Abstract
Recently we have demonstrated using a rat model of alcohol binge drinking that alcohol intoxication increases microvascular leakage in the gut. To investigate the endothelial mechanisms involved, we utilized a cultured endothelial cell (EC) model, utilizing human umbilical vein EC, human dermal microvascular EC, or human cardiac microvascular EC. We hypothesized that alcohol‐induced endothelial hyperpermeability is mediated by p38 MAP kinase signaling. Transendothelial electrical resistance (TER) of EC monolayers served as an index of barrier function. The pharmacological inhibitor SB203580 was used to test the role of p38 MAPK. In addition, localization of the intercellular junction protein VE‐cadherin was determined by immunofluorescence labeling. The results show that alcohol at concentrations greater than 20 mM significantly decrease TER and disrupt VE‐Cadherin continuity. Addition of 6 µM of SB203580, 30 min before addition of alcohol significantly inhibited the maximum decrease in TER (‐14.9% ± 1.9 vs. ‐36.8% ± 1.8, p<0.001). These data suggest that alcohol‐induced increase in endothelial permeability occurs due to activation of p38 MAP kinase and disruption of junctional VE‐Cadherin. Supported by NIH R01HL098215, R21AA020049, and the ABMRF/Foundation for Alcohol Research.
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