from inflammation to current and alternative therapies...

Review ArticleFrom Inflammation to Current and Alternative TherapiesInvolved in Wound Healing

Mariana Barreto Serra1 Wermerson Assunccedilatildeo Barroso12

Neemias Neves da Silva1 Selma do Nascimento Silva1 Antonio Carlos Romatildeo Borges1

Iracelle Carvalho Abreu1 andMarilene Oliveira da Rocha Borges1

1Physiological Sciences Department Federal University of Maranhao Sao Luıs MA Brazil2School of Medicine Emergency Medicine Department University of Sao Paulo Sao Paulo SP Brazil

Correspondence should be addressed to Wermerson Assuncao Barroso wermersonbarrosoyahoocom

Received 28 March 2017 Revised 1 June 2017 Accepted 6 June 2017 Published 25 July 2017

Academic Editor B L Slomiany

Copyright copy 2017 Mariana Barreto Serra 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

Wound healing is a complex event that develops in three overlapping phases inflammatory proliferative and remodeling Thesephases are distinct in function andhistological characteristicsHowever they depend on the interaction of cytokines growth factorschemokines and chemical mediators from cells to perform regulatory events In this article we will review the pathway in the skinhealing cascade relating themajor chemical inflammatorymediators cellular andmolecular as well as demonstrating the local andsystemic factors that interfere in healing and disorders associated with tissue repair deficiency Finally we will discuss the currenttherapeutic interventions in the wounds treatment and the alternative therapies used as promising results in the development ofnew products with healing potential

1 Introduction

The immune system is composed of an organs network andcells and molecules that maintain the bodyrsquos homeostasisFactors that compromise the functionality of the immunesystem can make simple infections spread becoming fatal [1]

The major innate immunity cells that reach the site ofinjury are neutrophils and macrophages These cells exertphagocytic activity releasing highly destructive substanceslike enzymes that digest proteins generating reactive chem-icals products When these cells fail to control infectionlymphocytes are activated and incorporate the adaptation andmemory functions allowing the immune system to elaborateincreasingly specific responses [2]

The first defense of the organism to tissue damage is theinflammatory response a complex biological process involv-ing vascular and cellular components and a diversity ofsoluble substances which presents as characteristic clinicalsigns flushing heat edema pain and functional impairment[3] The purpose of this process is to remove the inducing

stimulus from the response and initiate local tissue recoveryDuring inflammation several biochemical systems are acti-vated such as complement and coagulation cascades aidingin the establishment evolution and resolution of the processIn addition soluble substances of short half-life are releaseddevelop their action and then are degraded In generalsuccessful removal of triggering stimulus leads to the end ofacute response and tissue repair [4]

2 Inflammation and Tissue Repair

Wound healing is a complex event that develops in threephases inflammatory proliferative and remodeling (Fig-ure 1) These phases are distinct in function and histologicalcharacteristics However they depend on interaction ofcytokines growth factors chemokines and chemical medi-ators from cells to perform regulatory events [5 6]

The acute inflammatory response has an integral rolein tissue healing being fundamental for the homeostasis

HindawiInternational Journal of InflammationVolume 2017 Article ID 3406215 17 pageshttpsdoiorg10115520173406215

2 International Journal of Inflammation

Platelet invasion forhemostasis

Neutrophil

Monocyte

Collagen

M2

Anti-inammatory

M1BacteriaDebrisInammatory factors

Blood vessels (1) C

oagu

latio

n(2

) In

amm

ator

y ev

ents(IL-1 TNF- IL-6)

factors (IL-10 TGF-)

(a) Inflammation

Blood vessels Growth factors Platelet invasion forhemostasis

Fibroblast

Myofibroblast

Macrophage

Epidermis

CollagenGlycoprotein

Proteoglycan

MMP-9

Keratinocytes

Neutrophil

(3) A

ngio

gene

sis(4

) Ree

pith

eliz

atio

n an

dgr

anul

atio

n tis

sue

(PDGF TGF- VEGF)

(b) Proliferation

Blood vessels

Epidermis

Collagen III

Collagen I

Apoptosis

(5) R

eorg

aniz

atio

n of

EM

C(6

) Typ

e III

colla

gen

repl

aced

by

t ype

I

(c) Remodeling

Figure 1 Progression and overlap of the phases involved in the physiological wound healing process (a) inflammation begins with (1)coagulation platelet aggregation and fibrin clot formation (2) then inflammatory events occur through neutrophils and macrophagesinfiltration and phagocytosis of debris apoptotic cells and pathogens anti-inflammatory events occur through inhibition of destructiveinflammatory process and proliferation promotion (b) In the proliferation occurs (3) angiogenesis (4) reepithelization (epithelial cellmitosis and fibroblasts transformation into myofibroblasts) and granulation tissue formation (EMC composed of collagen glycoproteinproteoglycan fibroblasts and keratinocytes under modulation of MMP-9) (c) Remodeling is marked by the (5) EMC reorganization cellsapoptosis and angiogenesis regression and (6) type III collagen replaced by type I

reestablishment [3] Immediately after injury vasoconstric-tion occurs with the substances release such as serotoninthromboxane A2 and prostacyclin by cell membranes inorder to prevent blood leakage The exposed collagen signalsthe activation of coagulation cascade and in a coordinatedway the platelets adhere to damaged blood vessels initiatinghemostasis with the buffer formation composed of fibrinand thrombin This buffer will have main functions suchas to prevent the cellular elements loss to serve as physicalbarrier to microorganismsrsquo entry and to act as provisional

matrix cytokinesrsquo deposit and growth factors that will befundamental for maintenance of other healing phases [4]

The inflammatory response begins with vasodilationstimulated by soluble factors release such as nitric oxidebradykinin histamine and E and I series prostaglandinsTheincrease in vascular permeability with consequent fluid lossleads to slow blood flow allowing leukocytes mainly neu-trophils to interact with endothelium in an events sequenceinvolving margination (free leukocytes capture in the vas-cular lumen) rolling (weak interaction and activation)

International Journal of Inflammation 3

adhesion (firm interaction) transmigration (leukocyte pas-sage through endothelial cells) and finally the targetingof leukocytes to focus of lesion under influence of severalinflammatory mediators with chemotactic activity and alter-ations of vascular endothelial membrane proteins [7]

To achieve extravascular space towards the injured tis-sue leukocytes depend on adhesion molecules expressionsuch as selectins integrins and adhesion molecules of theimmunoglobulin family [intercellular adhesion molecule-1(ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)][8] Initially the selectin mediates the capture and recruit-ment of leukocytes along the endothelial cells followed bythe actions of ICAM-1 and VCAM-1 molecules to reduceleukocyte rolling velocity and allow its strong adhesion toendothelium [9]

In the first fewhours after injury neutrophils are recruitedand mediate tissue damage through the release of proteasescytokines and other factors contained in cytoplasmic gran-ules [10] These cells generate reactive oxygen species (ROS)and produce antimicrobial proteases (cathepsins defensinslactoferrin and lysozyme) with the function of destroyingpotentially pathogenic microorganisms In addition theyrelease enzymes such as collagenases and elastases that aiddevitalized tissues digestion essential for tissue renewal infollowing repair phases [11]

Neutrophils also produce various types of membranemetalloproteinases (MMPs) having as main subtypes MMP-8 which cleaves fibrillar collagen and MMP-2MMP-9which cleave collagen IV (among other substrates) bothinvolved in the extracellular matrix degradation The MMPsactivity is inhibited by a molecules class called tissueinhibitors of metalloproteinases (TIMPs) produced by a cellsvariety on skin If the proteases activity and their inhibitorsare not strictly regulated the granulation tissue formationmay be impaired [12] Thus uncontrolled neutrophil migra-tion generates a cycle of recruitment and activation ofthese cells leading to excessive ROS and proteases produc-tion causing undesired extracellular matrix degradation andadditional tissue damage which may progress to chronicinflammation with consequent defective collagen depositionreduced tissue resistance and late reepithelialization limitinghealing [13] Moreover they release cytokines such as tumornecrosis factor alpha (TNF-120572) interleukin- (IL-) 1120573 (IL-1120573)and IL-6 which amplify the inflammatory response by acti-vating more neutrophils and cells such as macrophages andwhich although essential for the repair cells activation cangenerate deleterious effects when exacerbated release occurs[5]

In intact skin macrophages are the most abundant celltypes performing sentinel and homeostatic function In skinlesion case the monocytes migrate from vascular circulationto wound Both infiltrating and resident macrophages onskin are activated by local signals and develop into severalsubpopulations defined by their different functional pheno-types [14] Pathogen-associated molecular patterns (PAMPs)

expressed by microbes and danger-associated molecularpatterns (DAMPs) produced during cell stress activatemacrophages in classic form typeM1 that act as host defenseperforming phagocytosis cleaning dead cells and debris andproducing proinflammatory mediators such as IL-1 IL-6 IL-12 TNF-120572 and inducible nitric oxide synthase (iNOS) as wellas chemokines to recruit additional leukocytes [15] In con-trast cytokines such as IL-4 and IL-13 lead to macrophagesformation of the M2 subset which regulate inflammation byexpressing mediators as IL-1 receptor antagonist (IL-1R) IL-1 type II receptor transforming growth factor-120573 (TGF-120573)vasopressin endothelial growth factor (VEGF) and insulin-like growth factor (IGF-1) promoting fibroblasts prolifer-ation extracellular matrix synthesis and angiogenesis [1617]

As the inflammation resolution occurs the involved cellsenter into apoptosis initiating the proliferative phase whichconsists of four fundamental stages reepithelization angio-genesis granulation tissue formation and collagen deposi-tion This phase is characterized by intense cellular activityaiming to repair the connective tissue and to form granula-tion tissue and epithelium [18]

During reepithelialization the keratinocytes migrationfromwound and epithelial attachments stimulated by growthfactors release aremainly responsible formitoses increase andepithelial hyperplasia [19] Fibroblasts migrate to provisionalmatrix to degrade it proliferating and producing MMPsThey also produce collagen proteoglycans hyaluronic acidglycosaminoglycans and fibronectin to form granulationtissue which fills the wound space and provides support forcell adhesion migration growth and differentiation duringwound repair [20]

Angiogenesis is essential for nutrition and oxygenationof new tissue being formed The formation of new bloodvessels is initiated by growth factors such as VEGF platelet-derived growth factor (PDGF) and basic fibroblast growthfactor (bFGF) After secreting proteolytic enzymes to dissolvethe basal lamina endothelial cells escape from existing bloodvessels proliferate and migrate to the source of angiogenicstimulus and providing oxygen for maintenance of cellularfunctions [21]

Collagen production starts from time of granulationtissue formation through production deposition digestionand reorganization steps Initially the collagen fibers aredeposited in disorganized form following a fibronectinmodel Subsequently in the attempt to organize these theyundergo digestion through enzymes of action produced byneutrophils macrophages and fibroblasts [18] Next newfibers will be produced and deposited in more organizedway following the adjacent connective tissue initiating theremodeling phase [22]

The remodeling phase occurs most expressively at theend of granulation tissue formation step Tissue developmentincreased mechanical stress and cytokine expression such asTGF-120573 stimulate fibroblasts to differentiate into myofibrob-lasts which express a smooth muscle actin with contractile


function favoring the locomotion of these cells from edgesto lesion center for wound contraction [23] At this stage thecollagen III produced rapidly in the extracellular matrix isreplaced by collagen I which has a higher tensile strengthbut takes more time to deposit [22] The new collagen willbe composed of larger fibers with greater fibrils numberand with significant amount of cross-links between themcharacterizing an increase in fiber diameter and tensilestrength acquired by scar [24]

3 Regulatory Factors Involved inInflammation and Healing

Wound healing is strongly regulated by a large number ofcytokines and growth factors acting as important mediatorsof differentiation proliferation and maintenance of impor-tant cells in repair process through various mechanisms [25]

There are currently 11members of IL-1 family ofwhich IL-1120572 and IL-1120573 are the most described differing in the way theyare activated and function IL-1120572 is translated into a biolog-ically active protein and IL-1 120573 is translated as a propeptidethat requires processing by caspase-1 enzyme in the inflam-masome [7 26] IL-1120573 is a key interleukin of antimicrobialresponse by inflammatory response amplification it stimu-lates leukocyte recruitment the acute phase proteins releaseand the increase of blood vessels permeability as well asstimulating Cox II expression and as a consequence theprostanoids formation and release [27ndash29]

Prostanoids have a central role in inflammation bloodcoagulation angiogenesis wound healing vascular tone andimmune responses among others [30 31] and the suppres-sion of their actions has been one of the main therapeutictargets for anti-inflammatory drugs development [32]

TNF-120572 is pleiotropic cytokine produced by a cell typesvariety including keratinocytesmacrophages andmast cellsIt acts on several stages of leukocyte recruitment mechanismmainly neutrophils inducing molecular adhesion regulationchemokine production and metalloproteinases matrix aswell as tissue inhibitors ofmetalloproteinases TNF-120572may actin a beneficial or deleterious way in wound healing and itselevation leads to decrease in granulation tissue productionwhile its reduction promotes a better collagen fibers arrange-ment Another function of this factor is to suppress TGF-120573in the stimulation of extracellular matrix (ECM) productionbut on the other hand it indirectly acts on reepithelializationby inducing keratinocyte growth factor production togetherwith IL-1 [25 33]

The keratinocyte growth factor (KGF) or fibroblastgrowth factor-7 (FGF-7) is an important member of FGFfamily involved in wound repair The injured epitheliumrepair also depends on the mitogenic potency of KGF whichis produced by dermal fibroblasts and acts by stimulatingkeratinocytes proliferation through receptors present in thesecells [33 34] KGF gene expression by dermal fibroblasts isincreased after cytokine signaling where some of these makepart in IL-1 family [35]

IL-8 which also acts as a chemokine (CXCL8) ismainly produced by monocytesmacrophages and in smaller

amounts by fibroblasts endothelial cells keratinocytes mel-anocytes hepatocytes and chondrocytes Their stimulationis usually IL-1 TNF-120572 and IFN-120574 (interferon-gamma) [10]The main action of IL-8 is great migratory motivation forimmune system cells mainly neutrophils also determiningan increase in the expression of adhesion molecules by endo-thelial cells [11]

Migration and cell proliferation are growth factor depen-dent mechanisms TGF-120573 inhibits matrix proteins degrada-tion decreasing MMPs synthesis and increasing TIMPs pro-duction [36] Low concentrations or suppression of TGF-120573exert a potentially negative influence indicating some distur-bance in the repair process [37]

The VEGF family proteins act as angiogenesis regulatorsduring cellular development [38] In response to hypoxiacaused by injury VEGF is released by macrophages fibrob-lasts and epithelial cells resulting in increased nitric oxideand endothelial progenitor cells mobilization [21] Angiogen-esis formation of new blood vessels from preexisting vesselsis an important phenomenon for the cicatrization prolifer-ative phase by temporarily increasing the vessels number atlesion site favoring oxygen and nutrients flow toxin removalcell migration and signal transduction [39] contributingfundamentally to tissues growth and regeneration Howeverwhen uncontrolled it also contributes to pathologies progres-sion such as arthritis psoriasis and cancer being regulatedby numerous pro- and antiangiogenic factors which are inequilibrium under normal conditions [39ndash41]

However situations such as wound healing growth-related hypoxia and inflammation cause imbalance inducingseveral proangiogenic factors activation such as cytokineslipidmediators and growth factors Skin regeneration duringthe wound healing process and bone regeneration are exam-ples that an increase in angiogenesis level can accelerate andimprove the outcome while avoiding necrosis [42]

One of the most important proangiogenic mediators isvascular endothelial growth factor (VEGF) by stimulatingthe endothelial cell functions necessary for new blood vesselsformation as well as for tissue proliferation migration dif-ferentiation and survival contributing to both angiogenesisand influencing wound repair and closure and granulationtissue formation [43]

VEGF is produced in response to lesions by a cells vari-ety including keratinocytes macrophages and fibroblastsdeveloping various roles in the healing process Acutely theyincrease vascular permeability adhesion cells expression andselectins recruiting inflammatory cells such as macrophagesandmast cells important in several stages of healing [44ndash46]In the proliferative phase it was verified that VEGF regulatesseveral aspects including epidermal repair and dermis barri-ers acting directly on keratinocytes and macrophages whichalso express receptors (VEGFRs) whose cellular activities arealso favored by oxygen and nutrients carried by new bloodvessels [47 48]

It is believed that VEGF levels present in wound canhave a healing impact Insufficient vascularization has beenassociated with abnormally low levels of active VEGF protein


in individuals with wound closure difficulties reduction ingranulation tissue reepithelialization and formation com-monly in diabetic patients [49 50] In addition drugs used toblock VEGF activity as in cancer treatment cases representa significant risk for tissue repair process [51] After topicaltreatment with recombinant VEGF or via viral vector orliposome mediated gene transfer there was acceleration inwound closure granulation tissue increasing and improvingthe resistance to wound rupture influencing deposited colla-gen production or arrangement [50 52ndash54]

One critical feature of remodeling phase is ECMremodel-ing to an architecture that approaches normal tissue [55 56]The known regression signals include soluble and ECM-derived antiangiogenicmediatorswhich lead to specific intra-cellular signaling pathways that result in cellular and micro-environmental changes associated with vessel regression [5758]

Once the endothelial cells (ECs) are primed by hypoxiaand activated by VEGF during the proliferative phase thereare probably several redundant intracellular negative feed-back mechanisms protecting ECs from VEGF overstimula-tion during the postproliferative and remodeling phases ofhealing which help to guide them into regression [59 60] Itappears that the postproliferative wound not only becomesmore resistant to proangiogenic stimuli by negative feedbackmechanisms but also generates active antiangiogenic signals[61]

Interestingly the proangiogenic mediator VEGF may beone of factors responsible for vessel regression initiation inpostproliferative phase Studies have found that ECs activa-tion by VEGF simultaneously marks these cells for death byinduction of death receptor Fas also known as CD95 whichinitiates apoptotic signaling pathways [59 60] making themless resistant to death by apoptosis-promoting signals

Finally different fibroblast subpopulationsmay play a rolein determining the fibroblastrsquos pro- or antiangiogenic func-tions Fibroblasts derived from papillary dermis and cocul-tured with ECs are angiopermissive stimulating robust vesselgrowth whereas reticular fibroblasts from deeper tissue areangiorestrictive presumably because of nonsoluble factorssuch as secreted ECM composition At the wound resolutionphase onset fibroblasts may switch to an antiangiogenic phe-notype due to contact inhibition and normalizing oxygen lev-els to regulate ECM remodeling indirectly mediating vesselregression [62] Besides the soluble and matricellular factorsan essential class of antiangiogenic molecules are thosederived from ECM components generated when specificmatrix proteases cleave large ECM proteins into bioactivepeptides [63]

Several antiangiogenesis factors act in different signalingpathways to regulate endothelial cell proliferation migrationand survival as well as help limit excessive angiogenesisduring wound healing inflammation and disease processes

(1) Inhibits the migration andor proliferation of endo-thelial cells chondromodulin-I (ChM-I) [64] pig-ment epithelium-derived factor (PEDF) [65] vaso-statin [66] antiangiogenic matricryptins derived of

type IV collagen including arresten canstatin andtumstatin [67ndash69] tissue inhibitor of matrix met-alloproteinase (TIMP) inhibits extracellular matrixdegradation and remodeling which is necessary forefficient endothelial cells migration and proliferation[70 71] endostatin was found to inhibit the migra-tion but not the proliferation of endothelial cells invitro and disrupt tumor vascularization and growthinmice [72] thrombospondin-1 inhibits angiogenesisthrough direct effects on endothelial migration andsurvival through indirect effects on growth factormobilization [73]

(2) Induces apoptotic death of endothelial cells inter-leukin 12 [74] plasminogenKringle 5 [75] interferons(120572 120573 and 120574) [76] in addition to these PEDF involvedin apoptosis stimulation in endothelial cells throughNF-120581B PPAR120574 and p53 mediated processes whileinhibiting their proliferation and migration [77ndash79]

(3) Reduction expression of angiogenesis activatorsinterferons (120572120573 and 120574) decreased expression of angi-ogenesis activators such as bFGF [80] a soluble formof VEGFR1 (sVEGFR1) with high affinity for VEGF-A has been shown to inhibit angiogenesis throughthe regulation of VEGFR2 activation and inhibitionof downstream mitogenic activities [81] endostatinblocks action of VEGF [82] whereas interleukin-10downregulates synthesis of VEGF and matrix metal-loproteinase 9 (MMP-9) [83]

Angiostatin derived from plasminogen able to suppressproliferation andmigration induces endothelial cells apopto-sis [84 85] and additionally downregulates VEGF expression[86ndash88] Twomembers of thrombospondin family TSP-1 andTSP-2 are relatively well-studied potent antiangiogenic fac-tors These molecules had been found to inhibit angiogenesisby downregulating EC proliferation and migration inhibit-ing VEGF signaling and initiating apoptosis [89] WhereasTSP-1 is produced during the early phases of healing andlikely functions to attenuate VEGF-mediated proangiogenicsignals TSP-2 is produced during the remodeling phase andis likely more involved in ECM remodeling-associated vesselregression [90]

IL-10 is a regulatory cytokine produced by different cellscapable of inhibiting the activities of Th1 cells natural killercells and M1 macrophages but stimulates M2 macrophagesto produce VEGF aiding in increased angiogenesis [91 92]It can also inhibit the production of other proinflammatorycytokines such as TNF-120572 IL-1120573 and IL-6 [91] In additionto its potent anti-inflammatory effects IL-10 has been shownto regulate fibrogenic cytokines such as transforming growthfactor-120573 (TGF-120573) as a part of its role in the regulationof tissue remodeling [93] Preclinical and clinical studieshave shown that rhIL-10-treated rat incisions healed withdecreased inflammation better scar histology and better


macroscopic scar appearance RhIL-10-treated human inci-sions at low concentrations healed with better macroscopicscar appearance and less red scars [94]

4 MicroRNA and Wound Healing

MicroRNAs (miRs) are approximately 22 nucleotides (nt) notencoding RNAs that bind to the 31015840-untranslated regions (31015840-UTR) of target messenger RNA (mRNA) and result in post-transcriptional regulation of gene expression [95] and havebeen found to regulate a variety of cellular and physiologicalfunctions in heath and disease The miRs expression deregu-lation has been shown to be associated with various diseasesDuring wound healing microRNAs play versatile roles buttheir functions are not yet understood [96] The abilityto therapeutically manipulate the miRs expression throughadministration of inducers andor inhibitors showed excite-ment about the therapeutic potential of miRs for nonhealingwounds [97]

MicroRNAs are present in all tissue types and regulatea wide variety of processes at the cellular level includingproliferation differentiation and apoptosis [98] The miRsact as agonists and antagonists in the process of restoringskin barrier functionChanges in the specificmiRs expressionduring different phases may be associated with abnormalwound healing [99]

Several pieces of evidence support that miRs regulate sig-nals in wound healing phases (1) In the inflammatory phasemacrophages are regulated by miR-146a and miR-155 whichpromote cytokines and growth factors production necessaryfor monocyte differentiation into macrophages [100 101]Toll-like receptor-4 (TLR-4)-mediated inflammation is reg-ulated by miR-21 effects on programmed cell-death protein4 (PDCD4) expression [102] miR-146a miR-155 and miR-21are reported to be linked to wound healing processes [103104] While miRs promote and induce inflammation theyalso downregulate and terminate the phase [101] (2) In theproliferation phase new blood vessels begin to form topromptly provide the healing area with abundant oxygenandnutrients through angiogenesisneovascularization [105]Several studies have identified miRs in the regulation of vari-ous aspects of the angiogenic response to various pathophys-iological stimuli For example miR-92a miR-217 miR-221and miR-222 inhibit angiogenic activity in endothelial cells(ECs) whereas miR-126 miR-130a miR-210 and the miR-23ndashmiR-27ndashmiR-24 cluster promote proangiogenic activity[106ndash112] Furthermore keratinocytes migrate from the edgeof the wound to the wound site and begin to proliferateand differentiate to restore skin integrity a process thatcan be inhibited by several miRs including miR-198 miR-203 and miR-483-3p [113ndash115] (3) The remodeling phasebegins whenwound is closed [103] miR-29a regulates dermalfibroblasts by their contractility control through TABL1 [116]miR-192215 increases E-cadherin expression by repressedtranslation of ZEB2 [117] while E-cadherin plays a role restor-ing the skin barrier integrity The discovery of several miRs

involved in the remodeling phase regulation still requiresfurther investigation

MicroRNA 26a (miR-26a) has been reported to partici-pate in normal development metabolic process and woundresponse [118] Furthermore miR-26a also regulates thegrowth of endothelial cells during physiological and patho-logical angiogenesis by targeting BMPSMAD1 signaling[119] Also a role for miR-26a in regulation of diabetic woundhealing progression was identified miR-26a expression isinduced in diabetic mice wounds and its neutralizationpromotewound closure through increased granulation tissueinduction of SMAD1 signaling in ECs and enhanced angio-genesis These findings indicate miR-26a therapeutic inhi-bition as promising treatment for diabetic subjects withimpaired dermal wound healing [96]

Though miRs could be new potential therapeutic targetfor wound healing it is still far from being a real applicationand further studies are needed to identify the miRs involvedin each wound healing phase

5 Toll-Like Receptors in Wound Healing

Toll-like receptors (TLRs) are a group of pattern recogni-tion receptors (PRRs) highly conserved that indicate thepresence of several pathogen-associated molecular patterns(PAMPs) to cellular constituents of the immune systemAfter binding to different biochemical components of pro-tozoa bacteria and viruses TLRs via NF-120581B-dependent andinterferon regulatory factor- (IRF-) dependent mechanismstrigger immune responses Moreover TLRs are also activatedby endogenous ligands called damage-associated molecularpatterns (DAMPs) that they are inaccessible to the immunesystem under physiological conditions or undergo changes inresponse to injury leading to recognition by PRRs Followingtissue injury these patterns are unmasked or released fromdamaged cells and subsequently trigger inflammation viaTLRs and other PRRs Consequently TLRs can be consideredasmaster safeguards of tissue structural integrity activated bymolecular indicators of infection or injury that play a key rolein the initiation of wound repair [120]

TLR activation in wound healing appears to be mediatedby two classes of ligands (1) In organs such as the gut skinand liver that are in direct contact with microbial productstissue lesions lead to a protective barriers breakdown andconsequently activation of TLR by bacteria PAMPs (2) Inmany organs such as the liver heart and kidney the tissueinjury leads to DAMPs release from dead cells resulting inTLRs activationThe endogenous TLR ligands release occurspredominantly after tissue damage especially in situationswhere a significant portion of cells undergo necrosis such asischemia-reperfusion injury [121ndash123]

According to their biological actions the TLRs wereimplicated in different phases of wound healing TLRs acti-vation modifies tissue injury in positive or negative way byrecruiting inflammatory cells that release cytotoxicmediators


or by activating cytoprotective signals enhances fibrogenicresponses in fibroblasts and promotes regenerative responses[124 125]

Several lines of evidence support that TLRs regulate sig-nals inwound healing (1) Topical application of TLR3 agonistpoly-(IC) for wound closure in mice promotes reepithe-lialization granulation and neovascularization Remarkablytopical application of poly-(IC) in patients with laser plasticsurgery accelerates wound closure [126] On the other handmice without TLR3 exhibit delayed wound healing parame-ters such as neovascularization granulation formation andreepithelialization [127] (2) Nucleic acids released by dam-aged skinwound cells stimulate TLR7 andTLR9 in infiltratedplasmacytoid dendritic cells leading to the transient produc-tion of type I interferon (IFN) Pharmacologic inhibition ofTLR7 or TLR9 or deficiency of MyD88 and TLR7 inhibitstype I IFN production The presence of dendritic cells andproduction of type I IFN are required for reepithelialization[128] TLR9 knockout mice exhibit a general delay in woundhealing Furthermore administration of the TLR9CpGODNagonist promotes influx of macrophages to the wound siteand increases the production of vascular endothelial growthfactor accelerating neovascularization of the wound in mice[129] and wound closure in nonhuman primates [130] (3)Excisional skin wounds in MyD88minusminus mice heal by slowerrate than wounds in wild-type MyD88++ showing delayedcontraction diminished and delayed granulation tissue andreduced density of fresh blood vessels [131] (4) In vitro andin vivo data has showed that TLR4 becomes upregulatedwithin the first 12ndash24 hours following injury and slowlydecreases at 10 days and is mainly concentrated in epidermalkeratinocytes The same study evidenced significant deterio-ration of wound healing in TLR4 deficient mice at days 1ndash5and no difference shown from wild-type at 10 days [132]Another study also observed impairment in wound healingin TLR2 and TLR4 deficient mice on days 3 and 7 [133] TheTLR4 and TLR2 activation appears to have a beneficial effecton wound healing in the early stages following acute injury[134] (5) The TLRs stimulation plays an important role inpromoting normal wound healing but that excessive TLRsignaling contributes to maladaptive or hypertrophic woundhealing and fibrosis [135]

Evidences suggest that TLRs have important roles inwound healing and modulate the innate immune responseNevertheless they differ in their expression pattern signalingpathways cellular localization and physiological outcomeson wound healing It will be important to identify the TLRsimpact on healing and innate immune responses [135] Thiswill improve the therapeutic strategies for the treatment ofwound healing

6 Healing Disturbances

The factors that influence tissue repair can be classified assystemic or local [136] By approaching factors that affect

healing locally it is important to note that oxygenation mod-ulation is very important for repair of cell maintenance activ-ities by stimulating cellular metabolism especially energyproduction by means of adenosine triphosphate (ATP) andis critical for almost all wound healing processes actingto prevent infections increasing angiogenesis keratinocytedifferentiation cell migration and reepithelialization [137]

Due to vascular ruptures and the high oxygen consump-tion by metabolically active cells the microenvironment atcicatrization beginning has a greater need for oxygenation Atthis time low oxygen flow (hypoxia) is temporarily importantfor healing but if prolonged as in some pathologies it canmake the wound chronic and difficult to heal [138] Hypoxiacan induce cytokines expression and production of growthfactors released by macrophages keratinocytes and fibrob-lasts Cytokines that are produced in response to hypoxiainclude PDGF TGF-120573 VEGF TNF-120572 and endothelin-1which are promoters of cell proliferation migration chemo-taxis and angiogenesis [139]

A factor that may negatively affect wound healing isinfections presence which may result in inflammatory phaseprolongation and increased production of reactive oxygenspecies (ROS) and proinflammatory cytokines such as IL-1and TNF-120572 induced by both bacteria and endotoxins presenton site If infection does not resolve the wound may becomechronic with persistent inflammation The bacteria presencein the lesion may also be associated with bacterial biofilmformation which creates a resistance microenvironment tomedications actionmaking healing evenmore difficult [140]

Systemic factors that may interfere with healing maybe age-related It has been observed that elderly healing isassociated with modified inflammatory responses such ascells late infiltration in wound area chemokine productionchanges phagocytes reduction delayed reepithelializationand impaired collagenization [141]

Sex also influences healing through hormonal regulationon a variety of genes associated with regeneration matrixproduction regeneration epidermal function [142] and pro-tease inhibition [143] and genes associated primarily withinflammation [144] It has been found that topical 17120573-estradiol enhances mRNA and procollagen type 1 proteinexpression significantly in aged human skin Expressions ofTGF-1205731 and TGF-120573 receptor type II were also increased andTNF-1205731 neutralizing antibody inhibits 17120573-estradiol inducedprocollagen synthesis in cultured fibroblasts Topical estra-diol also increased the keratinocytes proliferation and epider-mal thickness in aged human skin also observing the sameeffects in young skin [145] In addition the elderly estrogendeficiency is also associated with healing difficulty [146]

Stress is another factor that can critically influence heal-ing as it is associated with increased glucocorticoids (GCs)and reduced proinflammatory cytokines levels (IL-1120573 IL-6and TNF-120572) in the wound It also reduces the IL-1120572 andIL-8 expression both chemoattractants required for theinitial inflammatory phase [147] In addition GCs influence


immune cells by suppressing differentiation and prolifera-tion regulating gene transcription and reducing the expres-sion of cell adhesion molecules [148] Stress has been shownto reduce T cell proliferation and T cell dependent antibodiesproduction [149] besides increasing the phagocytic abilitiesof cells and the number of neutrophils in the wound area ofmice subjected to stress restriction [150]

Diabetes also interferes negatively in the wound healingprocess and many factors have been shown to be involved inthe poor wound healing ability of diabetic patients includinghyperglycemic environment chronic inflammation woundinfection vascular insufficiency hypoxia sensory neuropa-thy and abnormal neuropeptide signaling [151ndash153]

It has been postulated that hyperglycemia can lead to adeleterious effect on wound healing through the formationof advanced glycation end-products (AGEs) These end-products are a heterogeneous compounds complex group thatare formed when reducing sugar reactions in a nonenzymaticway with amino acids in proteins and other macromoleculesThis occurs both exogenously (in food) and endogenously (inhumans) with greater concentrations found in older adults[154 155] These end-products reduce the solubility of theextracellular matrix and perpetuate the inflammatory alter-ations observed in diabetes [156 157] The AGEs also stim-ulate the proinflammatory molecules release such as TNF-120572andMMPs which limit wound closure In addition theAGE-RAGE (AGE receptor) interaction in fibroblasts may causereduction of collagen deposition further compromising thenormal healing process [158]

An altered immune function may also contribute to poorwound healing in patients with diabetes Studies suggest thata failure in removal of inflammatory cells such as neutro-phils plays a role in the pathogenesis of nonhealing woundsA deficit in the capability of macrophages to effectivelyremove neutrophils has been reported to be a critical compo-nent of the impaired healing seen in diabetes [159 160] Otherstudies have shown that the prolonged inflammatory phaseis characterized by sustained expression and increased levelsof proinflammatory cytokines such as interleukin-1 (IL-1)interleukin-6 (IL-6) and tumor necrosis factor-120572 (TNF-120572) indiabetics [161 162]

Decreased peripheral blood flow and diminished localneovascularization are critical factors that contribute to thedelayed or nonhealing wounds in diabetics Endothelialprogenitor cells (EPCs) a specialized subset of hematopoieticprogenitor cells (HPC) are the key cellular effectors ofischemic neovascularization and play a central role in woundhealing [163] EPC are capable of inducing endothelial dif-ferentiation [164] and secretion of angiogenic growth factorsand cytokines [165 166] which are of paramount importancein neovascularization The circulating number of EPC andwound level are decreased in diabetes implying an abnormal-ity in EPC mobilizationThis deficiency in EPC mobilizationis presumably due to impairment of endothelial nitric oxidesynthase (eNOS-NO) cascade in bone marrow (BM) [163]

Abnormal expression of growth factors has beenobserved in diabetics Insulin-like growth factor I (IGF-1 agrowth factor similar to insulin) is a cytokine that participatesin the cellular granulation process duringwound healingTheIGF-1 anabolic effects include stimulation of DNA synthesiscell proliferation protein synthesis and glucose transportDuring healing its expression is increased However dia-betic patients show overall decreased levels of IGF-1 expres-sion [167]

Disturbed physiologic functions of epidermal keratino-cytes also have been found to play an important role inthe poor healing ability of diabetic wounds [168] Factorsinvolving keratinocytes that may contribute to the dysfunc-tional wound healing process in diabetes include impairedkeratinocytemigration and proliferation gap junction abnor-malities chronic inflammation chronic infections reducedangiogenesis oxidative stress and abnormal expression ofMMPs [153 169ndash171]

Some drugs that interfere with clot formation or plateletfunction or inflammatory responses and cell proliferationhave the ability to affect wound healing Systemic glucocorti-coids frequently used can inhibit tissue repair by suppressingimmune cells complicating cell signaling that compromisesthe other healing stages such as fibroblast proliferation andcollagen synthesis Systemic steroids cause scarring incom-plete granulation tissue and wound contraction reduction[172]

Nonsteroidal anti-inflammatory drugs (NSAIDs) such asibuprofen are widely used for inflammation and pain treat-ment and rheumatoid arthritis Low-dose aspirin becauseof its antiplatelet function is commonly used as a preven-tive therapy for cardiovascular disease but not as an anti-inflammatory [173] However it is important to be cautiouswith the use of these drugs during healing as they may affectthe inflammatory phase making hemostasis and clot forma-tion difficult at the process beginning [24]

Chemotherapeutic drugs also negatively interfere inwound healing since they are associated with delayed cellmigration extracellular matrix formation impairment col-lagen production fibroblast proliferation and inhibition ofwound contraction [174] Other factors such as alcoholism[175] smoke [176] and precarious nutrition [177] as wellas obesity [178] vascular diseases [179] and metabolic syn-drome [180] are also associated with healing damage

Disorders of wound healing have been found to be morefrequent in the inflammation andor proliferation phases anddepend on the interactions between different cell types andextracellular matrix predominantly synthesized by fibrob-lasts [18]

Wounds may have vascular traumatic inflammatoryinfectious or malignant lesions Acute scarring occurs alonga coordinate biochemical cascade however a wound maybecome chronic if the inflammatory and proliferative phasesof the cascade suffer some imbalance Chronic wounds are


prevalent and cause substantial morbidity mortality andincreased health costs [181]

Among the chronic injuries types are venous leg ulcerscommon in the elderly and resulting from chronic venoushypertension characterized by persistent inflammationhemosiderin deposition and lipodermatosclerosis [182]

7 Pharmacological Interventions

The skin wounds treatment is dynamic and depends ofthe healing phases evolution There are numerous curativeoptions on the market that are in the range of simplest cover-age such as hygiene and antisepsis solutions ointments gelsgrowth factors and even the most complex dressings typescalled ldquosmart dressingsrdquo or ldquobioactiverdquo [183]

To direct the choosing process of which therapy to useDas and Baker (2016) [201] emphasized that an accuratelesion assessment is essential carefully identifying the healingprocess stage In addition the benefits and costs evaluationare some of the aspects to be considered when choosing thetreatment type which should be appropriate to the naturelocation and size of the wound Although there are a widevariety of dressings a single type does not meet the require-ments to be applied to all cutaneous wounds types

According to Sibbald et al (2015) [183] the used therapiesfor healing can be classified as follows

(A) Resources intended to skin protect against mechani-cal or chemical aggression and infection prevention

(B) Hygiene and antisepsis products(C) Products for chemical enzymatic autolytic or

mechanical debridement(D) Primary covers (come in direct contact with wound

bed) or secondary (they serve to fix primary covers)(E) Products for fastening covers and accessories (bands

bandages)(F) Topical agents

Ointments containing debris agents (DNAse collage-nases fibrinolysins and papain) are topical options that actselectively promoting a smooth enzymatic digestion on devi-talized tissues but present low efficacy in chronic injuriestreatment [202] Dressings with hydrocolloids are also usedwhich aid in autolytic debridement and stimulate angiogen-esis but may cause maceration of adjacent tissue like cal-ciumalginate activated charcoal andhydropolymer adhesivedressing indicated for exudativewounds and contraindicatedfor dry wounds [4]

Molecules directly involved in the physiological healingprocess have also been studied as potential therapeutictargets since ulcers that are difficult to heal are related tolower expression of these factors Examples of molecules arePDGF (REGRANEX) and VEGF in addition to proteasesand degrading agents [32] but the high cost of these therapiesmakes access to them difficult for the population

The traditional therapies used in healing have also beenstrongly practiced since medicinal plants have historicallyproven their value as molecules source with therapeuticpotential and nowadays still represent an important target fornewdrugs identification [203]Themedicinal plants scientificevidence on wound healing indicates beneficial effects in dif-ferent lesions treatment [204ndash207] The good manufacturingpractices development and regulatory legislation also playsa key role in stimulating the traditional therapies used byclinicians and promote their integration into national healthsystem since there is widespread acceptance by population

In this sense it is important to remember that BrazilianMinistry of Health has stimulated the insertion of com-plementary care practices in the health system The imple-mentation of the National Policy of Medicinal Plants andPhytotherapy (PNPMF in Portuguese) [208] and NationalPolicy on Integrative and Complementary Practices (PNPICin Portuguese) [209] which aim to stimulate access tocomplementary practices andmedicinal plants for health carein an effective and safe way is worth noting

Another important publication is National Relation ofMedicinal Plants of interest toUnifiedHealth System (SUS inPortuguese) launched in 2009 containing 71medicinal plantsthat should be object of research and implementation of theBrazilian public health sectors and services [210] The Col-legiate Board of Directors Resolution (DRC in Portuguese)number 10 of the year 2010 (a and b) lists 66 medicinalplants with proven actions in human health Among theseseveral species are indicated for the cicatrization processwhich implies a great advance in the Brazilian public healththat begins to value the use of new therapies based onmedicinal plants a practice so widespread around the worldand generations

The chemical compounds present in plants are involved ina variety of steps in healing ranging from the inflammatoryprocess control to the granulation tissue formation increaseof the lesion contraction and collagen deposition [211]Pereira and Bartolo (2016) [212] described a review of sometraditional therapies most used in healing of cutaneousinjuries which can be seen in Table 1

It is noted that the pharmacological effects on healingobserved in the plants described in the table may be relatedto secondarymetabolites presence found in these plant mate-rials since several studies have shown that mainly tannins[213] flavonoids [214] triterpenes [215] and essential oils[216] may be associated with such activity

In view of the tissue repair response complexity it isperceived that the treatment with a single factor or cellularcomponent reaches limited effectiveness in the healing ofchronic wounds The challenge lies in the combined ther-apeutic approaches development or preferably in the prod-ucts development having more than one biologically activecompound such as a product that stimulates both angio-genesis and matrix deposition and epithelial migration [5]So researchersrsquo attention to factors that delay or acceleratewound healing is important in order to increase the thera-peutic arsenal and make wound healing more effective


Table 1

Herb Main constituents Laboratorial and clinical evidence References

Aloe veraSoluble sugars nonstarch

polysaccharides lignin polysaccharidesglycoproteins and antiseptic agents

Anti-inflammatory and antimicrobialactivities stimulates cell proliferationcollagen synthesis and angiogenesis

promotes wound contraction

[184ndash187]

Hippophae rhamnoides (seabuckthorn)

Flavonoids (eg quercetinisorhamnetin) carotenoids (eg a-

b-carotene lycopene) vitamins (C E K)tannins organic acids triterpenes

glycerides of palmitic stearic oleic acidsand amino acids

Antioxidant and anti-inflammatoryactivities stimulates the healing process

improves wound contraction andepithelialization increases the

hydroxyproline and protein content inthe wound

[188 189]

Angelica sinensisEssential oils and water-soluble

ingredients ferulic acid is the main activeconstituent

Stimulates the proliferation of humanskin fibroblasts the secretion of collagenand the expression of TGF-120573 in vitro

[190]

Catharanthus roseus (Vincarosea)

Contains two major classes of activecompounds alkaloids (eg vincamine)

and tannins

Antimicrobial activity againstPseudomonas aeruginosa and

Staphylococcus aureus increases woundstrength epithelialization and wound

contraction

[191]

Calendula officinalis(marigold) Triterpenoids and flavonoids

Anti-inflammatory and antibacterialactivities stimulates the proliferation and

migration of fibroblasts in vitrostimulates the collagen production and

angiogenesis

[192ndash194]

Sesamum indicumSesamol is the main antioxidant

constituent others include sesamolin andsesaminol

Improves the wound tensile strengthwound contraction and the

hydroxyproline levels in both normal anddelayed wound models in rats

[195]

Morinda citrifolia (noni)

Acids alcohols phenols estersanthraquinones sterols flavonoids

triterpenoids saccharides carotenoidsesters ketones lactones lignans and

nucleosides

Improves the hydroxyproline content andreduces both the wound area and the

epithelialization time in excision woundsin rats

[196 197]

Camellia sinensis Polyphenols flavonoids tannins caffeineand amino acids

Reduces the healing time and the woundlength of incision wounds created in

Wistar rats[198 199]

Rosmarinus officinalis L(rosemary)

Most bioactive constituents includeterpenoids and polyphenols such as

carnosol carnosic acid and rosmarinicacid

Reduces the inflammation and improvesthe wound contraction

reepithelialization angiogenesis andcollagen deposition on full-thickness

wounds in diabetic mice

[200]

Conflicts of Interest

The authors declare that they have no conflicts of interest

Acknowledgments

The authors thank Conselho Nacional de DesenvolvimentoCientıfico e Tecnologico (CNPq) Fundacao de Amparo aPesquisa e ao Desenvolvimento Cientıfico e Tecnologico doEstado de Maranhao (FAPEMA) and Universidade Federaldo Maranhao (UFMA) for providing financial support Theyare grateful to Flavio Freitas Soares Filho for English gram-mar revision

References

[1] P Parham O sistema imune BookPorto Alegre ArtMed 3rdedition 2011

[2] L B Nicholson ldquoThe imune systemrdquo Essays Biochem vol 60pp 275ndash301 2016

[3] G M Slavich and M R Irwin ldquoFrom stress to inflammationand major depressive disorder a social signal transductiontheory of depressionrdquo Psychological Bulletin vol 140 no 3 pp774ndash815 2014

[4] T N Demidova-RiceM RHamblin and IMHerman ldquoAcuteand impaired wound healing Pathophysiology and currentmethods for drug delivery part 1 normal and chronic woundsbiology causes and approaches to carerdquo Advances in Skin andWound Care vol 25 no 7 pp 304ndash314 2012


[5] S A Eming P Martin and M Tomic-Canic ldquoWound repairand regeneration mechanisms signaling and translationrdquoScience TranslationalMedicine vol 6 no 265 Article ID 265sr62014

[6] H-J You and S-K Han ldquoCell therapy for wound healingrdquoJournal of Korean Medical Science vol 29 no 3 pp 311ndash3192014

[7] A S MacLeod R Rudolph R Corriden I Ye O Garijo andW L Havran ldquoSkin-resident T cells sense ultraviolet radiation-induced injury and contribute to DNA repairrdquo Journal ofImmunology vol 192 no 12 pp 5695ndash5702 2014

[8] C Nussbaum S Bannenberg P Keul et al ldquoSphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizingendothelial P-selectinrdquo Nature Communications vol 6 article6416 2015

[9] K Noda S Nakao S Ishida and T Ishibashi ldquoLeukocyte adhe-sion molecules in diabetic retinopathyrdquo Journal of Ophthalmol-ogy vol 2012 Article ID 279037 6 pages 2012

[10] T N Mayadas X Cullere and C A Lowell ldquoThe multifacetedfunctions of neutrophilsrdquoAnnual Review of Pathology vol 9 pp181ndash218 2014

[11] E Kolaczkowska and P Kubes ldquoNeutrophil recruitment andfunction in health and inflammationrdquo Nature Reviews Immu-nology vol 13 no 3 pp 159ndash175 2013

[12] T A Wilgus S Roy and J C McDaniel ldquoNeutrophilsand wound repair positive actions and negative reactionsrdquoAdvances in Wound Care vol 2 no 7 pp 379ndash388 2013

[13] S De Oliveira E E Rosowski and A Huttenlocher ldquoNeu-trophil migration in infection and wound repair going forwardin reverserdquo Nature Reviews Immunology vol 16 no 6 pp 378ndash391 2016

[14] P J Murray and T A Wynn ldquoProtective and pathogenicfunctions of macrophage subsetsrdquoNature Reviews Immunologyvol 11 no 11 pp 723ndash737 2011

[15] S Galvan-Pena and L A J OrsquoNeill ldquoMetabolic reprogrammingin macrophage polarizationrdquo Frontiers in Immunology vol 5Article ID Article 420 2014

[16] M L Novak and T J Koh ldquoMacrophage phenotypes duringtissue repairrdquo Journal of Leukocyte Biology vol 93 no 6 pp875ndash881 2013

[17] A Mantovani S K Biswas M R Galdiero A Sica and MLocati ldquoMacrophage plasticity and polarization in tissue repairand remodellingrdquo The Journal of Pathology vol 229 no 2 pp176ndash185 2013

[18] N X Landen D Li and M Stahle ldquoTransition from inflam-mation to proliferation a critical step during wound healingrdquoCellular and Molecular Life Sciences vol 73 no 20 pp 3861ndash3885 2016

[19] I Pastar O Stojadinovic N C Yin et al ldquoEpithelialization inwound healing a comprehensive reviewrdquo Advances in WoundCare vol 3 no 7 pp 445ndash464 2014

[20] H Levinson ldquoA paradigm of fibroblast activation and dermalwound contraction to guide the development of therapies forchronicwounds andpathologic scarsrdquoAdvances inWoundCarevol 2 no 4 pp 149ndash159 2013

[21] L A Dipietro ldquoAngiogenesis and scar formation in healingwoundsrdquo Current Opinion in Rheumatology vol 25 no 1 pp87ndash91 2013

[22] MGaneshkumar T Ponrasu R Krithika K IyappanV S Gay-athri and L Suguna ldquoTopical application of Acalypha indicaaccelerates rat cutaneous wound healing by up-regulating the

expression of Type I and III collagenrdquo Journal of Ethnopharma-cology vol 142 no 1 pp 14ndash22 2012

[23] J W Penn O A Grobbelaar and K J Rolfe ldquoThe role of theTGF-120573 family in wound healing burns and scarring a reviewrdquoInternational Journal of Burns and Trauma vol 2 pp 18ndash282012

[24] F Siviero Biologia cellular bases moleculares e metodologia depesquisa Roca Sao Paulo Brazil 1st edition 2013

[25] Y Feng A J Sanders L D Morgan K G Harding and WG Jiang ldquoPotential roles of suppressor of cytokine signaling inwound healingrdquo Regenerative Medicine vol 11 no 2 pp 193ndash209 2016

[26] C-S Chen W-H Su M-H Cheng et al ldquoNonsteroidal anti-inflammatory drugs for wounds Pain relief or excessive scarformationrdquo Mediators of Inflammation vol 2010 Article ID413238 8 pages 2010

[27] C A Dinarello ldquoInterleukin-1 and the pathogenesis of theacute-phase responserdquo The New England Journal of Medicinevol 311 no 22 pp 1413ndash1418 1984

[28] A I Basbaum and D Julius ldquoNovos alvos contra a dorrdquo Sci-entific American Brasil vol 50 pp 76ndash83 2006

[29] W A Verri Jr T M Cunha C A Parada S Poole F QCunha and S H Ferreira ldquoHypernociceptive role of cytokinesand chemokines targets for analgesic drug developmentrdquoPharmacology ampTherapeutics vol 112 no 1 pp 116ndash138 2006

[30] C L Kummer and T C Coelho ldquoAntiinflamatorios nao esteroi-des inibidores da ciclooxigenase-2 (COX-2) aspectos atuaisrdquoRevista Brasileira de Anestesiologia vol 52 no 4 pp 498ndash5122002

[31] V Kvaternick M Pollmeier J Fischer and P D HansonldquoPharmacokinetics and metabolism of orally administeredfirocoxib a novel second generation coxib in horsesrdquo Journalof Veterinary Pharmacology and Therapeutics vol 30 no 3 pp208ndash217 2007

[32] S Yedgar M Krimsky Y Cohen and R J Flower ldquoTreatmentof inflammatory diseases by selective eicosanoid inhibition adouble-edged swordrdquo Trends in Pharmacological Sciences vol28 no 9 pp 459ndash464 2007

[33] A Gragnani B R Muller I D C G da Silva S M Rde Noronha and L M Ferreira ldquoKeratinocyte growth factortumor necrosis factor-alpha and interleukin-1 beta gene expres-sion in cultured fibroblasts and keratinocytes from burnedpatientsrdquo Acta Cirurgica Brasileira vol 28 no 8 pp 551ndash5582013

[34] S Barrientos H Brem O Stojadinovic and M Tomic-CanicldquoClinical application of growth factors and cytokines in woundhealingrdquoWoundRepair andRegeneration vol 22 no 5 pp 569ndash578 2014

[35] M Brauchle K Angermeyer G Hubner and S Werner ldquoLargeinduction of keratinocyte growth factor expression by serumgrowth factors and pro-inflammatory cytokines in culturedfibroblastsrdquo Oncogene vol 9 no 11 pp 3199ndash3204 1994

[36] P Vanezis ldquoBook review the wound healing process forensicpathological aspectsrdquoMedicine Science and the Law vol 40 no1 pp 88-89 2016

[37] L Kubiczkova L Sedlarikova R Hajek and S SevcikovaldquoTGF-120573mdashan excellent servant but a bad masterrdquo Journal ofTranslational Medicine vol 10 no 1 article 183 2012

[38] V Cury A I S Moretti L Assis et al ldquoLow level lasertherapy increases angiogenesis in a model of ischemic skin flapin rats mediated by VEGF HIF-1120572 and MMP-2rdquo Journal of


Photochemistry and Photobiology B Biology vol 125 pp 164ndash170 2013

[39] K E Johnson and T A Wilgus ldquoVascular endothelial growthfactor and angiogenesis in the regulation of cutaneous woundrepairrdquo Advances in Wound Care vol 3 no 10 pp 647ndash6612014

[40] P Carmeliet ldquoAngiogenesis in health and diseaserdquo NatureMedicine vol 9 no 6 pp 653ndash660 2003

[41] H Rossiter C Barresi J Pammer et al ldquoLoss of vascularendothelial growth factor A activity in murine epidermal ker-atinocytes delays wound healing and inhibits tumor formationrdquoCancer Research vol 64 no 10 pp 3508ndash3516 2004

[42] H C Ko B K Milthorpe and C D McFarland ldquoEngineeringthick tissues-the vascularization problemrdquo European Cells ampMaterials vol 14 pp 1ndash18 2007

[43] J Kim A C Mirando A S Popel and J J Green ldquoGenedelivery nanoparticles to modulate angiogenesisrdquo AdvancedDrug Delivery Reviews 2016

[44] M Detmar L F BrownM P Schon et al ldquoIncreasedmicrovas-cular density and enhanced leukocyte rolling and adhesionin the skin of VEGF transgenic micerdquo Journal of InvestigativeDermatology vol 111 no 1 pp 1ndash6 1998

[45] Y-K Hong B Lange-Asschenfeldt P Velasco et al ldquoVEGF-A promotes tissue repair-associated lymphatic vessel formationvia VEGFR-2 and the 12057211205731 and 12057221205731 integrinsrdquo FASEB Journalvol 18 no 10 pp 1111ndash1113 2004

[46] B C Wulff and T A Wilgus ldquoMast cell activity in the healingwound more than meets the eyerdquo Experimental Dermatologyvol 22 no 8 pp 507ndash510 2013

[47] T AWilgus AMMatthies K A Radek et al ldquoNovel functionfor vascular endothelial growth factor receptor-1 on epidermalkeratinocytesrdquoAmerican Journal of Pathology vol 167 no 5 pp1257ndash1266 2005

[48] T Lucas A Waisman R Ranjan et al ldquoDifferential rolesof macrophages in diverse phases of skin repairrdquo Journal ofImmunology vol 184 no 7 pp 3964ndash3977 2010

[49] G Lauer S Sollberg M Cole et al ldquoExpression and proteolysisof vascular endothelial growth factor is increased in chronicwoundsrdquo Journal of Investigative Dermatology vol 115 no 1 pp12ndash18 2000

[50] R D Galiano O M Tepper C R Pelo et al ldquoTopical vascularendothelial growth factor accelerates diabetic wound healingthrough increased angiogenesis and by mobilizing and recruit-ing bonemarrow-derived cellsrdquoTheAmerican Journal of Pathol-ogy vol 164 no 6 pp 1935ndash1947 2004

[51] B Stallmeyer J Pfeilschifter and S Frank ldquoSystemically andtopically supplemented leptin fails to reconstitute a normalangiogenic response during skin repair in diabetic obob micerdquoDiabetologia vol 44 no 4 pp 471ndash479 2001

[52] S Romano Di Peppe A Mangoni G Zambruno et alldquoAdenovirus-mediatedVEGF165 gene transfer enhanceswoundhealing by promoting angiogenesis in CD1 diabetic micerdquo GeneTherapy vol 9 no 19 pp 1271ndash1277 2002

[53] M Galeano B Deodato D Altavilla et al ldquoAdeno-associatedviral vector-mediated human vascular endothelial growth fac-tor gene transfer stimulates angiogenesis and wound healing inthe genetically diabetic mouserdquo Diabetologia vol 46 no 4 pp546ndash555 2003

[54] H Brem A Kodra M S Golinko et al ldquoMechanism ofsustained release of vascular endothelial growth factor in accel-erating experimental diabetic healingrdquo Journal of InvestigativeDermatology vol 129 no 9 pp 2275ndash2287 2009

[55] AGosain and LADiPietro ldquoAging andwoundhealingrdquoWorldJournal of Surgery vol 28 no 3 pp 321ndash326 2004

[56] A C L Campos A K Groth and A B Branco ldquoAssessmentand nutritional aspects of wound healingrdquo Current Opinion inClinical Nutrition andMetabolic Care vol 11 no 3 pp 281ndash2882008

[57] K Sakamaki ldquoRegulation of endothelial cell death and its rolein angiogenesis and vascular regressionrdquoCurrent NeurovascularResearch vol 1 no 4 pp 305ndash315 2004

[58] S Dimmeler and A M Zeiher ldquoEndothelial cell apoptosis inangiogenesis and vessel regressionrdquo Circulation Research vol87 no 6 pp 434ndash439 2000

[59] V E A Stoneman andM R Bennett ldquoRole of FasFas-L in vas-cular cell apoptosisrdquo Journal of Cardiovascular Pharmacologyvol 53 no 2 pp 100ndash108 2009

[60] O V Volpert T Zaichuk W Zhou et al ldquoInducer-stimulatedFas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derivedfactorrdquo Nature Medicine vol 8 no 4 pp 349ndash357 2002

[61] A Gosain A M Matthies J V Dovi A Barbul R L Gamelliand L A DiPietro ldquoExogenous pro-angiogenic stimuli can-not prevent physiologic vessel regressionrdquo Journal of SurgicalResearch vol 135 no 2 pp 218ndash225 2006

[62] J M Sorrell M A Baber and A I Caplan ldquoHuman dermalfibroblast subpopulations Differential interactions with vas-cular endothelial cells in coculture nonsoluble factors in theextracellular matrix influence interactionsrdquo Wound Repair andRegeneration vol 16 no 2 pp 300ndash309 2008

[63] F Suhr K Brixius and W Bloch ldquoAngiogenic and vascularmodulation by extracellular matrix cleavage productsrdquo CurrentPharmaceutical Design vol 15 no 4 pp 389ndash410 2009

[64] S Miura K Mitsui T Heishi et al ldquoImpairment of VEGF-A-stimulated lamellipodial extensions and motility of vascu-lar endothelial cells by chondromodulin-I a cartilage-derivedangiogenesis inhibitorrdquo Experimental Cell Research vol 316 no5 pp 775ndash788 2010

[65] J Loegl E Nussbaumer U Hiden et al ldquoPigment epithelium-derived factor (PEDF) a novel trophoblast-derived factor limit-ing feto-placental angiogenesis in late pregnancyrdquoAngiogenesisvol 19 no 3 pp 373ndash388 2016

[66] S Maestroni A Maestroni S Ceglia et al ldquoEffect of chro-mogranin A-derived vasostatin-1 on laser-induced choroidalneovascularization in the mouserdquo Acta Ophthalmologica vol93 no 3 pp e218ndashe222 2015

[67] G D Kamphaus P C Colorado D J Panka et al ldquoCanstatina novel matrix-derived inhibitor of angiogenesis and tumorgrowthrdquo Journal of Biological Chemistry vol 275 no 2 pp1209ndash1215 2000

[68] Y Hamano M Zeisberg H Sugimoto et al ldquoPhysiologicallevels of tumstatin a fragment of collagen IV 1205723 chain aregenerated by MMP-9 proteolysis and suppress angiogenesis via120572V1205733 integrinrdquo Cancer Cell vol 3 no 6 pp 589ndash601 2003

[69] P Nyberg L Xie H Sugimoto et al ldquoCharacterization ofthe anti-angiogenic properties of arresten an 12057211205731 integrin-dependent collagen-derived tumor suppressorrdquo ExperimentalCell Research vol 314 no 18 pp 3292ndash3305 2008

[70] A N Murphy E J Unsworth and W G Stetler-StevensonldquoTissue inhibitor of metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial cell proliferationrdquoJournal of Cellular Physiology vol 157 no 2 pp 351ndash358 1993


[71] H A Fernandez K Kallenbach G Seghezzi et al ldquoInhibitionof endothelial cell migration by gene transfer of tissue inhibitorofmetalloproteinases-1rdquo Journal of Surgical Research vol 82 no2 pp 156ndash162 1999

[72] M S OrsquoReilly T Boehm Y Shing et al ldquoEndostatin anendogenous inhibitor of angiogenesis and tumor growthrdquo Cellvol 88 no 2 pp 277ndash285 1997

[73] D Pinessi C Foglieni A Bugatti et al ldquoPO-15mdashantiangiogenicsmall molecule ligands of FGF2 derived from the endogenousinhibitor thrombospondin-1rdquo Thrombosis Research vol 140 pS182 2016

[74] D G Duda M Sunamura L Lozonschi et al ldquoDirect in vitroevidence and in vivo analysis of the antiangiogenesis effects ofinterleukin 12rdquo Cancer Research vol 60 no 4 pp 1111ndash11162000

[75] W-B Cai Y Zhang R Cheng et al ldquoDual inhibition of plas-minogen kringle 5 on angiogenesis and chemotaxis suppressestumor metastasis by targeting HIF-1120572 pathwayrdquo PLoS ONE vol7 no 12 Article ID e53152 2012

[76] E Jonasch and F G Haluska ldquoInterferon in oncologicalpractice review of interferon biology clinical applications andtoxicitiesrdquo Oncologist vol 6 no 1 pp 34ndash55 2001

[77] D W Dawson O V Volpert P Gillis et al ldquoPigment epithel-ium-derived factor a potent inhibitor of angiogenesisrdquo Sciencevol 285 no 5425 pp 245ndash248 1999

[78] T-C Ho S-L Chen Y-C Yang C-L Liao H-C Chengand Y-P Tsao ldquoPEDF induces p53-mediated apoptosis throughPPAR gamma signaling in human umbilical vein endothelialcellsrdquo Cardiovascular Research vol 76 no 2 pp 213ndash223 2007

[79] A B Aurora D Biyashev Y Mirochnik et al ldquoNF-kappaBbalances vascular regression and angiogenesis via chromatinremodeling and NFAT displacementrdquo Blood vol 116 no 3 pp475ndash484 2010

[80] J W Slaton P Perrotte K Inoue C P N Dinney and I JFidler ldquoInterferon-120572-mediated down-regulation of angiogene-sis-related genes and therapy of bladder cancer are dependenton optimization of biological dose and schedulerdquo ClinicalCancer Research vol 5 no 10 pp 2726ndash2734 1999

[81] A Ahmed S Ahmad P W Hewett et al ldquoAutocrine activity ofsoluble Flt-1 controls endothelial cell function and angiogene-sisrdquo Vascular Cell vol 3 article 15 2011

[82] Y-M Kim S Hwang B-J Pyun et al ldquoEndostatin blocks vas-cular endothelial growth factor-mediated signaling via directinteraction with KDRFlk-1rdquo The Journal of Biological Chem-istry vol 277 no 31 pp 27872ndash27879 2002

[83] S Huang S E Ullrich and M Bar-Eli ldquoRegulation of tumorgrowth and metastasis by interleukin-10 the melanoma experi-encerdquo Journal of Interferon and Cytokine Research vol 19 no 7pp 697ndash703 1999

[84] L Claesson-Welsh M Welsh N Ito et al ldquoAngiostatin inducesendothelial cell apoptosis and activation of focal adhesionkinase independently of the integrin-binding motif RGDrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 95 no 10 pp 5579ndash5583 1998

[85] K Eriksson P Magnusson J Dixelius L Claesson-Welsh andM J Cross ldquoAngiostatin and endostatin inhibit endothelial cellmigration in response to FGF and VEGF without interferingwith specific intracellular signal transduction pathwaysrdquo FEBSLetters vol 536 no 1ndash3 pp 19ndash24 2003

[86] F Griscelli H Li A Bennaceur-Griscelli et al ldquoAngiostatingene transfer inhibition of tumor growth in vivo by blockage

of endothelial cell proliferation associated with amitosis arrestrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 95 no 11 pp 6367ndash6372 1998

[87] T L Moser M S Stack I Asplin et al ldquoAngiostatin binds ATPsynthase on the surface of human endothelial cellsrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 96 no 6 pp 2811ndash2816 1999

[88] A Hajitou C Grignet L Devy et al ldquoThe antitumoral effect ofendostatin and angiostatin is associated with a down-regulationof vascular endothelial growth factor expression in tumor cellsrdquoThe FASEB Journal vol 16 no 13 pp 1802ndash1804 2002

[89] P R Lawler and J Lawler ldquoMolecular basis for the regulation ofangiogenesis by thrombospondin-1 and -2rdquo Cold Spring HarborPerspectives in Medicine vol 2 no 5 Article ID a006627 2012

[90] T R Kyriakides and S MacLauchlan ldquoThe role of throm-bospondins in wound healing ischemia and the foreign bodyreactionrdquo Journal of Cell Communication and Signaling vol 3no 3-4 pp 215ndash225 2009

[91] K N Couper D G Blount and E M Riley ldquoIL-10 the masterregulator of immunity to infectionrdquo Journal of Immunology vol180 no 9 pp 5771ndash5777 2008

[92] W-KWuO PC LlewellynDO Bates L BNicholson andAD Dick ldquoIL-10 regulation of macrophage VEGF production isdependent onmacrophage polarisation and hypoxiardquo Immuno-biology vol 215 no 9-10 pp 796ndash803 2010

[93] T Yamamoto B Eckes andTKrieg ldquoEffect of Interleukin-10 onthe gene expression of type I collagen fibronectin and decorinin human skin fibroblasts differential regulation by transform-ing growth factor-120573 and monocyte chemoattractant protein-1rdquoBiochemical and Biophysical Research Communications vol 281no 1 pp 200ndash205 2001

[94] I Kieran A Knock J Bush et al ldquoInterleukin-10 reducesscar formation in both animal and human cutaneous woundsResults of two preclinical and phase II randomized controlstudiesrdquoWound Repair and Regeneration vol 21 no 3 pp 428ndash436 2013

[95] A Wilczynska and M Bushell ldquoThe complexity of miRNA-mediated repressionrdquoCell Death andDifferentiation vol 22 no1 pp 22ndash33 2015

[96] B Icli C S Nabzdyk J Lujan-Hernandez et al ldquoRegulationof impaired angiogenesis in diabetic dermal wound healing bymicroRNA-26ardquo Journal of Molecular and Cellular Cardiologyvol 91 pp 151ndash159 2016

[97] J Banerjee and C K Sen ldquoMicrorna and wound healingrdquoAdvances in Experimental Medicine and Biology vol 888 pp291ndash305 2015

[98] L He and G J Hannon ldquoMicroRNAs small RNAs with a bigrole in gene regulationrdquo Nature Reviews Genetics vol 5 no 7pp 522ndash531 2004

[99] S Shilo S Roy S Khanna and C K Sen ldquoMicroRNA incutaneous wound healing a new paradigmrdquo DNA and CellBiology vol 26 no 4 pp 227ndash237 2007

[100] R I Gregory T P Chendrimada and R ShiekhattarldquoMicroRNA biogenesis isolation and characterization of themicroprocessor complexrdquo Methods in Molecular Biology vol342 pp 33ndash47 2006

[101] H Park X Huang C Lu M S Cairo and X ZhouldquoMicroRNA-146a and microRNA-146b regulate human den-dritic cell apoptosis and cytokine production by targetingTRAF6 and IRAK1 proteinsrdquo Journal of Biological Chemistryvol 290 no 5 pp 2831ndash2841 2015


[102] F J Sheedy E Palsson-Mcdermott E J Hennessy et al ldquoNeg-ative regulation of TLR4 via targeting of the proinflammatorytumor suppressor PDCD4 by the microRNA miR-21rdquo NatureImmunology vol 11 no 2 pp 141ndash147 2010

[103] X Yang J Wang S-L Guo et al ldquomiR-21 promotes ker-atinocyte migration and re-epithelialization during woundhealingrdquo International Journal of Biological Sciences vol 7 no5 pp 685ndash690 2011

[104] J Xu W Wu L Zhang et al ldquoThe role of MicroRNA-146a inthe pathogenesis of the diabetic wound-healing impairmentcorrection with mesenchymal stem cell treatmentrdquo Diabetesvol 61 no 11 pp 2906ndash2912 2012

[105] F Fahs X Bi F-S Yu L Zhou andQ-S Mi ldquoNew insights intomicroRNAs in skin wound healingrdquo IUBMB Life vol 67 no 12pp 889ndash896 2015

[106] S Wang A B Aurora B A Johnson et al ldquoThe endothelial-specific microRNA miR-126 governs vascular integrity andangiogenesisrdquo Developmental Cell vol 15 no 2 pp 261ndash2712008

[107] A Bonauer G Carmona M Iwasaki et al ldquoMicroRNA-92acontrols angiogenesis and functional recovery of ischemictissues in micerdquo Science vol 324 no 5935 pp 1710ndash1713 2009

[108] P Fasanaro Y DrsquoAlessandra V Di Stefano et al ldquoMicroRNA-210 modulates endothelial cell response to hypoxia and inhibitsthe receptor tyrosine kinase ligand ephrin-A3rdquo Journal ofBiological Chemistry vol 283 no 23 pp 15878ndash15883 2008

[109] Y Chen and D H Gorski ldquoRegulation of angiogenesis througha microRNA (miR-130a) that down-regulates antiangiogenichomeobox genes GAX and HOXA5rdquo Blood vol 111 no 3 pp1217ndash1226 2008

[110] Q Zhou R Gallagher R Ufret-Vincenty X Li E N Olsonand S Wang ldquoRegulation of angiogenesis and choroidal neo-vascularization by members of microRNA-23sim27sim24 clustersrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 108 no 20 pp 8287ndash8292 2011

[111] Y Suarez C Fernandez-Hernando J S Pober andW C SessaldquoDicer dependent microRNAs regulate gene expression andfunctions in human endothelial cellsrdquo Circulation Research vol100 no 8 pp 1164ndash1173 2007

[112] R Menghini V Casagrande and M Cardellini ldquoMicroRNA217modulates endothelial cell senescence via silent informationregulator 1rdquo Circulation vol 120 no 15 pp 1524ndash1532 2009

[113] G M Sundaram J E A Common F E Gopal et al ldquolsquoSee-sawrsquoexpression ofmicroRNA-198 and FSTL1 from a single transcriptin wound healingrdquoNature vol 494 no 7439 pp 103ndash106 2013

[114] G Viticchie A M Lena and F Cianfarani ldquoMicroRNA-203contributes to skin re-epithelializationrdquo Cell Death amp Diseasevol 3 no 11 article e435 2012

[115] T Bertero C Gastaldi I Bourget-Ponzio et al ldquomiR-483-3pcontrols proliferation in wounded epithelial cellsrdquo The FASEBJournal vol 25 no 9 pp 3092ndash3105 2011

[116] M Ciechomska S OrsquoReilly M Suwara K Bogunia-Kubikand J M Van Laar ldquoMiR-29a reduces TIMP-1 production bydermal fibroblasts via targeting TGF-120573 activated kinase 1 bind-ing protein 1 implications for systemic sclerosisrdquo PLoS ONEvol 9 no 12 Article ID e115596 2014

[117] B Wang M Herman-Edelstein P Koh et al ldquoE-cadherinexpression is regulated by miR-192215 by a mechanism that isindependent of the profibrotic effects of transforming growthfactor-120573rdquo Diabetes vol 59 no 7 pp 1794ndash1802 2010

[118] B K Dey J Gagan Z Yan and A Dutta ldquomiR-26a is requiredfor skeletal muscle differentiation and regeneration in micerdquoGenes and Development vol 26 no 19 pp 2180ndash2191 2012

[119] B Icli A K M Wara J Moslehi et al ldquoMicroRNA-26a regu-lates pathological and physiological angiogenesis by targetingBMPSMAD1 signalingrdquo Circulation Research vol 113 no 11pp 1231ndash1241 2013

[120] P Huebener and R F Schwabe ldquoRegulation of wound healingand organ fibrosis by toll-like receptorsrdquo Biochimica et Biophys-ica ActamdashMolecular Basis of Disease vol 1832 no 7 pp 1005ndash1017 2013

[121] Q Lin M Li D Fang J Fang and S B Su ldquoThe essential rolesof Toll-like receptor signaling pathways in sterile inflammatorydiseasesrdquo International Immunopharmacology vol 11 no 10 pp1422ndash1432 2011

[122] J Kluwe A Mencin and R F Schwabe ldquoToll-like recep-tors wound healing and carcinogenesisrdquo Journal of MolecularMedicine vol 87 no 2 pp 125ndash138 2009

[123] M Voulgarelis and S Ioannou ldquoToll-like receptors tissueinjury and tumourigenesisrdquo Mediators of Inflammation vol2010 Article ID 581837 9 pages 2010

[124] M T Lotze H J Zeh A Rubartelli et al ldquoThe grateful deaddamage-associated molecular pattern molecules and reduc-tionoxidation regulate immunityrdquo Immunological Reviews vol220 no 1 pp 60ndash81 2007

[125] B Beutler ldquoNeo-ligands for innate immune receptors andthe etiology of sterile inflammatory diseaserdquo ImmunologicalReviews vol 220 no 1 pp 113ndash128 2007

[126] Q Lin L Wang Y Lin et al ldquoToll-like receptor 3 ligandpolyinosinic polycytidylic acid promotes wound healing inhuman and murine skinrdquo Journal of Investigative Dermatologyvol 132 no 8 pp 2085ndash2092 2012

[127] Q Lin D Fang J Fang et al ldquoImpaired wound healing withdefective expression of chemokines and recruitment of myeloidcells in TLR3-deficient micerdquo Journal of Immunology vol 186no 6 pp 3710ndash3717 2011

[128] J Gregorio S Meller C Conrad et al ldquoPlasmacytoid dendriticcells sense skin injury and promotewound healing through typei interferonsrdquo Journal of Experimental Medicine vol 207 no 13pp 2921ndash2930 2010

[129] T Sato M Yamamoto T Shimosato and D M KlinmanldquoAccelerated wound healing mediated by activation of Toll-likereceptor 9rdquo Wound Repair and Regeneration vol 18 no 6 pp586ndash593 2010

[130] M Yamamoto T Sato J Beren D Verthelyi and D MKlinman ldquoThe acceleration of wound healing in primates bythe local administration of immunostimulatory CpG oligonu-cleotidesrdquo Biomaterials vol 32 no 18 pp 4238ndash4242 2011

[131] L Macedo G Pinhal-Enfield V Alshits G Elson B NCronstein and S J Leibovich ldquoWound healing is impaired inMyD88-deficient mice a role for MyD88 in the regulation ofwound healing by adenosine A2A receptorsrdquo American Journalof Pathology vol 171 no 6 pp 1774ndash1788 2007

[132] L Chen S Guo M J Ranzer and L A Dipietro ldquoToll-likereceptor 4 has an essential role in early skin wound healingrdquoJournal of Investigative Dermatology vol 133 no 1 pp 258ndash2672013

[133] H Suga M Sugaya H Fujita et al ldquoTLR4 rather than TLR2regulates wound healing throughTGF-120573 andCCL5 expressionrdquoJournal of Dermatological Science vol 73 no 2 pp 117ndash1242014


[134] M Portou D Baker D Abraham and J Tsui ldquoThe innateimmune system toll-like receptors and dermal wound healinga reviewrdquo Vascular Pharmacology vol 71 pp 31ndash36 2015

[135] M R Dasu and R Rivkah Isseroff ldquoToll-like receptors inwound healing location accessibility and timingrdquo Journal ofInvestigative Dermatology vol 132 no 8 pp 1955ndash1958 2012

[136] K Anderson and R L Hamm ldquoFactors that impair woundhealingrdquo Journal of the American College of Clinical WoundSpecialists vol 4 no 4 pp 84ndash91 2012

[137] D M Castilla Z Liu and O C Velazquez ldquoOxygen implica-tions for wound healingrdquo Advances inWound Care vol 1 no 6pp 225ndash230 2012

[138] W L Yip ldquoInfluence of oxygen onwoundhealingrdquo InternationalWound Journal vol 12 no 6 pp 620ndash624 2015

[139] Z Zhang G Cao L Sha D Wang and M Liu ldquoThe efficacy ofsodium aescinate on cutaneous wound healing in diabetic ratsrdquoInflammation vol 38 no 5 pp 1942ndash1948 2015

[140] L Gould P Abadir H Brem et al ldquoChronic wound repairand healing in older adults current status and future researchrdquoJournal of the AmericanGeriatrics Society vol 63 no 3 pp 427ndash438 2015

[141] G Gainza S Villullas J L Pedraz R M Hernandez and MIgartua ldquoAdvances in drug delivery systems (DDSs) to releasegrowth factors for wound healing and skin regenerationrdquoNanomedicine vol 11 no 6 pp 1551ndash1573 2015

[142] T Zhou Z Yang Y Chen et al ldquoEstrogen accelerates cutaneouswound healing by promoting proliferation of epidermal ker-atinocytes via ErkAkt signaling pathwayrdquo Cellular Physiologyand Biochemistry vol 38 no 3 pp 959ndash968 2016

[143] E D Son J Y Lee S Lee et al ldquoTopical application of17120573-estradiol increases extracellular matrix protein synthesisby stimulating TGF-120573 signaling in aged human skin in vivordquoJournal of Investigative Dermatology vol 124 no 6 pp 1149ndash1161 2005

[144] K R Thornton A J Foran and A D Long ldquoProperties andmodeling of GWAS when complex disease risk is due to non-complementing deleterious mutations in genes of large effectrdquoPLoS Genetics vol 9 no 2 Article ID e1003258 2013

[145] M J Hardman and G S Ashcroft ldquoEstrogen not intrinsicaging is the major regulator of delayed human wound healingin the elderlyrdquo Genome Biology vol 9 no 5 article R80 2008

[146] E Emmerson and M J Hardman ldquoThe role of estrogendeficiency in skin ageing and wound healingrdquo Biogerontologyvol 13 no 1 pp 3ndash20 2012

[147] L Boyapati and H-L Wang ldquoThe role of stress in periodontaldisease and wound healingrdquo Periodontology 2000 vol 44 no 1pp 195ndash210 2007

[148] B Romana-Souza T L Assis de Brito G R Pereira and AMonte-Alto-Costa ldquoGonadal hormones differently modulatecutaneous wound healing of chronically stressed micerdquo BrainBehavior and Immunity vol 36 pp 101ndash110 2014

[149] P K Gajendrareddy C G Engeland R Junges M P HoranI G Rojas and P T Marucha ldquoMMP-8 overexpression andpersistence of neutrophils relate to stress-impaired healingand poor collagen architecture in micerdquo Brain Behavior andImmunity vol 28 pp 44ndash48 2013

[150] S D Tymen I G Rojas X Zhou Z J Fang Y Zhao and PT Marucha ldquoRestraint stress alters neutrophil and macrophagephenotypes duringwound healingrdquoBrain Behavior and Immu-nity vol 28 pp 207ndash217 2013

[151] A J M Boulton ldquoThe pathway to foot ulceration in diabetesrdquoMedical Clinics of North America vol 97 no 5 pp 775ndash7902013

[152] G K Kolluru S C Bir and C G Kevil ldquoEndothelial dysfunc-tion and diabetes effects on angiogenesis vascular remodelingand wound healingrdquo International Journal of VascularMedicinevol 2012 Article ID 918267 30 pages 2012

[153] D Baltzis I Eleftheriadou and A Veves ldquoPathogenesis andtreatment of impaired wound healing in diabetes mellitus newinsightsrdquo Advances in Therapy vol 31 no 8 pp 817ndash836 2014

[154] C Luevano-Contreras and K Chapman-Novakofski ldquoDietaryadvanced glycation end products and agingrdquo Nutrients vol 2no 12 pp 1247ndash1265 2010

[155] N J Kellow and M T Coughlan ldquoEffect of diet-derivedadvanced glycation end products on inflammationrdquo NutritionReviews vol 73 no 11 Article ID nuv030 pp 737ndash759 2015

[156] L Pradhan C Nabzdyk N D Andersen F W LoGerfo andA Veves ldquoInflammation and neuropeptides the connection indiabetic wound healingrdquo Expert Reviews inMolecularMedicinevol 11 article e2 2009

[157] R Blakytny and E Jude ldquoThe molecular biology of chronicwounds and delayed healing in diabetesrdquoDiabeticMedicine vol23 no 6 pp 594ndash608 2006

[158] N Ahmed ldquoAdvanced glycation endproductsmdashrole in pathol-ogy of diabetic complicationsrdquo Diabetes Research and ClinicalPractice vol 67 no 1 pp 3ndash21 2005

[159] S Khanna S Biswas Y Shang et al ldquoMacrophage dysfunctionimpairs resolution of inflammation in the wounds of diabeticmicerdquo PLoS ONE vol 5 no 3 Article ID e9539 2010

[160] J B Acosta D Garcia Del Barco D Cibrian Vera et al ldquoThepro-inflammatory environment in recalcitrant diabetic footwoundsrdquo International Wound Journal vol 5 no 4 pp 530ndash539 2008

[161] T Dinh F Tecilazich A Kafanas et al ldquoMechanisms involvedin the development and healing of diabetic foot ulcerationrdquoDiabetes vol 61 no 11 pp 2937ndash2947 2012

[162] O Ochoa F M Torres and P K Shireman ldquoChemokines anddiabetic wound healingrdquo Vascular vol 15 no 6 pp 350ndash3552007

[163] Z-J Liu and O C Velazquez ldquoHyperoxia endothelial progeni-tor cell mobilization and diabetic wound healingrdquoAntioxidantsand Redox Signaling vol 10 no 11 pp 1869ndash1882 2008

[164] M Peichev A J Naiyer D Pereira et al ldquoExpression ofVEGFR-2 and AC133 by circulating human CD34+ cells identifies apopulation of functional endothelial precursorsrdquo Blood vol 95no 3 pp 952ndash958 2000

[165] H Kamihata H Matsubara T Nishiue et al ldquoImplantationof bone marrow mononuclear cells into ischemic myocardiumenhances collateral perfusion and regional function via sidesupply of angioblasts angiogenic ligands and cytokinesrdquo Cir-culation vol 104 no 9 pp 1046ndash1052 2001

[166] C Urbich A Aicher C Heeschen et al ldquoSoluble factorsreleased by endothelial progenitor cells promote migration ofendothelial cells and cardiac resident progenitor cellsrdquo Journalof Molecular and Cellular Cardiology vol 39 no 5 pp 733ndash7422005

[167] B Bruhn-Olszewska A Korzon-Burakowska M Gabig-Ciminska P Olszewski A Wegrzyn and J Jakobkiewicz-Banecka ldquoMolecular factors involved in the development ofdiabetic foot syndromerdquo Acta Biochimica Polonica vol 59 pp507ndash513 2012


[168] S C-S Hu and C-C E Lan ldquoHigh-glucose environmentdisturbs the physiologic functions of keratinocytes focusing ondiabetic wound healingrdquo Journal of Dermatological Science vol84 no 2 pp 121ndash127 2016

[169] V Falanga ldquoWound healing and its impairment in the diabeticfootrdquoThe Lancet vol 366 no 9498 pp 1736ndash1743 2005

[170] A Kasuya and Y Tokura ldquoAttempts to accelerate woundhealingrdquo Journal of Dermatological Science vol 76 no 3 pp169ndash172 2014

[171] H Huang W Cui W Qiu et al ldquoImpaired wound healingresults from the dysfunction of the AktmTOR pathway indiabetic ratsrdquo Journal of Dermatological Science vol 79 no 3pp 241ndash251 2015

[172] A S Wang E J Armstrong and A W Armstrong ldquoCorti-costeroids and wound healing clinical considerations in theperioperative periodrdquoAmerican Journal of Surgery vol 206 no3 pp 410ndash417 2013

[173] M Batlouni ldquoNonsteroidal anti-inflammatory drugs cardio-vascular cerebrovascular and renal effectsrdquo Arquivos Brasileirosde Cardiologia vol 94 no 4 pp 522ndash563 2010

[174] J P Erinjeri A J Fong N E Kemeny K T Brown G IGetrajdman and S B Solomon ldquoTiming of administration ofbevacizumab chemotherapy affects wound healing after chestwall port placementrdquo Cancer vol 117 no 6 pp 1296ndash1301 2011

[175] M J Ranzer L Chen and L A DiPietro ldquoFibroblast functionand wound breaking strength is impaired by acute ethanolintoxicationrdquo Alcoholism Clinical and Experimental Researchvol 35 no 1 pp 83ndash90 2011

[176] L T Soslashrensen ldquoWound healing and infection in surgery thepathophysiological impact of smoking smoking cessation andnicotine replacement therapy a systematic reviewrdquo Annals ofSurgery vol 255 no 6 pp 1069ndash1079 2012

[177] A M Quain and N M Khardori ldquoNutrition in wound caremanagement a comprehensive overviewrdquo Wounds vol 27article 12 2015

[178] I J Wagner C Szpalski R J Allen Jr et al ldquoObesity impairswound closure through a vasculogenic mechanismrdquo WoundRepair and Regeneration vol 20 no 4 pp 512ndash522 2012

[179] L Yazdanpanah M Nasiri and S Adarvishi ldquoLiterature reviewon the management of diabetic foot ulcerrdquo World Journal ofDiabetes vol 6 no 1 pp 37ndash53 2015

[180] B D Pence and J A Woods ldquoExercise obesity and cutaneouswound healing evidence from rodent and human studiesrdquoAdvances in Wound Care vol 3 no 1 pp 71ndash79 2014

[181] J Paul ldquoCharacteristics of chronic wounds that itchrdquo Advancesin Skin and Wound Care vol 26 no 7 pp 320ndash332 2013

[182] T Y A F Dias I K F Costa M M Melo S M D S G S deOliveira Torres M C E Maia and G de Vasconcelos TorresldquoQuality of life assessment of patients with and without venousulcerrdquo Revista Latino-Americana de Enfermagem vol 22 no 4pp 576ndash581 2014

[183] R G Sibbald J A Elliott E A Ayello and R Somayaji ldquoOpti-mizing the moisture management tightrope with wound bedpreparation 2015copyrdquo Advances in Skin and Wound Care vol 28no 10 pp 466ndash476 2015

[184] P Inpanya A Faikrua A Ounaroon A Sittichokechaiwut andJ Viyoch ldquoEffects of the blended fibroinaloe gel film on woundhealing in streptozotocin-induced diabetic ratsrdquo BiomedicalMaterials vol 7 no 3 Article ID 035008 13 pages 2012

[185] M Tarameshloo M Norouzian S Zarein-Dolab M Dadpay JMohsenifar and R Gazor ldquoAloe vera gel and thyroid hormone

cream may improve wound healing in Wistar ratsrdquo Anatomy ampCell Biology vol 45 no 3 pp 170ndash177 2012

[186] A Atiba M Nishimura S Kakinuma et al ldquoAloe vera oraladministration accelerates acute radiation-delayedwound heal-ing by stimulating transforming growth factor-120573 and fibroblastgrowth factor productionrdquo American Journal of Surgery vol201 no 6 pp 809ndash818 2011

[187] A Atiba H Ueno and Y Uzuka ldquoThe effect of aloe vera oraladministration on cutaneous wound healing in type 2 diabeticratsrdquo Journal of Veterinary Medical Science vol 73 no 5 pp583ndash589 2011

[188] N K Upadhyay R Kumar S K Mandotra et al ldquoSafety andhealing efficacy of Sea buckthorn (Hippophae rhamnoides L)seed oil on burn wounds in ratsrdquo Food and Chemical Toxicologyvol 47 no 6 pp 1146ndash1153 2009

[189] A Gupta R Kumar K Pal V Singh P K Banerjee and R CSawhney ldquoInfluence of sea buckthorn (Hippophae rhamnoidesL) flavone on dermal wound healing in ratsrdquo Molecular andCellular Biochemistry vol 290 no 1-2 pp 193ndash198 2006

[190] C-Y Hsiao C-Y Hung T-H Tsai and K-F Chak ldquoA studyof the wound healing mechanism of a traditional chinesemedicine Angelica sinensis using a proteomic approachrdquoEvidence-Based Complementary and Alternative Medicine vol2012 Article ID 467531 14 pages 2012

[191] B S Nayak and LM Pinto Pereira ldquoCatharanthus roseus flowerextract has wound-healing activity in Sprague Dawley ratsrdquoBMC Complementary and Alternative Medicine vol 6 article41 2006

[192] A T Naeini R Miri N Shafiei M R Tabandeh A Oryan andS Nazifi ldquoEffects of topical application of Calendula officinalisgel on collagen and hydroxyproline content of skin in ratsrdquoComparative Clinical Pathology vol 21 no 3 pp 253ndash257 2012

[193] L M L Parente R D S Lino Junior L M F Tresvenzol MC Vinaud J R De Paula and N M Paulo ldquoWound healingand anti-inflammatory effect in animal models of Calendulaofficinalis L growing in Brazilrdquo Evidence-Based Complementaryand Alternative Medicine vol 2012 Article ID 375671 7 pages2012

[194] M Fronza B Heinzmann M Hamburger S Laufer and IMerfort ldquoDetermination of the wound healing effect of Cal-endula extracts using the scratch assay with 3T3 fibroblastsrdquoJournal of Ethnopharmacology vol 126 no 3 pp 463ndash467 2009

[195] R R Shenoy A T Sudheendra P G Nayak P Paul N GKutty and C M Rao ldquoNormal and delayed wound healing isimproved by sesamol an active constituent of Sesamum indicum(L) in albino ratsrdquo Journal of Ethnopharmacology vol 133 no2 pp 608ndash612 2011

[196] D R Singh ldquoMorinda citrifolia L (Noni) A review of the sci-entific validation for its nutritional and therapeutic propertiesrdquoJournal of Diabetes and Endocrinology vol 3 no 6 pp 77ndash912012

[197] B S Nayak S Sandiford and A Maxwell ldquoEvaluation of thewound-healing activity of ethanolic extract of Morinda citri-folia L leafrdquo Evidence-Based Complementary and AlternativeMedicine vol 6 no 3 pp 351ndash356 2009

[198] A B Sharangi ldquoMedicinal and therapeutic potentialities of tea(Camellia sinensis L)mdasha reviewrdquo Food Research Internationalvol 42 no 5-6 pp 529ndash535 2009

[199] S Y Asadi P Parsaei M Karimi et al ldquoEffect of greentea (Camellia sinensis) extract on healing process of surgicalwounds in ratrdquo International Journal of Surgery vol 11 no 4pp 332ndash337 2013


[200] M A Abu-Al-Basal ldquoHealing potential of Rosmarinus offici-nalis L on full-thickness excision cutaneous wounds in alloxan-induced-diabetic BALBc micerdquo Journal of Ethnopharmacologyvol 131 no 2 pp 443ndash450 2010

[201] S Das and A B Baker ldquoBiomaterials and nanotherapeutics forenhancing skin wound healingrdquo Frontiers in Bioengineering andBiotechnology vol 31 article 82 2016

[202] R J Mendonca and J Coutinho-Netto ldquoCellular aspects ofwound healingrdquo Anais Brasileiros de Dermatologia vol 84 no3 pp 257ndash262 2009

[203] A G Atanasov B Waltenberger and E M Pferschy-WenzigldquoDiscovery and resupply of pharmacologically active plant-derived natural products a reviewrdquoBiotechnologyAdvances vol33 pp 1582ndash1614 2015

[204] A Singhal H Gupta and V Bhati ldquoWound healing activity ofArgyreia nervosa leaves extractrdquo International Journal of Appliedand Basic Medical Research vol 1 no 1 pp 36ndash39 2011

[205] I F da Silva Junior S O Balogun R G de Oliveira A SDamazo and D T D O Martins ldquoPiper umbellatum L amedicinal plant with gastric-ulcer protective and ulcer healingeffects in experimental rodent modelsrdquo Journal of Ethnophar-macology vol 192 pp 123ndash131 2016

[206] D Akbik M Ghadiri W Chrzanowski and R RohanizadehldquoCurcumin as a wound healing agentrdquo Life Sciences vol 116 no1 pp 1ndash7 2014

[207] L R M Estevao J P de Medeiros L Baratella-Evencio R SSimoes F D S Mendonca and J Evencio-Neto ldquoEffects ofthe topical administration of copaiba oil ointment (Copaiferalangsdorffii) in skin flaps viability of ratsrdquo Acta CirurgicaBrasileira vol 28 no 12 pp 863ndash869 2013

[208] Brasil ldquoMinisterio da Saude Secretaria de Ciencia Tecnologia eInsumos Estrategicos Departamento de Assistencia Farmaceu-tica Polıtica nacional de plantas medicinais e fitoterapicosBrasılia Ministerio da Sauderdquo 2006

[209] Brasil ldquoMinisterio da Saude Secretaria de Atencao a SaudeDepartamento de Atencao Basica Polıtica Nacional de PraticasIntegrativas e Complementares no SUS - PNPIC-SUS Min-isterio da Saude Secretaria de Atencao a Saude Departamentode Atencao Basica - Brasılia Ministerio da Sauderdquo 2006

[210] Brasil ldquoMinisterio da Saude Secretaria de Ciencia Tecnologiae Insumos Estrategicos Departamento de Assistencia Far-maceutica e Insumos Estrategicos Programa Nacional de Plan-tas Medicinais e Fitoterapicos Ministerio da Saude Secretariade Ciencia Tecnologia e Insumos Estrategicos Departamentode Assistencia Farmaceutica e Insumos Estrategicos ndash BrasıliaMinisterio da Sauderdquo 2009

[211] R K Sivamani B R Ma L N Wehrli and E MaverakisldquoPhytochemicals and naturally derived substances for woundhealingrdquoAdvances inWoundCare vol 1 no 5 pp 213ndash217 2012

[212] R F Pereira and P J Bartolo ldquoTraditional therapies for skinwound healingrdquoAdvances inWound Care vol 5 no 5 pp 208ndash229 2016

[213] K Li Y Diao H Zhang et al ldquoTannin extracts from immaturefruits of Terminalia chebula Fructus Retz promote cutaneouswound healing in ratsrdquo BMC Complementary and AlternativeMedicine vol 11 article 86 2011

[214] K Fujita KKugeNOzawa et al ldquoCinnamtanninB-1 promotesmigration of mesenchymal stem cells and accelerates woundhealing in micerdquo PLoS ONE vol 10 no 12 Article ID e01441662015

[215] H-MMori H Kawanami H Kawahata andMAoki ldquoWoundhealing potential of lavender oil by acceleration of granulation

and wound contraction through induction of TGF-120573 in a ratmodelrdquo BMC Complementary and Alternative Medicine vol 16no 1 article 144 2016

[216] Y-S Wu and S-N Chen ldquoExtracted triterpenes from Antrodiacinnamomea reduce the inflammation to promote the woundhealing via the STZ inducing hyperglycemia-diabetes micemodelrdquo Frontiers in Pharmacology vol 7 article 154 2016

Submit your manuscripts athttpswwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Platelet invasion forhemostasis

Neutrophil

Monocyte

Collagen

M2

Anti-inammatory

M1BacteriaDebrisInammatory factors

Blood vessels (1) C

oagu

latio

n(2

) In

amm

ator

y ev

ents(IL-1 TNF- IL-6)

factors (IL-10 TGF-)

(a) Inflammation

Blood vessels Growth factors Platelet invasion forhemostasis

Fibroblast

Myofibroblast

Macrophage

Epidermis

CollagenGlycoprotein

Proteoglycan

MMP-9

Keratinocytes

Neutrophil

(3) A

ngio

gene

sis(4

) Ree

pith

eliz

atio

n an

dgr

anul

atio

n tis

sue

(PDGF TGF- VEGF)

(b) Proliferation

Blood vessels

Epidermis

Collagen III

Collagen I

Apoptosis

(5) R

eorg

aniz

atio

n of

EM

C(6

) Typ

e III

colla

gen

repl

aced

by

t ype

I

(c) Remodeling

Figure 1 Progression and overlap of the phases involved in the physiological wound healing process (a) inflammation begins with (1)coagulation platelet aggregation and fibrin clot formation (2) then inflammatory events occur through neutrophils and macrophagesinfiltration and phagocytosis of debris apoptotic cells and pathogens anti-inflammatory events occur through inhibition of destructiveinflammatory process and proliferation promotion (b) In the proliferation occurs (3) angiogenesis (4) reepithelization (epithelial cellmitosis and fibroblasts transformation into myofibroblasts) and granulation tissue formation (EMC composed of collagen glycoproteinproteoglycan fibroblasts and keratinocytes under modulation of MMP-9) (c) Remodeling is marked by the (5) EMC reorganization cellsapoptosis and angiogenesis regression and (6) type III collagen replaced by type I

reestablishment [3] Immediately after injury vasoconstric-tion occurs with the substances release such as serotoninthromboxane A2 and prostacyclin by cell membranes inorder to prevent blood leakage The exposed collagen signalsthe activation of coagulation cascade and in a coordinatedway the platelets adhere to damaged blood vessels initiatinghemostasis with the buffer formation composed of fibrinand thrombin This buffer will have main functions suchas to prevent the cellular elements loss to serve as physicalbarrier to microorganismsrsquo entry and to act as provisional

matrix cytokinesrsquo deposit and growth factors that will befundamental for maintenance of other healing phases [4]

The inflammatory response begins with vasodilationstimulated by soluble factors release such as nitric oxidebradykinin histamine and E and I series prostaglandinsTheincrease in vascular permeability with consequent fluid lossleads to slow blood flow allowing leukocytes mainly neu-trophils to interact with endothelium in an events sequenceinvolving margination (free leukocytes capture in the vas-cular lumen) rolling (weak interaction and activation)





































































































Table 1






[184ndash187]








[188 189]




[190]



and tannins



contraction

[191]




angiogenesis

[192ndash194]





[195]




nucleosides



[196 197]










[200]



Acknowledgments


References










































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















































































































Table 1






[184ndash187]








[188 189]




[190]



and tannins



contraction

[191]




angiogenesis

[192ndash194]





[195]




nucleosides



[196 197]










[200]



Acknowledgments


References










































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















































































































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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