Chronic alcohol abuse impairs both alveolar epithelial and macrophage function, and renders individuals susceptible to acute lung injury, pneumonia, and other serious lung diseases. Zinc deficiency, which is known to impact both epithelial and immune cell functions, is also associated with alcohol abuse. In this study, chronic alcohol ingestion (6 wk) in rats altered expression of key zinc transporters and storage proteins in the small intestine and the lung, and decreased zinc levels in the alveolar compartment. Zinc supplementation of alveolar epithelial monolayers derived from alcohol-fed rats in vitro, or of the diets of alcohol-fed rats in vivo, restored alveolar epithelial barrier function, and these improvements were associated with salutary changes in tight junction protein expression and membrane localization. In parallel, dietary zinc supplementation increased intracellular zinc levels, GM-CSF receptor expression, and bacterial phagocytic capacity in the alveolar macrophages of alcoholfed rats. Together, these studies implicate zinc deficiency as a novel mechanism mediating alcohol-induced alveolar epithelial and macrophage dysfunction. Importantly, these findings argue that dietary supplementation can overcome alcohol-induced zinc deficiency and restore alveolar epithelial and macrophage function, and therefore could be an effective treatment for the susceptible alcoholic lung phenotype.

Normal alveolar function depends on the ability of the epithelial cells to form tight junctions. We have shown that chronic ethanol ingestion increased alveolar epithelial cell permeability, and rendered the lung susceptible to acute injury. Alcoholics are known to be zinc deficient, and zinc is implicated in diverse cellular function including membrane stability. Therefore, we hypothesized that zinc deficiency at the cellular level can lead to alveolar epithelial barrier dysfunction, and that it might be possible to rescue these cells from further damage with zinc supplementation. We treated alveolar epithelial cell lines with or without the zinc chelator TPEN (5μM) for 48 hr, then washed the cells and cultured them for 6 days with or without zinc acetate (10μM). Treatment with TPEN significantly increased the alveolar epithelial permeability, as reflected by the flux of radioactive sucrose, and zinc supplementation restored it to the control level. In parallel, in vitro zinc supplementation tightened the barrier in epithelial cells from chronic alcohol‐fed rats. In addition, zinc acetate (2 mg/liter) added to the diets of rats for 3 wks while recovering from 6 wks of alcohol ingestion rescued alveolar epithelial cells from alcohol‐induced barrier dysfunction. These data suggest that zinc deficiency may be one of the factors responsible for alcohol‐induced alveolar epithelial barrier dysfunction, and that it might be possible to improve the alveolar epithelial barrier in alcoholics with zinc supplementation.