Angiotensin II mediates glutathione depletion, transforming growth factor-beta1 expression, and epithelial barrier dysfunction in the alcoholic rat lung.
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-beta1), and alveolar epithelial barrier dysfunction, even though the lung appears grossly normal. However, during endotoxemia, ethanol-fed rats release more activated TGF-beta1 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-beta1 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-beta1 expression. The glutathione precursor procysteine also prevented TGF-beta1 expression, suggesting that TGF-beta1 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-beta1 protein release into the alveolar space during endotoxemia. Together, these results suggest that angiotensin II mediates oxidative stress and the consequent TGF-beta1 expression and alveolar epithelial barrier dysfunction that characterize the alcoholic lung.
Bechara
Rabih I
RI
Atlanta Veterans Affairs Medical Center Pulmonary Section, Decatur, GA 30033, USA.
Pelaez
Andres
A
Palacio
Andres
A
Joshi
Pratibha C
PC
Hart
C Michael
CM
Brown
Lou Ann S
LA
Raynor
Robert
R
Guidot
David M
DM
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D015824:Blood-Air Barrier / Q000187:drug effects; D019446:Endotoxemia / Q000503:physiopathology; D000431:Ethanol; D005978:Glutathione / Q000172:deficiency* / Q000494:pharmacology; D017706:Lisinopril / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D011506:Proteins / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
D000806:Angiotensin-Converting Enzyme Inhibitors; D011506:Proteins; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D000431:Ethanol; D017706:Lisinopril; D005978:Glutathione