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Article Dans Une Revue Scientific Reports Année : 2017

RAGE inhibition reduces acute lung injury in mice

Jean Lutz
  • Fonction : Auteur
Damien Bouvier
Vincent Sapin
Matthieu Jabaudon

Résumé

The receptor for advanced glycation end-products (RAGE) is involved in inflammatory response during acute respiratory distress syndrome (ARDS). Growing body of evidence support strategies of RAGE inhibition in experimental lung injury, but its modalities and effects remain underinvestigated. Anesthetised C57BL/6JRj mice were divided in four groups; three of them underwent orotracheal instillation of acid and were treated with anti-RAGE monoclonal antibody (mAb) or recombinant soluble RAGE (sRAGE), acting as a decoy receptor. The fourth group served as a control. Lung injury was assessed by the analysis of blood gases, alveolar permeability, histology, AFC, and cytokines. Lung expression and distribution epithelial channels ENaC, Na,K-ATPase, and aquaporin (AQP)−5 were assessed. Treatment with either anti-RAGE mAb or sRAGE improved lung injury, arterial oxygenation and decreased alveolar inflammation in acid-injured animals. Anti-RAGE therapies were associated with restored AFC and increased lung expression of AQP-5 in alveolar cell. Blocking RAGE had potential therapeutic effects in a translational mouse model of ARDS, possibly through a decrease in alveolar type 1 epithelial cell injury as shown by restored AFC and lung AQP-5 expression. Further mechanistic studies are warranted to describe intracellular pathways that may control such effects of RAGE on lung epithelial injury and repair. Acute respiratory distress syndrome (ARDS) is a syndrome of diffuse inflammatory lung injury with increased pulmonary oedema and the rapid onset of hypoxemic respiratory failure 1. ARDS is still undertreated 2 , with high mortality and few effective therapies 3-5. RAGE is a membrane receptor that is expressed in alveolar type (AT)-1 epithelial cells of the lung and a marker of epithelial injury 6. There are many RAGE ligands, including high-mobility group box 1 protein (HMGB1), advanced glycation end-products (AGEs) and S100 protein 7, 8. RAGE controls a variety of cellular processes such as cell proliferation and migration, inflammation, apoptosis and microtubule stabilization 9. Its main soluble forms, referred to as soluble RAGE (sRAGE), include the extra-cellular domain of membrane RAGE (mRAGE) which is cleaved by proteinases and endogenous secretory RAGE (esRAGE, produced after alternative splicing) 10. In clinical ARDS, sRAGE has good diagnostic value and is associated with lung injury severity, impaired alveolar fluid clearance (AFC) and prognosis 6, 11-13. Impaired AFC is a major feature of ARDS that contributes to mortality 14. The main mechanism responsible for the resolution of alveolar oedema is ion transport across the alveolar epithelium, primarily through epithe-lial sodium (ENaC), Na,K-ATPase and aquaporin (AQP)-5 channels, thus creating a local osmotic gradient to reabsorb the water fraction of the oedema fluid from the airspaces of the lungs 15-17. Recent data support an effect of RAGE activation on ENaC activity in cultured AT-1 cells 18. However, in contrast to the situation in mice, the clearance of alveolar fluid after birth in humans may not critically depend on ENaC, at least in part because of greater reliance on other epithelial channels 15. The modulation of RAGE may reduce inflammatory responses in several models 19. Intratracheal administration of HMGB1 induced lung injury in mice and the pathological effects of intratracheal lipopolysaccharide (LPS) were partially ameliorated by systemic administration of anti-HMGB1 antibodies 8 , thereby implicating pattern-recognition receptors such as RAGE or toll-like receptors in the pathogenesis of ARDS. Experimental murine pulmonary ischemia followed by reperfusion caused lung injury that was ameliorated in mice treated with sRAGE and in RAGE −/− mice 20. Using a mouse model of lung
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Dates et versions

hal-01919223 , version 1 (12-11-2018)

Identifiants

Citer

Raiko Blondonnet, Jules Audard, Corinne Belville, Gael Clairefond, Jean Lutz, et al.. RAGE inhibition reduces acute lung injury in mice. Scientific Reports, 2017, 7 (1), ⟨10.1038/s41598-017-07638-2⟩. ⟨hal-01919223⟩
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