Inhibition of the Receptor for Advanced Glycation End-Products in Acute Respiratory Distress Syndrome: A Randomised Laboratory Trial in Piglets

Abstract

Background: The receptor for advanced glycation end products (RAGE) modulates the pathogenesis of acute respiratory distress syndrome (ARDS). RAGE inhibition was recently associated with attenuated lung injury and restored alveolar fluid clearance (AFC) in a mouse model of ARDS. However, clinical translation will first require assessment of this strategy in larger animals. Methods: Forty-eight anaesthetised Landrace piglets were randomised into a control group and three treatment groups. Animals allocated to treatment groups underwent orotracheal instillation of hydrochloric acid i) alone; ii) in combination with intravenous administration of a RAGE antagonist peptide (RAP), a S100P-derived peptide that prevents activation of RAGE by its ligands, or iii) in combination with intravenous administration of recombinant soluble (s)RAGE that acted as a decoy receptor. The primary outcome measure was net AFC at 4 h. Arterial oxygenation was assessed hourly for 4 h and alveolar-capillary permeability, alveolar inflammation, lung histology and lung mRNA expression of the epithelial sodium channel (α1-ENaC), α1-Na,K-ATPase and aquaporin (AQP)-5 were assessed at 4 h. Findings: Treatment with either RAP or sRAGE improved net AFC rates (median [interquartile range], 21.2 [18.8-21.7] and 19.5 [17.1-21.5] %/h, respectively, versus 12.6 [3.2-18.8] %/h in injured, untreated controls), improved oxygenation and decreased alveolar inflammation and histological evidence of tissue injury after acid-induced ARDS. RAGE inhibition also restored lung mRNA expression of α1-Na, K-ATPase and AQP-5. Interpretation: RAGE inhibition restored AFC and attenuated lung injury in a piglet model of acid-induced ARDS. Funding: Auvergne Regional Council, Agence Nationale de la Recherche, Direction Generale de l'Offre de Soins. Declaration of Interest: No conflict of interest, other source of financial support, corporate involvement, patent holdings, etc. is to be declared for all authors. Ethical Approval: Animals were maintained and all procedures were performed with the approval of the ethics committee of the French Ministere de l’Education Nationale, de l’Enseignement Superieur et de la Recherche in the Centre International de Chirurgie Endoscopique, School of Medicine - University of Clermont-Ferrand (approval number 01505.03). All experiments were performed in accordance with the “Animal Research: Reporting In Vivo Experiments” (ARRIVE) guidelines.