Glutathione replacement preserves the functional surfactant phospholipid pool size and decreases sepsis-mediated lung dysfunction in ethanol-fed rats

Background: Alcohol abuse increases the incidence of acute respiratory distress syndrome (ARDS). Previous evidence from our laboratory links ethanol-mediated glutathione depletion to impaired surfactant production by alveolar epithelial cells in vitro and to endotoxin-mediated edematous injury in isolated lungs ex vivo. ARDS patients have an imbalance between the inactive small aggregate (SA) and the bioactive large aggregate (LA) forms of surfactant phospholipid (as reflected by increased SA/LA ratios). Therefore, we hypothesized that ethanol ingestion, via glutathione depletion, could alter surfactant phospholipid distribution between LA and SA forms and thereby exacerbate sepsis-mediated lung dysfunction in vivo. Methods: Rats fed an isocaloric diet with or without ethanol (36% total calories) for 6 weeks were made septic via cecal ligation and perforation. Some ethanol-fed rats had their diets supplemented with the glutathione precursor procysteine (L-2-oxothiaxolidine-4-carboxylate). Sepsis physiology was assessed by determining respiratory rates, arterial blood pressures, and plasma lactate levels, and lung dysfunction was assessed by determining lung lavage fluid protein levels (index of alveolar endothelial/epithelial barrier disruption), arterial hypoxemia (index of impaired gas exchange) and surfactant phospholipid SA and LA fractions (index of the alveolar epithelium's ability to maintain a functional surfactant pool during sepsis). Results: Ethanol ingestion decreased (p < 0.05) lung lavage fluid glutathione levels, and this defect was prevented by procysteine. Although ethanol ingestion had no effect (p < 0.05) on any of the indices of sepsis, it increased (p < 0.05) lung lavage fluid protein levels, worsened hypoxemia, and decreased the functional (LA) surfactant phospholipid pool after sepsis, all of which was prevented by procysteine. Conclusions: Ethanol ingestion, via glutathione depletion, increased sepsis-mediated lung dysfunction, and these effects could contribute to the increased risk of ARDS seen in alcoholic patients.