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TRANSLATIONAL PHYSIOLOGY

Angiotensin II mediates glutathione depletion, transforming growth factor-1 expression, and epithelial barrier dysfunction in the alcoholic rat lung

¹Atlanta Veterans Affairs Medical Center Pulmonary Section, Decatur; ²Division of Pulmonary, Allergy, and Critical Care Medicine, and ³Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia

Submitted 29 April 2005 ; accepted in final form 17 May 2005

Alcohol abuse markedly increases the risk of sepsis-mediated acute lung injury. In a rat model, ethanol ingestion alone (in the absence of any other stress) causes pulmonary glutathione depletion, increased expression of transforming growth factor-1 (TGF-1), and alveolar epithelial barrier dysfunction, even though the lung appears grossly normal. However, during endotoxemia, ethanol-fed rats release more activated TGF-1 into the alveolar space where it can exacerbate epithelial barrier dysfunction and lung edema. Ethanol ingestion activates the renin-angiotensin system, and angiotensin II is capable of inducing oxidative stress and TGF-1 expression. We determined that lisinopril, an angiotensin-converting enzyme inhibitor that decreases angiotensin II formation, limited lung glutathione depletion, and treatment with either lisinopril or losartan, a selective angiotensin II type 1 receptor blocker, normalized TGF-1 expression. The glutathione precursor procysteine also prevented TGF-1 expression, suggesting that TGF-1 may be induced indirectly by angiotensin II-mediated oxidative stress and glutathione depletion. Importantly, lisinopril treatment normalized barrier function in alveolar epithelial cell monolayers from ethanol-fed rats, and treatment with either lisinopril or losartan normalized alveolar epithelial barrier function in ethanol-fed rats in vivo, as reflected by lung liquid clearance of an intratracheal saline challenge, even during endotoxemia. In parallel, lisinopril treatment limited TGF-1 protein release into the alveolar space during endotoxemia. Together, these results suggest that angiotensin II mediates oxidative stress and the consequent TGF-1 expression and alveolar epithelial barrier dysfunction that characterize the alcoholic lung.

acute respiratory distress syndrome; epithelium; angiotensin-converting enzyme; alcohol abuse

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