways of human acute respiratory distresssyndromerdquo Journal of Critical Care vol 28 no 1 pp 111e9ndash111e15 2013

[91] D Talmor T Sarge A Legedza et al ldquoCytokine releasefollowing recruitment maneuversrdquo Chest vol 132 no 5 pp1434ndash1439 2007

[92] J M Walter J Wilson and L B Ware ldquoBiomarkers in acuterespiratory distress syndrome from pathobiology to improvingpatient carerdquo Expert Review of Respiratory Medicine vol 8 no5 pp 573ndash586 2014

[93] C S Calfee K Delucchi P E Parsons B T Thompson L BWare and M A Matthay ldquoLatent class models identify twosubphenotypes in respiratory distress syndrome with differen-tial response to positive end-expiratory pressurerdquo Annals of theAmerican Thoracic Society vol 12 supplement 1 p S77 2015

[94] V Newman R F Gonzalez M A Matthay and L G Dobbs ldquoAnovel alveolar type I cell-specific biochemical marker of humanacute lung injuryrdquo American Journal of Respiratory and CriticalCare Medicine vol 161 no 3 pp 990ndash995 2000

[95] AM Schmidt SD Yan S F Yan andDM Stern ldquoThebiologyof the receptor for advanced glycation end products and itsligandsrdquo Biochimica et Biophysica Acta (BBA)mdashMolecular CellResearch vol 1498 no 2-3 pp 99ndash111 2000

[96] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[97] M T Kuipers T van der Poll M J Schultz and C WWielandldquoBench-to-bedside review damage-associated molecular pat-terns in the onset of ventilator-induced lung injuryrdquo CriticalCare vol 15 no 6 article 235 2011

[98] T Uchida M Shirasawa L B Ware et al ldquoReceptor foradvanced glycation end-products is a marker of type I cellinjury in acute lung injuryrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 173 no 9 pp 1008ndash1015 2006

[99] C S Calfee L B Ware M D Eisner et al ldquoPlasma receptor foradvanced glycation end products and clinical outcomes in acutelung injuryrdquoThorax vol 63 no 12 pp 1083ndash1089 2008

[100] M Jabaudon E Futier L Roszyk et al ldquoSoluble form of thereceptor for advanced glycation end products is a marker ofacute lung injury but not of severe sepsis in critically ill patientsrdquoCritical Care Medicine vol 39 no 3 pp 480ndash488 2011

[101] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble RAGEpredicts impaired alveolar fluid clearance in acute respiratorydistress syndromerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 192 no 2 2015

[102] M D Johnson J H Widdicombe L Allen P Barbry and LG Dobbs ldquoAlveolar epithelial I cells contain transport proteinsand transport sodium supporting an active role for type I cellsin regulation of lung liquid homeostasisrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 99 no 4 pp 1966ndash1971 2002

[103] L E Hanford J J Enghild Z Valnickova et al ldquoPurificationand characterization of mouse soluble receptor for advancedglycation end products (sRAGE)rdquo The Journal of BiologicalChemistry vol 279 no 48 pp 50019ndash50024 2004

[104] C Cheng K Tsuneyama R Kominami et al ldquoExpression pro-filing of endogenous secretory receptor for advanced glycationend products in human organsrdquoModern Pathology vol 18 no10 pp 1385ndash1396 2005

[105] J Brett A M Schmidt S D Yan et al ldquoSurvey of thedistribution of a newly characterized receptor for advancedglycation end products in tissuesrdquo The American Journal ofPathology vol 143 no 6 pp 1699ndash1712 1993

[106] L E Hanford C L Fattman L M Schaefer J J EnghildZ Valnickova and T D Oury ldquoRegulation of receptor foradvanced glycation end products during bleomycin-inducedlung injuryrdquoAmerican Journal of Respiratory Cell andMolecularBiology vol 29 no 3 pp S77ndashS81 2003

[107] J M Englert L E Hanford N Kaminski et al ldquoA role forthe receptor for advanced glycation end products in idiopathicpulmonary fibrosisrdquoTheAmerican Journal of Pathology vol 172no 3 pp 583ndash591 2008

[108] A M Schmidt S D Yan S F Yan and D M Stern ldquoThemultiligand receptor RAGE as a progression factor amplifyingimmune and inflammatory responsesrdquo The Journal of ClinicalInvestigation vol 108 no 7 pp 949ndash955 2001

[109] M Jabaudon R Blondonnet L Roszyk et al ldquoSoluble formsand ligands of the receptor for advanced glycation end-productsin patients with acute respiratory distress syndrome an obser-vational prospective studyrdquo PLoS ONE vol 10 no 8 Article IDe0135857 2015

[110] C A Downs L H Kreiner N M Johnson L A Brown andM N Helms ldquoReceptor for advanced glycation end-productsregulates lung fluid balance via protein kinase C-gp91phoxsignaling to epithelial sodium channelsrdquo American Journal ofRespiratory Cell and Molecular Biology vol 52 no 1 pp 75ndash872015

[111] R Briot J A Frank T Uchida J W Lee C S Calfee andM AMatthay ldquoElevated levels of the receptor for advanced glycationend products a marker of alveolar epithelial type i cell injurypredict impaired alveolar fluid clearance in isolated perfusedhuman lungsrdquo Chest vol 135 no 2 pp 269ndash275 2009

[112] J-M Constantin ldquoImpact of Inflammation Biomarkerson the Acute Respiratory Distress Syndrome (ARDS)Definitionrdquo (NCT01161901) httpsclinicaltrialsgovct2showNCT01161901term=constantin+clermontamprank=5

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Disease Markers 17

[113] M Jabaudon N Hamroun L Roszyk et al ldquoEffects of a recruit-ment maneuver on plasma levels of soluble RAGE in patientswith diffuse acute respiratory distress syndrome a prospectiverandomized crossover studyrdquo Intensive Care Medicine vol 41no 5 pp 846ndash855 2015

[114] M Jabaudon ldquoPredictiveValues of Plasma SolubleRAGELevelsand RAGE Polymorphisms for the Onset of Acute Respira-tory Distress Syndrome in Critically Ill Patients (PrediRAGEStudy)rdquo in ClinicalTrialsgov 2014 httpclinicaltrialsgovshowNCT02070536

[115] J Bhattacharya andMAMatthay ldquoRegulation and repair of thealveolar-capillary barrier in acute lung injuryrdquoAnnual Review ofPhysiology vol 75 pp 593ndash615 2013

[116] I Frerking A Gunther W Seeger and U Pison ldquoPulmonarysurfactant functions abnormalities and therapeutic optionsrdquoIntensive Care Medicine vol 27 no 11 pp 1699ndash1717 2001

[117] D G Ashbaugh D B Bigelow T L Petty and B E LevineldquoAcute respiratory distress in adultsrdquoThe Lancet vol 2 no 7511pp 319ndash323 1967

[118] I R Doyle A D Bersten and T E Nicholas ldquoSurfactantproteins-A and -B are elevated in plasma of patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 156 no 4 pp 1217ndash1229 1997

[119] K E Greene S Ye R J Mason and P E Parsons ldquoSerumsurfactant protein-A levels predict development of ARDS in at-risk patientsrdquo Chest vol 116 supplement 1 pp 90Sndash91S 1999

[120] A D Bersten T Hunt T E Nicholas and I R DoyleldquoElevated plasma surfactant protein-B predicts developmentof acute respiratory distress syndrome in patients with acuterespiratory failurerdquoAmerican Journal of Respiratory and CriticalCare Medicine vol 164 no 4 pp 648ndash652 2001

[121] A Ishizaka TMatsuda K H Albertine et al ldquoElevation of KL-6 a lung epithelial cell marker in plasma and epithelial liningfluid in acute respiratory distress syndromerdquo The AmericanJournal of PhysiologymdashLung Cellular and Molecular Physiologyvol 286 no 6 pp L1088ndashL1094 2004

[122] N Nathani G D PerkinsW Tunnicliffe NMurphyMManjiand D RThickett ldquoKerbs von Lungren 6 antigen is a marker ofalveolar inflammation but not of infection in patients with acuterespiratory distress syndromerdquo Critical Care vol 12 article R122008

[123] T Kondo N Hattori N Ishikawa et al ldquoKL-6 concentrationin pulmonary epithelial lining fluid is a useful prognosticindicator in patients with acute respiratory distress syndromerdquoRespiratory Research vol 12 article 32 2011

[124] R Lucas ADVerin SM Black and JDCatravas ldquoRegulatorsof endothelial and epithelial barrier integrity and function inacute lung injuryrdquo Biochemical Pharmacology vol 77 no 12 pp1763ndash1772 2009

[125] A Binnie J L Tsang and C C dos Santos ldquoBiomarkersin acute respiratory distress syndromerdquo Current Opinion inCritical Care vol 20 no 1 pp 47ndash55 2014

[126] S Tsigkos M Koutsilieris and A Papapetropoulos ldquoAngiopoi-etins in angiogenesis and beyondrdquo Expert Opinion on Investiga-tional Drugs vol 12 no 6 pp 933ndash941 2003

[127] U Fiedler Y Reiss M Scharpfenecker et al ldquoAngiopoietin-2sensitizes endothelial cells to TNF-120572 and has a crucial role inthe induction of inflammationrdquo Nature Medicine vol 12 no 2pp 235ndash239 2006

[128] V Bhandari and J A Elias ldquoThe role of angiopoietin 2 inhyperoxia-induced acute lung injuryrdquo Cell Cycle vol 6 no 9pp 1049ndash1052 2007

[129] N J Meyer M Li R Feng et al ldquoANGPT2 genetic variantis associated with trauma-associated acute lung injury andaltered plasma angiopoietin-2 isoform ratiordquo American Journalof Respiratory and Critical Care Medicine vol 183 no 10 pp1344ndash1353 2011

[130] A Agrawal M A Matthay K N Kangelaris et al ldquoPlasmaangiopoietin-2 predicts the onset of acute lung injury in criti-cally ill patientsrdquo American Journal of Respiratory and CriticalCare Medicine vol 187 no 7 pp 736ndash742 2013

[131] T Wada S Jesmin S Gando et al ldquoThe role of angiogenicfactors and their soluble receptors in acute lung injury (ALI)acute respiratory distress syndrome (ARDS) associated withcritical illnessrdquo Journal of Inflammation vol 10 article 6 2013

[132] T Ong D E McClintock R H Kallet L B Ware MA Matthay and K D Liu ldquoRatio of angiopoietin-2 toangiopoietin-1 as a predictor of mortality in acute lung injurypatientsrdquo Critical Care Medicine vol 38 no 9 pp 1845ndash18512010

[133] K A Roebuck and A Finnegan ldquoRegulation of intercellularadhesionmolecule-1 (CD54) gene expressionrdquo Journal of Leuko-cyte Biology vol 66 no 6 pp 876ndash888 1999

[134] E R Conner L B Ware G Modin and M A MatthayldquoElevated pulmonary edema fluid concentrations of solubleintercellular adhesion molecule-1 in patients with acute lunginjury biological and clinical significancerdquo Chest vol 116 pp83Sndash84S 1999

[135] C S Calfee M D Eisner P E Parsons et al ldquoSoluble inter-cellular adhesion molecule-1 and clinical outcomes in patientswith acute lung injuryrdquo Intensive Care Medicine vol 35 no 2pp 248ndash257 2009

[136] P Agouridakis D Kyriakou M G Alexandrakis et al ldquoThepredictive role of serum and bronchoalveolar lavage cytokinesand adhesionmolecules for acute respiratory distress syndromedevelopment and outcomerdquo Respiratory Research vol 3 article25 2002

[137] H R Flori L B Ware D Glidden and M A Matthay ldquoEarlyelevation of plasma soluble intercellular adhesionmolecule-1 inpediatric acute lung injury identifies patients at increased risk ofdeath and prolonged mechanical ventilationrdquo Pediatric CriticalCare Medicine vol 4 no 3 pp 315ndash321 2003

[138] A Sousa F Raposo S Fonseca et al ldquoMeasurement ofcytokines and adhesion molecules in the first 72 hours aftersevere trauma association with severity and outcomerdquo DiseaseMarkers vol 2015 Article ID 747036 8 pages 2015

[139] S Gando T Kameue N Matsuda et al ldquoCombined activationof coagulation and inflammation has an important role inmultiple organ dysfunction and poor outcome after severetraumardquo Thrombosis and Haemostasis vol 88 no 6 pp 943ndash949 2002

[140] K Xing S Murthy W C Liles and J M Singh ldquoClinical utilityof biomarkers of endothelial activation in sepsis-a systematicreviewrdquo Critical Care vol 16 article R7 2012

[141] J Boldt M Wollbruck D Kuhn L C Linke and G Hempel-mann ldquoDo plasma levels of circulating soluble adhesionmolecules differ between surviving and nonsurviving criticallyill patientsrdquo Chest vol 107 no 3 pp 787ndash792 1995

[142] F Sakamaki A Ishizaka M Handa et al ldquoSoluble form of P-selectin in plasma is elevated in acute lung injuryrdquo AmericanJournal of Respiratory and Critical Care Medicine vol 151 no 6pp 1821ndash1826 1995

[143] E L BurnhamMMoss FHarris and L A S Brown ldquoElevatedplasma and lung endothelial selectin levels in patients with

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

18 Disease Markers

acute respiratory distress syndrome and a history of chronicalcohol abuserdquo Critical Care Medicine vol 32 no 3 pp 675ndash679 2004

[144] KOkajimaNHaradaG Sakurai et al ldquoRapid assay for plasmasoluble E-selectin predicts the development of acute respiratorydistress syndrome in patients with systemic inflammatoryresponse syndromerdquo Translational Research vol 148 no 6 pp295ndash300 2006

[145] A R L Medford and A B Millar ldquoVascular endothelial growthfactor (VEGF) in acute lung injury (ALI) and acute respiratorydistress syndrome (ARDS) paradox or paradigmrdquoThorax vol61 no 7 pp 621ndash626 2006

[146] M Shibuya ldquoDifferential roles of vascular endothelial growthfactor receptor-1 and receptor-2 in angiogenesisrdquo Journal ofBiochemistry and Molecular Biology vol 39 no 5 pp 469ndash4782006

[147] R J Kaner J V Ladetto R Singh N Fukuda M A Matthayand R G Crystal ldquoLung overexpression of the vascularendothelial growth factor gene induces pulmonary edemardquoAmerican Journal of Respiratory Cell andMolecular Biology vol22 no 6 pp 657ndash664 2000

[148] L Azamfirei S Gurzu R Solomon et al ldquoVascular endothelialgrowth factor a possible mediator of endothelial activation inacute respiratory distress syndromerdquo Minerva Anestesiologicavol 76 no 8 pp 609ndash616 2010

[149] D R Thickett L Armstrong and A B Millar ldquoA role forvascular endothelial growth factor in acute and resolving lunginjuryrdquo American Journal of Respiratory and Critical CareMedicine vol 166 no 10 pp 1332ndash1337 2002

[150] A C A Carvalho S M Bellman V J Saullo D Quinn andWM Zapol ldquoAltered factor VIII in acute respiratory failurerdquo TheNew England Journal of Medicine vol 307 no 18 pp 1113ndash11191982

[151] D B Rubin J P Wiener-Kronish J F Murray et al ldquoElevatedvon Willebrand factor antigen is an early plasma predictor ofacute lung injury in nonpulmonary sepsis syndromerdquo Journalof Clinical Investigation vol 86 no 2 pp 474ndash480 1990

[152] M Moss L Ackerson M K Gillespie F A Moore E EMoore and P E Parsons ldquoVon willebrand factor antigen levelsare not predictive for the adult respiratory distress syndromerdquoAmerican Journal of Respiratory and Critical Care Medicine vol151 no 1 pp 15ndash20 1995

[153] A K Sabharwal S P Bajaj A Ameri et al ldquoTissue factorpathway inhibitor and von Willebrand factor antigen levels inadult respiratory distress syndrome and in a primate modelof sepsisrdquo American Journal of Respiratory and Critical CareMedicine vol 151 no 3 I pp 758ndash767 1995

[154] P R M Rocco C Dos Santos and P Pelosi ldquoLung parenchymaremodeling in acute respiratory distress syndromerdquo MinervaAnestesiologica vol 75 no 12 pp 730ndash740 2009

[155] B C Starcher ldquoLung elastin and matrixrdquo Chest vol 117 no 5supplement 1 pp 229Sndash234S 2000

[156] GMAlbaiceta A Gutierrez-Fernandez E Garcıa-Prieto et alldquoAbsence or inhibition of matrix metalloproteinase-8 decreasesventilator-induced lung injuryrdquoAmerican Journal of RespiratoryCell and Molecular Biology vol 43 no 5 pp 555ndash563 2010

[157] S E G Fligiel T Standiford H M Fligiel et al ldquoMatrixmetalloproteinases and matrix metalloproteinase inhibitors inacute lung injuryrdquoHuman Pathology vol 37 no 4 pp 422ndash4302006

[158] M Y F Kong Y Li R Oster A Gaggar and J P ClancyldquoEarly elevation of matrix metalloproteinase-8 and -9 in pedi-atric ARDS is associated with an increased risk of prolongedmechanical ventilationrdquo PLoS ONE vol 6 no 8 Article IDe22596 2011

[159] A Gonzalez-Lopez and G M Albaiceta ldquoRepair after acutelung injury molecular mechanisms and therapeutic opportu-nitiesrdquo Critical Care vol 16 no 2 article 209 2012

[160] M Bhatia and S Moochhala ldquoRole of inflammatory mediatorsin the pathophysiology of acute respiratory distress syndromerdquoJournal of Pathology vol 202 no 2 pp 145ndash156 2004

[161] L A Dada and J I Sznajder ldquoHypoxic inhibition of alveolarfluid reabsorptionrdquo inHypoxia and the Circulation pp 159ndash168Springer US 2007

[162] A E Postlethwaite and J M Seyer ldquoStimulation of fibroblastchemotaxis by human recombinant tumor necrosis factor 120572(TNF-120572) and a synthetic TNF-12057231-68 peptiderdquo The Journal ofExperimental Medicine vol 172 no 6 pp 1749ndash1756 1990

[163] P F Piguet M A Collart G E Grau A-P Sappino and P Vas-salli ldquoRequirement of tumour necrosis factor for developmentof silica-induced pulmonary fibrosisrdquoNature vol 344 no 6263pp 245ndash247 1990

[164] W Y Park R B Goodman K P Steinberg et al ldquoCytokinebalance in the lungs of patients with acute respiratory distresssyndromerdquo American Journal of Respiratory and Critical CareMedicine vol 164 no 10 pp 1896ndash1903 2001

[165] J Pugin B Ricou K P Steinberg P M Suter and T R MartinldquoProinflammatory activity in bronchoalveolar lavage fluidsfrom patients with ARDS a prominent role for interleukin-1rdquoAmerican Journal of Respiratory and Critical Care Medicine vol153 no 6 pp 1850ndash1856 1996

[166] G U Meduri G Kohler S Headley E Tolley F Stentzand A Postlethwaite ldquoInflammatory cytokines in the BAL ofpatients with ARDS Persistent elevation over time predictspoor outcomerdquo Chest vol 108 no 5 pp 1303ndash1314 1995

[167] R RotenMMarkert F Feihl M-D SchallerM-C Tagan andC Perret ldquoPlasma levels of tumor necrosis factor in the adultrespiratory distress syndromerdquo American Review of RespiratoryDisease vol 143 no 3 pp 590ndash592 1991

[168] T Dolinay Y S Kim J Howrylak et al ldquoInflammasome-regulated cytokines are critical mediators of acute lung injuryrdquoAmerican Journal of Respiratory and Critical Care Medicine vol185 no 11 pp 1225ndash1234 2012

[169] D McClintock H Zhuo N Wickersham M A Matthay andL B Ware ldquoBiomarkers of inflammation coagulation andfibrinolysis predict mortality in acute lung injuryrdquoCritical Carevol 12 no 2 article R41 2008

[170] R P Baughman K L Gunther M C Rashkin D A Keetonand E N Pattishall ldquoChanges in the inflammatory response ofthe lung during acute respiratory distress syndrome prognosticindicatorsrdquo American Journal of Respiratory and Critical CareMedicine vol 154 no 1 pp 76ndash81 1996

[171] H Schutte J Lohmeyer S Rosseau et al ldquoBronchoalveolarand systemic cytokine profiles in patients with ARDS severepneumonia and cardiogenic pulmonary oedemardquo EuropeanRespiratory Journal vol 9 no 9 pp 1858ndash1867 1996

[172] A Kurdowska E J Miller J M Noble et al ldquoAnti-IL-8autoantibodies in alveolar fluid from patients with the adultrespiratory distress syndromerdquoThe Journal of Immunology vol157 no 6 pp 2699ndash2706 1996

[173] A Kurdowska J M Noble I S Grant C R Robertson CHaslett and S C Donnelly ldquoAnti-interleukin-8 autoantibodies

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Disease Markers 19

in patients at risk for acute respiratory distress syndromerdquoCritical Care Medicine vol 30 no 10 pp 2335ndash2337 2002

[174] A Krupa H Kato M A Matthay and A K KurdowskaldquoProinflammatory activity of anti-IL-8 autoantibodyIL-8 com-plexes in alveolar edema fluid from patients with acute lunginjuryrdquoThe American Journal of PhysiologymdashLung Cellular andMolecular Physiology vol 286 no 6 pp L1105ndashL1113 2004

[175] R Fudala A Krupa M A Matthay T C Allen and A KKurdowska ldquoAnti-IL-8 autoantibodyIL-8 immune complexessuppress spontaneous apoptosis of neutrophilsrdquoAmerican Jour-nal of PhysiologymdashLung Cellular and Molecular Physiology vol293 no 2 pp L364ndashL374 2007

[176] M A Matthay and L B Ware ldquoResolution of alveolar edema inacute respiratory distress syndrome Physiology and biologyrdquoAmerican Journal of Respiratory and Critical Care Medicine vol192 no 2 pp 124ndash125 2015

[177] P Ralph I Nakoinz A Sampson-Johannes et al ldquoIL-10 Tlymphocyte inhibitor of human blood cell production of IL-1and tumor necrosis factorrdquoThe Journal of Immunology vol 148no 3 pp 808ndash814 1992

[178] M Seitz P Loetscher B Dewald H Towbin H Gallati andM Baggiolini ldquoInterleukin-10 differentially regulates cytokineinhibitor and chemokine release from blood mononuclear cellsand fibroblastsrdquo European Journal of Immunology vol 25 no 4pp 1129ndash1132 1995

[179] C-J LoM Fu andHG Cryer ldquoInterleukin 10 inhibits alveolarmacrophage production of inflammatory mediators involvedin adult respiratory distress syndromerdquo Journal of SurgicalResearch vol 79 no 2 pp 179ndash184 1998

[180] A Sapru J L Wiemels J S Witte L B Ware and M AMatthay ldquoAcute lung injury and the coagulation pathwaypotential role of gene polymorphisms in the protein C andfibrinolytic pathwaysrdquo Intensive CareMedicine vol 32 no 9 pp1293ndash1303 2006

[181] V Jalkanen R Yang R Linko et al ldquoSuPAR and PAI-1 incritically ill mechanically ventilated patientsrdquo Intensive CareMedicine vol 39 no 3 pp 489ndash496 2013

[182] L BWareM AMatthay P E Parsons et al ldquoPathogenetic andprognostic significance of altered coagulation andfibrinolysis inacute lung injuryacute respiratory distress syndromerdquo CriticalCare Medicine vol 35 no 8 pp 1821ndash1828 2007

[183] C T Esmon ldquoInflammation and the activated protein C antico-agulant pathwayrdquo Seminars in Thrombosis and Hemostasis vol32 supplement 1 pp 49ndash60 2006

[184] M F Nold C A Nold-Petry D Fischer et al ldquoActivatedprotein C downregulates p38 mitogen-activated protein kinaseand improves clinical parameters in an in-vivo model of septicshockrdquoThrombosis andHaemostasis vol 98 no 5 pp 1118ndash11262007

[185] T Cheng D Liu J H Griffin et al ldquoActivated protein C blocksp53-mediated apoptosis in ischemic human brain endotheliumand is neuroprotectiverdquo Nature Medicine vol 9 no 3 pp 338ndash342 2003

[186] S C Christiaans B M Wagener C T Esmon and J F PittetldquoProtein C and acute inflammation a clinical and biologicalperspectiverdquoTheAmerican Journal of PhysiologymdashLungCellularand Molecular Physiology vol 305 no 7 pp L455ndashL466 2013

[187] J A Bastarache L Wang T Geiser et al ldquoThe alveolar epithe-lium can initiate the extrinsic coagulation cascade throughexpression of tissue factorrdquo Thorax vol 62 no 7 pp 608ndash6162007

[188] A J Ghio J H Richards KM Crissman and J D Carter ldquoIrondisequilibrium in the rat lung after instilled bloodrdquo Chest vol118 no 3 pp 814ndash823 2000

[189] J A Bastarache J L Wynn and L B Ware ldquoFanningthe fire can methemoglobin enhance neutrophil activationrdquoEBioMedicine vol 2 no 3 pp 184ndash185 2015

[190] E L Burnham W J Janssen D W H Riches M Moss andG P Downey ldquoThe fibroproliferative response in acute respira-tory distress syndrome mechanisms and clinical significancerdquoEuropean Respiratory Journal vol 43 no 1 pp 276ndash285 2014

[191] T Geiser K Atabai P-H Jarreau L B Ware J Pugin and MA Matthay ldquoPulmonary edema fluid from patients with acutelung injury augments in vitro alveolar epithelial repair by an IL-1120573-dependentmechanismrdquoAmerican Journal of Respiratory andCritical Care Medicine vol 163 no 6 pp 1384ndash1388 2001

[192] KAtabaiM Ishigaki TGeiser I UekiMAMatthay andL BWare ldquoKeratinocyte growth factor can enhance alveolar epithe-lial repair by nonmitogenic mechanismsrdquo American Journal ofPhysiologymdashLung Cellular and Molecular Physiology vol 283no 1 pp L163ndashL169 2002

[193] M Mura C C dos Santos D Stewart and M Liu ldquoVascularendothelial growth factor and related molecules in acute lunginjuryrdquo Journal of Applied Physiology vol 97 no 5 pp 1605ndash1617 2004

[194] C Quesnel S Marchand-Adam A Fabre et al ldquoRegulationof hepatocyte growth factor secretion by fibroblasts in patientswith acute lung injuryrdquo American Journal of PhysiologymdashLungCellular and Molecular Physiology vol 294 no 2 pp L334ndashL343 2008

[195] S Fan Y X Ma J-A Wang et al ldquoThe cytokine hepatocytegrowth factorscatter factor inhibits apoptosis and enhancesDNA repair by a common mechanism involving signalingthrough phosphatidyl inositol 31015840 kinaserdquo Oncogene vol 19 no18 pp 2212ndash2223 2000

[196] J-B Stern L Fierobe C Paugam et al ldquoKeratinocyte growthfactor and hepatocyte growth factor in bronchoalveolar lavagefluid in acute respiratory distress syndrome patientsrdquo CriticalCare Medicine vol 28 no 7 pp 2326ndash2333 2000

[197] G M Verghese K McCormick-Shannon R J Mason and MAMatthay ldquoHepatocyte growth factor and keratinocyte growthfactor in the pulmonary edema fluid of patients with acute lunginjury biologic and clinical significancerdquo American Journal ofRespiratory and Critical Care Medicine vol 158 no 2 pp 386ndash394 1998

[198] M A Rahman K Sundaram S Mitra M A Gavrilin andM D Wewers ldquoReceptor interacting protein-2 plays a criticalrole in human lung epithelial cells survival in response to Fas-induced cell-deathrdquo PLoS ONE vol 9 no 3 Article ID e927312014

[199] A D Lopez S Avasarala S Grewal A K Murali and LLondon ldquoDifferential role of the FasFas ligand apoptoticpathway in inflammation and lung fibrosis associated withreovirus 1L-induced bronchiolitis obliterans organizing pneu-monia and acute respiratory distress syndromerdquoThe Journal ofImmunology vol 183 no 12 pp 8244ndash8257 2009

[200] G Matute-Bello W C Liles K P Steinberg et al ldquoSoluble Fasligand induces epithelial cell apoptosis in humans with acutelung injury (ARDS)rdquo Journal of Immunology vol 163 no 4 pp2217ndash2225 1999

[201] M Tanaka T Suda T Takahashi and S Nagata ldquoExpressionof the functional soluble form of human Fas ligand in activated

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

20 Disease Markers

lymphocytesrdquo The EMBO Journal vol 14 no 6 pp 1129ndash11351995

[202] K H Albertine M F Soulier ZWang et al ldquoFas and fas ligandare up-regulated in pulmonary edema fluid and lung tissue ofpatients with acute lung injury and the acute respiratory distresssyndromerdquoTheAmerican Journal of Pathology vol 161 no 5 pp1783ndash1796 2002

[203] J Farjanel D J Hartmann B Guidet L Luquel and GOffenstadt ldquoFour markers of collagen metabolism as possibleindicators of disease in the adult respiratory distress syndromerdquoAmerican Review of Respiratory Disease vol 147 no 5 pp 1091ndash1099 1993

[204] A N Chesnutt M A Matthay F A Tibayan and J G ClarkldquoEarly detection of type iii procollagen peptide in acute lunginjury pathogenetic and prognostic significancerdquo AmericanJournal of Respiratory and Critical Care Medicine vol 156 no3 pp 840ndash845 1997

[205] J G Clark J A Milberg K P Steinberg and L D HudsonldquoType III procollagen peptide in the adult respiratory distresssyndrome association of increased peptide levels in bron-choalveolar lavage fluid with increased risk for deathrdquo Annalsof Internal Medicine vol 122 no 1 pp 17ndash23 1995

[206] J-M Forel C Guervilly S Hraiech et al ldquoType III procollagenis a reliablemarker of ARDS-associated lung fibroproliferationrdquoIntensive Care Medicine vol 41 no 1 pp 1ndash11 2015

[207] C M Hendrickson B Crestani and M A Matthay ldquoBiologyand pathology of fibroproliferation following the acute respira-tory distress syndromerdquo Intensive Care Medicine vol 41 no 1pp 147ndash150 2015

[208] L B Ware T Koyama D D Billheimer et al ldquoPrognosticand pathogenetic value of combining clinical and biochemicalindices in patients with acute lung injuryrdquo Chest vol 137 no 2pp 288ndash296 2010

[209] J-M Constantin and E Futier ldquoLung imaging in patients withacute respiratory distress syndrome from an understanding ofpathophysiology to bedside monitoringrdquoMinerva Anestesiolog-ica vol 79 no 2 pp 176ndash184 2013

[210] L Puybasset P Gusman J-C Muller P Cluzel P Coriat andJ-J Rouby ldquoRegional distribution of gas and tissue in acuterespiratory distress syndrome III Consequences for the effectsof positive end-expiratory pressurerdquo Intensive Care Medicinevol 26 no 9 pp 1215ndash1227 2000

[211] J-M Constantin S Jaber E Futier et al ldquoRespiratory effectsof different recruitment maneuvers in acute respiratory distresssyndromerdquo Critical Care vol 12 article R50 2008

[212] J-M Constantin S Cayot-Constantin L Roszyk et alldquoResponse to recruitment maneuver influences net alveolarfluid clearance in acute respiratory distress syndromerdquoAnesthe-siology vol 106 no 5 pp 944ndash951 2007

[213] R Mayeux ldquoBiomarkers potential uses and limitationsrdquo Neu-roRx vol 1 no 2 pp 182ndash188 2004

[214] V G De Gruttola P Clax D L DeMets et al ldquoConsiderationsin the evaluation of surrogate endpoints in clinical trials sum-mary of a National Institutes of Health Workshoprdquo ControlledClinical Trials vol 22 no 5 pp 485ndash502 2001

[215] P Ray Y L Manach B Riou and T T Houle ldquoStatisticalevaluation of a biomarkerrdquo Anesthesiology vol 112 no 4 pp1023ndash1040 2010

[216] H Gerlach and S Toussaint ldquoSensitive specific predictive statistical basics how to use biomarkersrdquo Critical Care Clinicsvol 27 no 2 pp 215ndash227 2011

[217] M Bhargava and C H Wendt ldquoBiomarkers in acute lunginjuryrdquo Translational Research vol 159 no 4 pp 205ndash217 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom