TY - JOUR
T1 - Angiotensin II mediates glutathione depletion, transforming growth factor-β1 expression, and epithelial barrier dysfunction in the alcoholic rat lung
AU - Bechara, Rabih I.
AU - Pelaez, Andres
AU - Palacio, Andres
AU - Joshi, Pratibha C.
AU - Hart, C. Michael
AU - Brown, Lou Ann S.
AU - Raynor, Robert
AU - Guidot, David M.
PY - 2005/9
Y1 - 2005/9
N2 - 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-β1 (TGF-β1), and alveolar epithelial barrier dysfunction, even though the lung appears grossly normal. However, during endotoxemia, ethanol-fed rats release more activated TGF-β1 into the alveolar space where it can exacerbate epithelial barrier dysfunction and lung edema. Ethanol ingestion activates the reninangiotensin system, and angiotensin II is capable of inducing oxidative stress and TGF-β1 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-β1 expression. The glutathione precursor procysteine also prevented TGF-β1 expression, suggesting that TGF-β1 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-β1 protein release into the alveolar space during endotoxemia. Together, these results suggest that angiotensin II mediates oxidative stress and the consequent TGF-β1 expression and alveolar epithelial barrier dysfunction that characterize the alcoholic lung.
AB - 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-β1 (TGF-β1), and alveolar epithelial barrier dysfunction, even though the lung appears grossly normal. However, during endotoxemia, ethanol-fed rats release more activated TGF-β1 into the alveolar space where it can exacerbate epithelial barrier dysfunction and lung edema. Ethanol ingestion activates the reninangiotensin system, and angiotensin II is capable of inducing oxidative stress and TGF-β1 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-β1 expression. The glutathione precursor procysteine also prevented TGF-β1 expression, suggesting that TGF-β1 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-β1 protein release into the alveolar space during endotoxemia. Together, these results suggest that angiotensin II mediates oxidative stress and the consequent TGF-β1 expression and alveolar epithelial barrier dysfunction that characterize the alcoholic lung.
KW - Acute respiratory distress syndrome
KW - Alcohol abuse
KW - Angiotensin-converting enzyme
KW - Epithelium
UR - http://www.scopus.com/inward/record.url?scp=23944514761&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=23944514761&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00141.2005
DO - 10.1152/ajplung.00141.2005
M3 - Article
C2 - 15908476
AN - SCOPUS:23944514761
SN - 1040-0605
VL - 289
SP - L363-L370
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
IS - 3 33-3
ER -