Translational Approach to Understanding RAGE pathway in Acute respiratory distress syndrome : physiopathologic, diagnostic and therapeutic implications – TAURA

Our goal is to characterize functional and biological determinants associated with the receptor for advanced glycation end-products (RAGE) pathway during acute lung injury, through a translational approach including animal (mouse and pig models) and clinical studies. We will combine our competences in biochemistry, cellular biology, in vivo studies with the support of clinical data in order to develop and validate a novel biomarker of lung epithelial injury during acute respiratory distress syndrome (ARDS) and to explore therapeutic implications of a multimodal approach to RAGE modulation in both the preclinical and clinical settings.

Our results aim at establishing the proof-of-concept of the efficacy of a multimodal approach to RAGE inhibition on lung injury in experimental (mouse and pig) models and at characterizing functional respiratory consequences and biological determinants of RAGE inhibition at the tissular, cellular and molecular levels. Continuation of our clinical research effort on RAGE axis during ARDS should permit the rigorous validation of a novel biomarker of lung injury and the design of a large prospective multicenter randomized controlled trial of RAGE modulation in patients with ARDS.

Our project will contribute to an improved understanding of the pathogenesis of ARDS and a potential future treatment to moderate the severity of the condition. Basic research-issued hypotheses will subsequently be tested in the clinical setting. The development of a novel biomarker bedside measurement test (with a perspective of an industrial patent) along with new therapeutic strategies (including the project of a patent for an inhibitory peptide) will improve patients care and outcome.

Every task of our project will be valorized through publications in high-ranked international journals and scientific communications at national and international meetings. An industrial valorization is also expected through projects of patents (novel bedside biomarker test and inhibitory peptide).

Acute respiratory distress syndrome (ARDS) remains a major cause of acute respiratory failure and death in critically ill patients. Despite therapeutic advances in ventilation strategy and fluid management, mortality and morbidity remain high, and no effective pharmacologic therapies for the syndrome have yet been identified. ARDS is characterized by diffuse alveolar epithelial and lung endothelial injury leading to increased permeability pulmonary edema, alveolar filling, and respiratory failure. Type I epithelial cells play a key role in epithelial integrity and alveolar fluid clearance. The magnitude of damage to the alveolar type I cell could be a major determinant of the severity of ARDS and of its clinical outcomes.
The receptor for advanced glycation end-products (RAGE) was recently identified as a promising new marker of alveolar type I cell injury. RAGE is a transmembrane pattern-recognition receptor of the immunoglobulin superfamily that is abundantly expressed in the lung and primarily located on the basal surface of alveolar type I cells. Activation of RAGE modulates cell signaling, culminating in a sustained inflammatory response. RAGE binds diverse damage-associated molecular patterns including some S100 proteins and HMGB1. RAGE is implicated in ARDS as an important pathway to alveolar inflammation and, when the soluble form is assayed in plasma or pulmonary edema fluid, as a marker of alveolar injury. Recent data suggest that targeting RAGE may attenuate lung injury, and gaining further knowledge about the ligands and basic mechanisms of this receptor may offer new therapeutic options. RAGE inhibition strategies include preventing the activation of transmembrane RAGE with monoclonal antibody or soluble RAGE (sRAGE), acting as a decoy receptor preventing ligands from interacting with the RAGE.
Our group and others have found sRAGE expression to be enhanced during ARDS. sRAGE elevation in plasma and alveolar fluid correlates with the extent of alveolar damage, suggesting that sRAGE may serve as a biomarker of alveolar type I cell injury and lung damage during ARDS. We now aim to focus on RAGE implications in acute lung injury and its resolution. Therefore our goals are to propose novel diagnostic and therapeutic strategies through a translational approach comprising 5 major objectives:
1/ Establishment of a proof-of-concept of the efficacy of a multimodal approach to RAGE inhibition on lung injury in a translational mouse model.
2/ Characterization of functional respiratory consequences and biological determinants of RAGE inhibition at the tissular, cellular and molecular levels in a murine model (regulation of the expression of soluble forms, signaling pathways).
3/ Translation of our results to an experimental porcine model of ARDS, in order to assess various candidates to RAGE inhibition, their modalities of administration, and to test clinical, functional and biological outcomes, with special emphasis on ventilatory aspects.
4/ Continuation of our clinical research effort on RAGE axis during ARDS, as promoted by our university hospital (CHU Clermont-Ferrand): descriptive analysis of RAGE soluble isoforms and ligands; predictive value of plasma levels of sRAGE on the rate of alveolar fluid clearance; impact of various interventions on sRAGE expression in the plasma and the alveolar space (ventilatory strategies, recruitment maneuvers, fluid resuscitation, weaning from mechanical ventilation); diagnostic, predictive and pronostic values of plasma sRAGE during ARDS, including a large prospective observational multicenter study in patients under mechanical ventilation in the intensive care unit setting. These data will reinforce the role for sRAGE as a biomarker of ARDS and will help in designing futur interventional studies.
5/ In fine, translation of our research to clinical care, with a prospective multicenter randomized controlled trial of RAGE modulation in patients with ARDS.