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1 expression, and epithelial barrier dysfunction in the alcoholic rat lung
1 Pulmonary Section, Atlanta Veterans Affairs Medical Center, Decatur, GA, USA; Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University, Atlanta, GA, USA
2 Department of Pediatrics, Emory University, Atlanta, GA, USA
* To whom correspondence should be addressed. E-mail: dguidot{at}emory.edu.
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 beta1 (TGF
1), and alveolar epithelial barrier dysfunction, even though the lung appears grossly normal. However, during endotoxemia ethanol-fed rats release more activated TGF1 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 TGF1 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 (AT1) receptor blocker, normalized TGF1 expression. The glutathione precursor, procysteine, also prevented TGF1 expression, suggesting that TGF1 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 TGF1 protein release into the alveolar space during endotoxemia. Taken together, these results suggest that angiotensin II mediates oxidative stress and the consequent TGF1 expression and alveolar epithelial barrier dysfunction that characterize the alcoholic lung.
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