Chronic ethanol ingestion and the risk of acute lung injury: a role for glutathione availability?
Although pulmonary function is not altered, a history of alcohol abuse is an independent outcome variable in the development of acute respiratory distress syndrome. In the absence of cirrhosis, alcohol abuse decreased glutathione, the key antioxidant lining the alveolar space, by 80% and is associated with alveolar barrier leak. Neither the glutathione pool nor barrier leak was corrected by abstinence for 1 week. This aberrant glutathione homeostasis may contribute to enhanced alveolar permeability, thereby increasing susceptibility to the development of acute respiratory distress syndrome. In a rat model, chronic ingestion of ethanol decreased pulmonary glutathione concentration, increased alveolar barrier permeability, and increased the risk of acute lung injury. In alveolar type II cells, chronic ingestion of ethanol altered cellular functions such as decreased surfactant processing, decreased barrier integrity, and increased sensitivity to cytotoxin-induced apoptosis in vitro and in vivo. In alveolar macrophages, chronic ingestion of ethanol decreased phagocytosis of microorganisms and decreased cell viability, events that would increase the risk of pneumonia. A central role for glutathione availability was demonstrated by the normalization of cellular function and viability of type II cells and macrophages as well as decreased sensitivity to endotoxemia-induced acute lung injury when glutathione precursors were added to the ethanol diet. These results support the suggestion that chronic ingestion of ethanol increased the risk of acute lung injury not through ethanol per se but through the chronic oxidative stress that resulted from ethanol-induced glutathione depletion. Because chronic oxidative stress alters cellular functions and viability, the lung becomes more susceptible when a second hit such as sepsis occurs.
Brown
Lou Ann S
LA
Department of Pediatrics, Emory University, 2015 Uppergate Drive, NE, Atlanta, GA 30322, USA. lbrow03@emory.edu
Harris
Frank L
FL
Ping
Xiao-Du
XD
Gauthier
Theresa W
TW
D000437:Alcoholism / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology; D005978:Glutathione / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D012128:Respiratory Distress Syndrome / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D012307:Risk Factors
D005978:Glutathione