The Integrin αvβ6/TGF-β1/Smad4 signaling pathway regulates ENaC in Alcohol induced ARDS

Background Acute respiratory distress syndrome (ARDS) is characterized by impaired alveolar-capillary permeability and pulmonary edema. Alveolar fluid clearance (AFC) is strongly associated with patient prognosis. Objective This study aimed to investigate whether chronic alcohol consumption affects sodium channel regulation in ARDS via the Integrin αvβ6/TGF-β1/Smad4 signaling pathway. Methods We established chronic alcohol exposure models in mice and MLE-12 cells, followed by lipopolysaccharide (LPS)-induced ARDS in both systems. The Integrin αvβ6/TGF-β1/Smad4 pathway was inhibited to explore its regulatory effect on ENaC and Na⁺,K⁺-ATPase during alcohol-induced ARDS. Results We found that chronic alcohol consumption exacerbated lung injury by activating this signaling pathway, which suppressed ENaC and Na⁺,K⁺-ATPase protein expression. Inhibition of the pathway alleviated pulmonary edema and inflammation and improved survival rates. Both in vivo and in vitro results demonstrated that the Integrin αvβ6/TGF-β1/Smad4 pathway regulates ENaC and Na⁺,K⁺-ATPase in alcohol-induced ARDS. Conclusions These findings may clarify the regulatory mechanisms of sodium channels in ARDS associated with chronic alcohol consumption.