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.

Beyond the Alveolar Epithelium: Plasma Soluble Receptor for Advanced Glycation End Products Is Associated With Oxygenation Impairment, Mortality, and Extrapulmonary Organ Failure in Children With Acute Respiratory Distress Syndrome

“…In a murine model of indirect lung injury, treatment with anti-RAGE antibody has been shown to abrogate lung damage and improve mortality, an effect likely related to mitigation of the RAGE-triggered pro-inflammatory signaling (45). Anti-RAGE therapies are currently being evaluated in human clinical trials for the treatment of chronic neurodegenerative disease and are actively being investigated for the treatment of acute sepsis and chronic inflammatory diseases (46)(47)(48)(49). It is plausible that anti-RAGE therapy may eventually have a role in patients with indirect lung injury and multiple organ dysfunction, especially among those patients with elevated sRAGE levels.…”

Emerging pharmacological therapies for ARDS: COVID-19 and beyond

“…RAGE Inhibitors RAGE neutralization 1. RAGE inhibition (peptides, monoclonal antibodies, or soluble RAGE decoy receptors) restored lung function in acid instillation lung injury models in mice and in piglets [ 53 , 54 ] Endothelial/vascular dysfunction 1. Haptoglobin Scavengers of plasma-free hemoglobin 1.…”

“…Plasma-soluble RAGE concentrations constitute a marker of epithelial lung injury, are increased in ARDS patients, and can predict ARDS development in ‘at risk’ patients [ 52 ]. RAGE appears to drive lung injury also, as evidenced by the finding that blockade of RAGE (using peptides, monoclonal antibodies, or soluble RAGE decoy receptors) reduced acid-induced lung injury in mice [ 53 ] and piglets [ 54 ].…”

The receptor for advanced glycation end-products enhances lung epithelial wound repair: An in vitro study

“…After three washes with PBS (1X), wounded cells were either left untreated (control) or treated with RAGE agonists alone or combined with RAP (12.5 µg/mL), before being incubated at 37°C with 95% humidified air and 5% CO2. The dose of RAP was chosen based on the findings from previous studies [29,[32][33][34]. The wound area was observed immediately after the scratch (h0) and 12, 24, and 48 h after treatment using a Nikon polarized optical microscope with 40x magnification and a digital camera body.…”

“…Recent clinical and preclinical research has suggested that soluble RAGE (sRAGE) could be a biomarker of lung epithelial injury associated with severity and outcome in ARDS [19][20][21][22][23][24][25]. Moreover, RAGE inhibition or AGER gene deficiency decreased lung injury in animal models of experimental ARDS from both septic or non-septic causes [26][27][28][29]. Although the RAGE pathway has a major role in initiating and perpetuating nuclear factor-kappa B (NF-κB)mediated inflammation, it also contributes, among many other potential effects [11], to repair mechanisms such as peripheral nerve regeneration through the recruitment of axonal outgrowth pathways [14,30] or extracellular matrix synthesis and wound repair in human bronchial epithelial cells through stimulation by HMGB1 [31].…”