RAGE: It’s relevance in ARDS

Professor Timothy EvansImperial College & Royal Brompton &

Harefield NHS Foundation Trust

Potential conflicts of interest

– None to declare

– Ben Creagh Brown, Anne Burke Gaffney, Doverdale Trust

Acknowledgements

RAGE: What is it? • The receptor for advanced glycation end products;

trans membrane receptor of immunoglobulin superfamily; constitutively expressed in all cells

• Diverse ligands upregulate [HMGB1, S100]

• Two hit hypothesis of inflammation:• Chronic inflammation (eg diabetes) up

regulates RAGE & RAGE ligands• Superimposed acute inflammation

further elevates leading to excessive and prolonged inflammation

RAGE: What does it do?

Intensive Care Medicine 2010; 36: 1644-1656

RAGE axis in critical illness: The two hit hypothesis [Biochim Biophys Acta 2000; 1498: 99-111] Intensive Care Medicine 2010; 36: 1644-1656

RAGE subtypes: Genesis, structure, signal transduction capacity: Intensive Care Medicine 2010; 36: 1644-1656

RAGE: Where is it?

• Probably ubiquitous in all cells• Certainly in vascular tissue (eg

endothelium), neural tissue, neutrophils • Most abundantly isolated in lung so far;

primarily located on basal surface of alveolar type 1 cells

• Levels in BAL higher in permeabilty than hydrostatic pulmonary oedema

• In specific populations associated with longer mechanical ventilation and ICU LOS

• Animal studies: RAGE & RAGE ligands• Clinical studies:

• The ARDSNet study• RAGE ligands in uncomplicated

pneumonia & when complicated by sepsis• sRAGE in ALI; & in ALI with sepsis• sRAGE and RAGE ligands in a population

at risk of developing ALI• Conclusions

RAGE: What do we know in experimental & clinical settings?

Murine studies, RAGE inhibition. Intensive Care Medicine 2010; 36: 1644-1656

Critical Care Medicine 2010: 38: 1414-1422

RAGE & sepsis syndromes: Human studies. Intensive Care Med 2010; 36: 1644

Thorax 2008; 63: 1083-1089

Thorax 2008; 63: 1083-1089RAGE and survival

RAGE: baseline and day 3

Thorax 2008; 63: 1083-1089

• Baseline levels of plasma RAGE associated independently with clinical outcome in patients randomised to 12 ml/kg TV

• In this group, higher baseline RAGE associated with increased mortality, fewer VF and organ failure free days

• 6 ml/kg increased the fall in RAGE seen between day 0 and 3

Thorax 2008; 63: 1083-1089

Critical Care Medicine 2007; 37: 1061-1067

A marker of the (activated) host response to infection; not a ’late’ mediator

Critical Care Medicine 2011; 39: 480-8

• 64 patients with ALI/ARDS; ALI/ARDS plus sepsis/septic shock; sepsis/SS alone; ventilated controls

• sRAGE at baseline and day 3,6,28/ICU discharge

• Correlations sought between sRAGE and clinical and radiographic markers of severity

Critical Care Medicine 2011; 39: 480-8

sRAGE and (A) PaO2:FiO2 and (B) LIS

Critical Care Medicine 2011; 39: 480-8

Critical Care Medicine 2011; 39: 480-8

Critical Care Medicine 2011; 39: 480-8

• sRAGE correlated with clinical and radiographic severity of ALI

• Focal loss of aeration on CT associated with significantly lower sRAGE levels

• BAL levels in pARDS and non pARDS not different • Plasma levels decreased over time (?repair)• sRAGE elevated in ALI/ARDS regardless of presence

of sepsis/septic shock

• Surgery necessitating CPB leads to inflammation & is a risk factor for ALI

• Levels and expression of sRAGE and ligands (S100B, S100A8/9, S100A12, HMGB1) measured; associations sought with relevant markers (IL-8, CRP) & clinical outcomes

• Patients undergoing CPB (n=177)

Preoperative RAGE: An independent predictor of outcome in patients at risk of ALI?

Creagh Brown B et al [submitted]

Creagh-Brown B et al; Submitted to Intensive Care Medicine 2011

Patient demographics and operative variables

Creagh-Brown B et al; Submitted 2011

Post operative variables; † p<0.001; ‡ p<0.005

Plasma RAGE ligand levels pre and 2hr post CPB; * p<0.05; *** p<0.001

Plasma sRAGE levels:

(A)Pre and 2hr post CPB [n=162]

(B)Pre intra and post CPB [n=13]

(C)esRAGE and shed RAGE levels pre and 2 hr post [n=19]

[*** p<0.001; * p<0.01]

• Neutrophil membrane RAGE expression significantly reduced post op

• Intra cellular RAGE unaltered

[* p<0.01]

Creagh-Brown B et al; Submitted to Intensive Care Medicine 2011

Assn of clinical and assay variables, > median ICU LOS (34.5 hrs)

Creagh-Brown |B et al, Submitted 2011

Preoperative RAGE: An independent predictor of outcome in patients at risk of ALI?

Conclusions

• Surgery necessitating CPB leads to substantial increases in 4 RAGE ligands

• Strong relationship between duration of CPB and S100 release

• Elevated sRAGE maximal in surgery; pre op levels predictive of ICU LOS

• Leukocytes probable contributors• sRAGE: biomarker/mediator of SIRS?

Critical Care Medicine 2011; 39: 589-590

• Is biologically plausible as a mediator or a marker • Relates to clinical outcomes in:

– Acute lung injury (regardless of presence of sepsis)– In SIRS

• Has some relationship to structural changes in patients with acute lung injury:– Radiographic (CT) but not BAL

• BUT as yet sparse evidence it is: – Predictive of ALI in at risk populations – Modified by therapeutic intervention – Easily and reliably measured

Creagh-Brown B et al; Submitted 2011

Assn of clinical and assay variables, > 75% percentile ICU LOS [MBLR]