Effect of chronic ethanol ingestion on alveolar type II cell: Glutathione and inflammatory mediator-induced apoptosis

Background: In septic patients, chronic alcohol abuse increases the inciden ce of the acute respiratory distress syndrome, a syndrome that requires alv eolar type II cellproliferation and differentiation for repair of the damag ed alveolar epithelium. We previously showed in a rat model that chronic et hanol ingestion decreased the antioxidant glutathione (GSH) in type II cell s and exacerbated endotoxin-mediated acute lung injury. We hypothesized tha t this GSH depletion by ethanol, particularly mitochondrial GSH, predispose d type II cells to inflammatory mediator-induced apoptosis. Methods: Adult male rats were fed the Lieber-DeCarli diet for 2, 6, or 16 w eeks. Alveolar type II cells were then isolated and treated with hydrogen p eroxide or TNF-alpha. The effect on glutathione (cytosolic and mitochondria l), apoptotic events, and necrosis were determined. in other studies, rats were fed ethanol for 6 weeks and were treated with endotoxin and apoptosis of type II cells determined by the TUNEL method. Results: Chronic ethanol ingestion alone resulted in a progressive decrease in mitochondrial GSH and a progressive increase in the basal apoptosis and necrosis rate (p less than or equal to 0.05). Furthermore; there was a pro gressive increase in the sensitivity of the cells to H2O2 or TNF-alpha indu ced cytochrome c release, caspase 3 activation, apoptosis, and necrosis (p less than or equal to 0.05). Finally, there was a 2-fold increase in apopto tic type II cells in vivo when chronic ethanol ingestion was superimposed o n endotoxemia. Conclusions: These results suggested that chronic ethanol ingestion resulte d in a progressive depletion of mitochondrial GSH and sensitization of type II cells to inflammatory mediator-induced apoptosis and necrosis. These ef fects may be particularly relevant during acute stress when proliferation a nd differentiation of these cells are critical to repair of the damaged alv eolar epithelium and may have important ramifications for the treatment of acute respiratory distress syndrome in patients with a history of alcohol. abuse.