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.

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 Gα(12) 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.