Ethanol promotes protease activated receptor 1: Chemokine (C-X-C motif) receptor 4 heteromerization and enhances thrombin-induced impairment of human lung endothelial cell barrier function

Abstract

-Ethanol enhances the propensity of PAR1 and CXCR4 to form heteromers.-Ethanol increases PAR1:CXCR4 heteromer expression in human lung microvascular endothelial cells (HULEC-5a).-Ethanol enhances the efficacy of PAR1 to activate Gα12 upon thrombin stimulation in cells co-expressing CXCR4.-Ethanol dose-dependently increases the efficacy of thrombin to impair HULEC-5a barrier function at clinically relevant concentrations.-Interference with PAR1:CXCR4 heteromerization mitigates effects of ethanol on thrombin-induced impairment of HULEC-5a barrier function.-Our findings provide a molecular mechanism that is likely to contribute to the increased risk of acute respiratory distress syndrome with alcohol abuse.