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(Chest. 1999;116:82S.)
© 1999 American College of Chest Physicians

Ethanol Ingestion Impairs Alveolar Epithelial Glutathione Homeostasis and Function, and Predisposes to Endotoxin-Mediated Acute Lung Injury*

David Guidot, MD; M. Moss, MD; F. Holguin, MD; M. Lois, MD and L. Brown

* From the Departments of Medicine and Pediatrics, Atlanta Veterans Affairs Medical Center and Emory University, Atlanta, GA

Correspondence to: David M. Guidot, MD, Emory University School of Medicine, Atlanta VA Medical Center, 1670 Clairmont Rd, Decatur, GA 30033

Although we now know that alcohol abuse increases the incidence and severity of ARDS, the mechanisms are unknown. Because ethanol impairs hepatic synthesis and secretion of glutathione (GSH), a critical antioxidant in the alveolar lining fluid, we hypothesized that alcohol abuse disrupts alveolar GSH homeostasis, and that the consequent epithelial dysfunction predisposes alcoholics to acute lung injury. We first developed an animal model and determined that long-term (> 2 weeks) ethanol ingestion in rats decreased (p < 0.05) GSH levels by > 75% in the lung lavage fluid and by > 90% in isolated type II cells. In parallel, lungs from ethanol-fed rats had more (p < 0.05) edematous injury after endotoxin priming and perfusion ex vivo than lungs from control-fed rats. Furthermore, GSH precursors (N-acetylcysteine [NAC] + S-adenosyl-L-methionine) added to the diet of ethanol-fed rats decreased (p < 0.05) lung injury. These findings support a direct role for GSH depletion in ethanol-mediated susceptibility to lung injury. We then examined how ethanol ingestion and GSH depletion affect alveolar epithelial cell function. Type II cells from ethanol-fed rats had abnormal surfactant synthesis and secretion and impaired differentiation into a tight epithelial monolayer in vitro, and lungs from ethanol-fed rats had impaired surfactant composition and barrier function in vivo. To examine a fundamental mechanism by which ethanol disrupts multiple alveolar epithelial functions, we determined that type II cells from ethanol-fed rats had decreased mitochondrial levels of GSH, decreased mitochondrial membrane potentials, and decreased levels of the antiapoptotic protein Bcl-2, all features associated with decreased cell viability. In parallel, type II cells isolated from ethanol-fed rats had higher (p < 0.05) rates of oxidant-induced apoptosis and necrosis in vitro. Importantly, treatment with NAC and S-adenosyl-L-methionine, but not with NAC alone, restored mitochondrial GSH to control levels in ethanol-fed rats. Finally, we extended these findings back to the clinical setting and determined that lung lavage fluid GSH levels were decreased (p < 0.05) > 75% in healthy alcoholic men. We conclude that long-term ethanol ingestion depletes alveolar epithelial mitochondrial GSH, thereby decreasing cell viability and function, and rendering the lung more vulnerable to acute edematous injury. We speculate that GSH replacement, particularly targeted to the mitochondrial pool, may decrease the severity of acute lung injury in alcoholic patients who are at risk for developing ARDS.





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