The Mechanism Of Receptor For Advanced Glycation End Products Mediating Dysfunction Of Airway Epithelial Barrier In A Lipopolysaccharides-Induced Murine Acute Lung Injury Model

Background:Acute lung injury(ALI)and acute respiratory distress syndrome(ARDS),which is always associated with high morbidity and mortality,is a complex clinical syndrome,characterized by acute non-cardiogenic pulmonary edema and hypoxaemia.Airway epithelial cells(AECs)act as the first barrier protecting against invasion of environment agents and maintain integrity of lung structure and function.Dysfunction of airway epithelial barrier has been shown to be involved in ALI/ARDS pathogenesis.Yet,the exact mechanism is still obscure.Our study evaluated whether the receptor for advanced glycation end products(RAGE)mediates impaired airway epithelial barrier in LPS-induced murine ALI model.Methods:Six to eight weeks male BALB/c mice were randomly selected and divided into the following four groups:(1)control group;(2)LPS treatment group;(3)LPS+FPS-ZM1 treatment group;(4)LPS+Azeliragon treatment group.Mice were subjected to LPS(20 μg LPS in 50 μL sterile saline)through intratracheal instillation to generate an ALI model.Inhibitors of RAGE,FPS-ZM1(1.5 mg/kg;i.p.)and Azeliragon(4 mg/kg;i.p.)were respectively given to the mice through intraperitoneal injection 1 h prior LPS treatment.Mice were anesthetized with an overdose of pentobarbital and then sacrificed at 24 h after intratracheal instillation of LPS.Bronchoalveolar lavage fluid(BALF)and bronchi-lung tissues were collected for further analysis.Results:LPS exposure led to markedly increased expression of RAGE and its ligands HMGB1,HSP70,S100b.Treatment of FPS-ZM1 or Azeliragon not only effectively descended the expression of RAGE and its ligands but also attenuated LPS-induced neutrophil-predominant airway inflammation and injury,decreased levels of IL-6,IL-1β and TNF-α in BALF,alleviated increased alveolar-capillary permeability and pulmonary edema.LPS stimulation significantly impaired the integrity of airway epithelium,paralleled with dislocation of adheren junction(AJ)protein E-cadherin at cell-cell contacts and down-expression of both AJ and tight junction(TJ)proteins Claudin-2 and occludin.RAGE inhibition by administration of FPS-ZM1 or Azeliragon can partly restored the expression of E-cadherin,Claudin-2 and occludin and alleviated the dysfunction of airway epithelial cells barrier.Conclusion:RAGE signaling mediates airway epithelial cells barrier dysfunction in a LPS-induced ALI murine model.