Systemic inflammation, whether caused by infection or injury, is frequently complicated by the development of ALI, and its extreme manifestation, ARDS. The clinical and pathological characteristics, defining criteria, and reported mortality rates are discussed in Section 1.2.2.1.
3.4.1. RAGE-mediated inflammation is implicated in the pathogenesis of ALI
RAGE is implicated in ALI both as a marker of alveolar injury and as an important contributor to alveolar inflammation. Thus, in rodents with experimental lung injury induced either by
98 intra-tracheal LPS or acid, increased levels of sRAGE in serum and broncho-alveolar lavage (BAL) and serum correlate with the severity of insult [482]. In experimental models, BAL RAGE levels could distinguish between direct (precipitating factor involves the lung) and indirect (precipitating factor does not involve the lung) types of ALI, with raised RAGE levels only detectable in the direct lung injury group [483]. However, this finding was not replicated in patients with ALI [454].
Intra-tracheal administration of HMGB1 induced ALI in mice, thereby implicating RAGE more directly in the genesis of ALI. Moreover, the pathological effects of intra-tracheal LPS were partially ameliorated by systemic administration of sRAGE or anti-HMGB1 antibodies [374, 484]. Experimental endotoxaemia in rats induced ALI and increased tissue and circulating levels of HMGB1, effects that were aggravated by concurrently induced hyperglycaemia; and abrogated when combined with insulin therapy[485]. Experimental murine pulmonary ischaemia followed by reperfusion also caused ALI that was ameliorated by pre-treatment with sRAGE, and reduced when performed in RAGE deleted mice [486]. In rabbits, injuriously high tidal volume ventilation caused ALI and increased HMGB1 content in BAL when compared with lower tidal volumes, an effect attenuated by antibodies to HMGB1 [487]. Together, these data suggest strongly that RAGE plays a fundamental role in modulating pulmonary inflammation.
3.4.2. sRAGE as a biomarker for ALI
Patients with ALI have increased levels of sRAGE in pulmonary oedema fluid compared to those with cardiogenic pulmonary oedema. Moreover, sRAGE levels in oedema fluid were 100 times higher than plasma levels, supporting the hypothesis that sRAGE is generated in the lung [482]. Plasma sRAGE levels from patients enrolled in the influential ARMA trial (comparing high versus low tidal volume ventilation for ALI) correlated with the severity of illness and of ALI. Once corrected for other dependent variables (including age and severity of illness scores), baseline levels of sRAGE in patients randomised to receive high tidal volume ventilation correlated with mortality [459]. In a more recent study, extent of elevation of sRAGE levels in plasma from patients with ALI, with or without concurrent severe sepsis, correlated with markers of lung injury severity (quantified by PFR and Murray lung injury score) and radiographic appearance [454]. Another recent study demonstrated serum levels of HMGB1 and sRAGE were significantly higher in non-survivors of ARDS
99 compared with survivors; with plasma sRAGE levels being independently predictive of mortality [453]. Further observational trials are currently recruiting patients with ALI in order to measure RAGE ligands and soluble forms and gain further insight into their relationship with clinical parameters (clinicaltrials.gov, NCT01270295).
Primary graft dysfunction (an ALI-like syndrome) is a common and serious complication of lung transplantation. Plasma sRAGE measured shortly after reperfusion correlated with adverse short-term outcomes [488]. These results may be partially explained by the observation that in isolated perfused human lungs, elevated levels of sRAGE in the airspace were associated with impaired alveolar fluid clearance, a measure of epithelial integrity [489]. Patients with ARDS have increased levels of S100A12 and A8/9 in their BAL and increased S100A12 expression in lung biopsies [343, 490]. Furthermore, inhalation of LPS by healthy volunteers increased S100A12 content in BAL [343] and clinical ALI is associated with elevated levels of serum S100A12 [456].
The utility of measuring aspects of the RAGE axis to monitor the contribution of ventilation to lung injury has been assessed in several studies. Firstly, patients receiving mechanical ventilation for major elective surgery were either randomized to receive lung protective (low tidal volume, positive end expiratory pressure, PEEP) or conventional (high tidal volume, no PEEP) ventilation. sRAGE was found to be elevated post-operatively irrespective of ventilatory strategy [464]. Secondly, in critically ill patients without ALI, BAL levels of HMGB1 were greater in those who had undergone long-term (7.6 days mean) mechanical ventilation (MV) in comparison to short-term (5 hours mean) MV [491]. Finally, in patients undergoing lung resection surgery requiring one-lung ventilation (a major risk for post- operative ALI) levels of sRAGE did not relate to ventilatory parameters or clinical outcomes[470].
Despite extensive study of potential biomarkers of ALI none have entered routine clinical use [492, 493]; predominantly because they have not demonstrated any clear advantage over clinical predictors. An ideal biomarker for ALI would be highly specific and sensitive, vary in proportion to the severity of injury and reflect the effect of therapy. It would add independent prognostic information, have biological plausibility and potentially identify patient subgroups that would benefit from specific therapy. Finally, the assay should be
100 inexpensive, rapid and highly reproducible. Systemic inflammation typically either precipitates or complicates ALI, and the utility of plasma sRAGE as a specific biomarker of alveolar damage is therefore likely to be limited.
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4. INFLUENCES ON THE RAGE-AXIS AND OUTCOME FROM ACUTE SYSTEMIC
INFLAMMATION
A range of conditions and acquired characteristics affect the RAGE-axis and the acute inflammatory response. The same conditions may be associated with adverse outcome from acute systemic inflammation. Of particular relevance are conditions associated with increased RAGE ligands: old age, diabetes, chronic kidney disease and rheumatoid arthritis, the commonest chronic inflammatory arthritis.