Alcohol Inhibits Alveolar Fluid Clearance Through the Epithelial Sodium Channel Via the A2 Adenosine Receptor in Acute Lung Injury.
Molecular Medicine Reports(2021)
摘要
Chronic alcohol abuse increases the risk of mortality and poor outcomes in patients with acute respiratory distress syndrome. However, the underlying mechanisms remain to be elucidated. The present study aimed to investigate the effects of chronic alcohol consumption on lung injury and clarify the signaling pathways involved in the inhibition of alveolar fluid clearance (AFC). In order to produce rodent models with chronic alcohol consumption, wild-type C57BL/6 mice were treated with alcohol. A2a adenosine receptor (AR) small interfering (si)RNA or A2bAR siRNA were transfected into the lung tissue of mice and primary rat alveolar type II (ATII) cells. The rate of AFC in lung tissue was measured during exposure to lipopolysaccharide (LPS). Epithelial sodium channel (ENaC) expression was determined to investigate the mechanisms underlying alcohol-induced regulation of AFC. In the present study, exposure to alcohol reduced AFC, exacerbated pulmonary edema and worsened LPS-induced lung injury. Alcohol caused a decrease in cyclic adenosine monophosphate (cAMP) levels and inhibited alpha-ENaC, beta-ENaC and gamma-ENaC expression levels in the lung tissue of mice and ATII cells. Furthermore, alcohol decreased alpha-ENaC, beta-ENaC and gamma-ENaC expression levels via the A2aAR or A2bAR-cAMP signaling pathways in vitro. In conclusion, the results of the present study demonstrated that chronic alcohol consumption worsened lung injury by aggravating pulmonary edema and impairing AFC. An alcohol-induced decrease of alpha-ENaC, beta-ENaC and gamma-ENaC expression levels by the A2AR-mediated cAMP pathway may be responsible for the exacerbated effects of chronic alcohol consumption in lung injury.
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关键词
epithelial sodium channel,alcohol,adenosine receptor,alveolar fluid clearance,acute respiratory distress syndrome
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