Angiotensin II mediates glutathione depletion, transforming growth factor-β1 expression, and epithelial barrier dysfunction in the alcoholic rat lung
Angiotensin II mediates glutathione depletion, transforming growth factor-β1 expression, and epithelial barrier dysfunction in the alcoholic rat lung
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DOI：
10.1152/ajplung.00141.2005
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发表时间：
2005-09-01
影响因子：
4.9
通讯作者：
Guidot, DM
中科院分区：
文献类型：
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作者：
Bechara, RI;Pelaez, A;Guidot, DM
酒精滥用显著增加脓毒症介导的急性肺损伤的风险。在大鼠模型中，单独摄入乙醇（在没有任何其他应激的情况下）会导致肺谷胱甘肽耗竭、转化生长因子-β 1（TGF-β 1）表达增加和肺泡上皮屏障功能障碍，即使肺表现正常。然而，在内毒素血症期间，乙醇喂养的大鼠释放更多活化的TGF-β 1进入肺泡腔，在那里它可以加重上皮屏障功能障碍和肺水肿。乙醇的摄入激活了肾素-血管紧张素系统，血管紧张素II能够诱导氧化应激和TGF-β 1的表达。我们确定，赖诺普利，一种血管紧张素转换酶抑制剂，减少血管紧张素II的形成，限制肺谷胱甘肽消耗，并与赖诺普利或氯沙坦，选择性血管紧张素II 1型受体阻滞剂，正常化TGF-β 1的表达。谷胱甘肽前体原半胱氨酸还阻止了TGF-β 1的表达，这表明TGF-β 1可能是由血管紧张素II介导的氧化应激和谷胱甘肽消耗间接诱导的。重要的是，赖诺普利治疗使乙醇喂养大鼠肺泡上皮细胞单层的屏障功能正常化，并且用赖诺普利或氯沙坦治疗使乙醇喂养大鼠体内肺泡上皮屏障功能正常化，如肺内盐水激发的肺液体清除率所反映的，即使在内毒素血症期间。同时，赖诺普利治疗限制了内毒素血症期间TGF-β 1蛋白释放到肺泡腔中。总之，这些结果表明，血管紧张素II介导氧化应激和随后的TGF-β 1表达和肺泡上皮屏障功能障碍，其特征是酒精性肺。
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-beta 1 ( TGF-beta 1), and alveolar epithelial barrier dysfunction, even though the lung appears grossly normal. However, during endotoxemia, ethanol-fed rats release more activated TGF-beta 1 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-beta 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-beta 1 expression. The glutathione precursor procysteine also prevented TGF-beta 1 expression, suggesting that TGF-beta 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-beta 1 protein release into the alveolar space during endotoxemia. Together, these results suggest that angiotensin II mediates oxidative stress and the consequent TGF-beta 1 expression and alveolar epithelial barrier dysfunction that characterize the alcoholic lung.