RAGE: a biomarker for acute lung injury
- 1Royal Brompton Hospital, AICU, London, UK
- 2Unit of Critical Care, National Heart and Lung Institute, Imperial College London, London, UK
- 3UK and Eire Acute Lung Injury Research Group
- 4Northern Ireland Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, UK
- 5Respiratory Medicine Research Group, The Queen’s University of Belfast, Belfast, UK
- Dr Mark Griffiths, Unit of Critical Care, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK;
Acute lung injury (ALI), and its more severe counterpart the acute respiratory distress syndrome (ARDS), are syndromes of acute respiratory failure associated with pulmonary oedema caused by increased permeability of the alveolar–capillary membrane. Many clinical scenarios are recognised as being associated with a high incidence of ALI, including the archetypal direct pulmonary and blood borne insults of pneumonia and severe sepsis, respectively. The internationally accepted diagnostic criteria1 are non-specific to the point of including patients with relatively mild hypoxia and patients with lung pathology that may be different from the classical diffuse alveolar damage.2 ALI is not uncommon but it is challenging to study, partly because the patients are heterogenous in the causes and severity of their illness. Furthermore, patients die with rather than from respiratory failure in the majority of cases.3 These issues partly account for the fact that only one intervention has been shown to affect the survival of patients with ALI. The National Heart, Lung and Blood Institute (NHLBI) ARDS Network ARMA study,4 arguably the most important trial in respiratory medicine in the last 20 years, demonstrated an approximately 10% survival advantage in favour of a ventilation strategy that limited tidal volume (6 ml/kg predicted body weight) and plateau pressure (⩽30 cm H2O) compared with “standard” ventilatory parameters (12 ml/kg and ⩽50 cm H2O).
A biomarker is a clinical parameter that is measured with a view to providing information about a disease process, in this case ALI (box 1). Apart from informing the diagnostic process, biomarkers might be used to predict which patients at risk of ALI develop severe ARDS, which of these will develop pulmonary fibrosis requiring prolonged ventilatory support5 and ultimately who dies. Soluble receptor of advanced glycation end-products (RAGE), the cleaved form of the receptor, measured in plasma has been proposed as a biomarker of type I alveolar cell injury. Plasma RAGE concentrations were elevated in samples from patients with ALI compared with healthy controls and patients with hydrostatic oedema.6 In this issue of Thorax, Calfee and colleagues7 from the NHLBI ARDS Network report the results of measuring soluble RAGE levels in plasma samples from 676 patients enrolled in the ARMA study, both at entry to the study and after 3 days of standard or protective ventilation (see page 1083). At entry, higher RAGE levels were associated with higher radiographic and physiological indices of ALI severity as well as the non-pulmonary Acute Physiology and Chronic Health Evaluation (APACHE 3) score.7 These data suggest that RAGE may be a marker of disease severity but the potential predictive value of a raised plasma RAGE level needs to be tested in patients at risk of developing ALI in a prospective longitudinal study. Furthermore, in the group randomised to the “standard” mechanical ventilation but not the protective ventilation group, higher baseline RAGE was associated with increased mortality and fewer ventilator-free and organ failure-free days. Because ventilation using 6 ml/kg predicted body weight has become a standard of care,8 this observation casts a shadow over the potential usefulness of RAGE although, as the authors state, such subgroup analyses should be viewed with caution.
Box 1 Properties of an ideal biomarker for acute lung injury and the acute respiratory distress syndrome
Modified from Bucher and colleagues.27
Has biological plausibility in terms of its role in the pathogenesis of disease
Associated with a clinically important outcome such as mortality
Modified by an effective intervention to change the target outcome of interest
Measurement is safely, easily and reproducibly carried out in the critically ill
In both groups plasma RAGE levels decreased 3 days after enrolment, but had fallen by 15% more in the protective ventilation group. Does this mean that RAGE joins the list of potential biomarkers of ventilator associated lung injury?9 The answer is possibly. Why would such a biomarker be so valuable? It is accepted that a low tidal volume and low airway pressure mechanical ventilation strategy confers a survival advantage and it seems likely that there is no safe threshold for these parameters.10 In contrast, the best efforts to characterise the effects of other ventilatory parameters, for example the optimum level of positive end-expiratory pressure,11–13 on the survival of patients with ALI have yielded inconclusive and for the most part negative results. An ideal biomarker of ventilator associated lung injury could, therefore, be used as a surrogate outcome measure in clinical studies and could guide ventilation strategy in individual patients. To be clinically useful, a biomarker would need to change significantly within hours rather than days of a change in a ventilatory parameter. Secondly, the biomarker should be specifically affected by ventilator associated lung injury, rather than its downstream consequences that can be affected by other variables, such as systemic inflammation and dysfunction of other organs.14 Circulating RAGE levels respond rapidly after lung injury: in an animal model of ALI induced by intratracheal hydrochloric acid, RAGE was elevated in bronchoalveolar lavage fluid and to a lesser extent serum only 2 h after injury.6 Secondly, RAGE is highly expressed in the lung compared with other organs and particularly on alveolar type I epithelial15 and endothelial cells16 and so the release of RAGE in the lung may follow alveolar epithelial and endothelial injury. Alternatively, it may occur as part of a pulmonary inflammatory response. Whatever the initiating stimulus, the movement of soluble RAGE into the systemic circulation may be enhanced by increased permeability of the alveolar–capillary membrane. While all of these processes are thought to be mediated by ventilator associated lung injury, none is specific for this mechanism of injury.17
Soluble RAGE shows considerable promise as a biomarker in ALI but is it just an epiphenomenon or do RAGE and its ligands contribute to the pathogenesis of ALI? RAGE is a member of the immunoglobulin superfamily whose ligands include advanced glycation end-product modified proteins, β-amyloid, S100A12 (also known as calgranulin C and EN-RAGE) and high mobility group box-1 (HMGB-1 or amphoterin).18 Ligand binding to the intact receptor activates signalling pathways, including nuclear factor κB, leading to induction of inflammatory cytokines, proteases and oxidative stress.19 20 When RAGE induced effects were suppressed by a neutralising antibody, survival in a mouse model of sepsis was improved21 and inflammation in models of diabetes and chronic joint inflammation was reduced. Similarly, both HMGB-1 and S100A12 have been implicated in the overwhelming inflammatory response that characterises ALI22 but the contribution of RAGE activation to alveolar inflammation in ALI is not well understood. However, recent data suggest that in a murine model of lipopolysaccharide induced lung injury, exogenous soluble RAGE reduced the inflammatory response, perhaps acting as a decoy receptor.23 Hence increased soluble RAGE in a tissue compartment may actually reflect an anti-inflammatory response rather than a consequence of parenchymal lung injury, which suggests that an elevated soluble RAGE level would predict a favourable outcome from ALI.
Finally, RAGE expression is depressed in the lungs of patients with established idiopathic pulmonary fibrosis and those of mice treated with bleomycin, which induces a fibrosing alveolitis.24 25 An antifibrotic role for RAGE has been inferred from experimental models of fibrosing alveolitis in knockout mice lacking membrane RAGE.25 26
The ARDS Network investigators have again used their unrivalled source of study material to produce more thought provoking insights into a means of improving the management of patients with ALI. Measurement of soluble RAGE in plasma joins an increasing list of candidate biomarkers of important processes that constitute ALI. It remains to be seen whether a single marker or a panel of markers will emerge to become robust outcomes for studies or useful tools in the management of individual patients.