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

Jules Audard,Bertille Paquette,Thomas Godet,Raiko Blondonnet,Marilyne Lavergne,Christelle Gross,Jean-Michel Constantin,Jean-Baptiste Joffredo,Loic Blanchon,Justine Pasteur,Vincent Sapin,Matthieu Jabaudon,Damien Bouvier,Bruno Pereira,Corinne Belville

doi:10.1038/s41598-019-45798-5

Abstract

The receptor for advanced glycation end-products (RAGE) modulates the pathogenesis of acute respiratory distress syndrome (ARDS). RAGE inhibition attenuated lung injury and restored alveolar fluid clearance (AFC) in a mouse model of ARDS. However, clinical translation will require assessment of this strategy in larger animals. 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), or (iii) recombinant soluble (s)RAGE. The primary outcome was net AFC at 4 h. Arterial oxygenation was assessed hourly and alveolar-capillary permeability, alveolar inflammation and lung histology were assessed at 4 h. Treatment with either RAP or sRAGE improved net AFC (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), oxygenation and decreased alveolar inflammation and histological evidence of tissue injury after ARDS. These findings suggest that RAGE inhibition restored AFC and attenuated lung injury in a piglet model of acid-induced ARDS.

Highlights

Acute respiratory distress syndrome (ARDS) is a frequent cause of respiratory failure and death in critically ill patients[1]
In both groups of ARDS animals treated with RAGE antagonist peptide (RAP) or soluble RAGE (sRAGE), arterial oxygenation was preserved at all time points when compared with otherwise untreated, injured animals (419 [385–452] and 431 [412–466] mmHg at four hours, respectively)
The main goal of this study was to determine the impact of a receptor for advanced glycation end-products (RAGE) inhibition strategy, based either on sRAGE or RAP administration, in a piglet model of hydrochloric acid (HCl)-induced ARDS12,22

Summary

Introduction

Acute respiratory distress syndrome (ARDS) is a frequent cause of respiratory failure and death in critically ill patients[1]. The anti-RAGE therapies restored AFC and increased lung expression of AQP-5 in alveolar cells, thereby providing a possible link between RAGE modulation and the mechanisms of lung epithelial injury and repair relevant to clinical ARDS7. This type of strategy for RAGE inhibition has never been tested in a large animal model, either to determine the precise functional and biological effects of RAGE modulation in ARDS or in preparation for translation of this strategy to the clinical setting as an ARDS treatment. RAP is a small S100P-derived peptide with similar blocking effects to those of anti-RAGE monoclonal antibody, as it prevents RAGE from binding with several of its most important ligands, including HMGB1 and S100 proteins, in cancer cells in vitro and in vivo[21]

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