Acute Respiratory Distress Syndrome (ARDS) is a common and severe form of acute lung injury that is associated with mortality of approximately 50 percent. A prospective study of 351 critically ill patients recently identified a history of chronic alcohol abuse with an increased incidence and severity of ARDS, regardless of the at-risk diagnosis. This observation identifies chronic alcohol abuse as the first reported comorbid variable that significantly increases the patient's risk of developing ARDS. Glutathione (GSH) is an essential component of the pulmonary antioxidant system and decreased GSH in the epithelial lining fluid has been associated with ARDS. Studies in the investigator's laboratory demonstrated that alcoholic adults without cirrhosis have and 80 percent decrease in GSH in the epithelial lining fluid, possibly due to decreased GSH availability from plasma. In a rat model of chronic ethanol ingestion, decreased GSH in the epithelial lining fluid and alveolar type II cells was associated with increased susceptibility to sepis-mediated acute lung injury. The mechanisms by which ethanol-induced GSH depletion increases susceptibility to acute lung injury is the focus of this application. One hallmark of ARDS is altered alveolar matrix homeostasis as characterized by excessive alveolar matrix deposition and matrix turnover. Studies in the investigator's laboratory have demonstrated that in the rat model, ethanol-induced GSH depletion was associated with alveolar type II cells that produce an altered, unstable extracellular matrix that was unable to support type II cell functions. When sepsis was superimposed on ethanol ingestion, the lavage fluid had greater gelatinase activity. Prevention of many of these altered parameters with GSH precursors indicates the central role of GSH depletion in the process. This lead to the following hypothesis: chronic ethanol ingestion predisposes to acute lung injury by decreasing alveolar GSH which subsequently alters the homeostasis of the alveolar epithelial extracellular matrix. In the first three aims, the investigators will use the rat model of chronic ethanol ingestion to determine if ethanol predisposes to acute lung injury via altered matrix homeostasis (Aim1), if sepsis potentiates the ethanol-induced effects on matrix homeostasis (Aim 2) and if GSH availability mediates these effects on matrix homeostasis (Aim3).
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