Chronic alcohol abuse increases the risk of the acute respiratory distress syndrome (ARDS) by ˜four-fold. Experimentally, chronic ethanol ingestion alters alveolar epithelial barrier function by increasing paracellular leak. While the clinical link between alcohol abuse and ARDS has been established, the cellular mechanisms by which this occurs are not known. We hypothesized that chronic ethanol ingestion alters the membrane expression of tight junction proteins, thereby perturbing the permeability of the alveolar epithelium. To test this hypothesis, we examined whole lungs of rats for changes in expression of several key tight junction proteins, including claudin-3, claudin-4, and claudin-5 after ingesting an isocaloric liquid diet 6 ethanol for 6 weeks. By immunoblot, we determined that chronic ethanol ingestion increased claudin-4 and claudin-5 protein expression in the whole lungs of ethanol-fed rats. In contrast, claudin-3 expression was decreased in the whole lungs of ethanol-fed rats as compared to controls. Thus, rather than an overall net decrease in expression, there were relative changes in the claudin expression profile that correlated with increased epithelial permeability due to chronic alcohol ingestion. Consistent with deficient lung barrier function, alveolar epithelial cells (AECs) isolated and cultured from ethanol-fed rats also had increased paracellular leak as compared to AECs from control-fed animals. By immunofluorescence, this difference in permeability correlated with changes in tight junction protein localization, as AECs isolated from ethanol-fed rats had prominent intracellular vesicles containing claudins, occludin, and ZO-1 as compared to control AECs where these proteins were mainly localized to the plasma membrane. We conclude that chronic ethanol ingestion interferes with tight junction protein expression and speculate that altered expression of these proteins leads to increased paracellular leak and alveolar fluid extravasation. This, in turn, may increase the susceptibility of the lung to acute inflammatory stresses. If this is the case, then alterations in tight junction protein expression may contribute to the higher incidence of ARDS in alcoholic patients. We speculate that interventions that restore the proper balance of tight junction protein expression have the potential to decrease the severity of acute lung injury in high-risk alcoholic patients.
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