Aggarwal Saurabh, Dimitropoulou Christiana, Lu Qing, Black Stephen M, Sharma Shruti
Vascular Biology Center, Georgia Health Sciences University Augusta, GA, USA.
Front Physiol. 2012 May 28;3:161. doi: 10.3389/fphys.2012.00161. eCollection 2012.
Acute lung injury (ALI) is a life threatening condition associated with hypoxemia, diffuse alveolar damage, inflammation, and loss of lung function. Lipopolysaccharide (LPS; endotoxin) from the outer membrane of Gram-negative bacteria is a major virulence factor involved in the development of ALI. The depletion of glutathione (GSH), an essential intra- and extra-cellular protective antioxidant, by LPS is an important event that contributes to the elevation in reactive oxygen species. Whether restoring GSH homeostasis can effectively ameliorate mitochondrial dysfunction and cellular apoptosis in ALI is unknown and therefore, was the focus of this study. In peripheral lung tissue of LPS-treated mice, hydrogen peroxide and protein nitration levels were significantly increased. Pre-treatment with GSH-ethyl ester (GSH-EE) prevented this increase in oxidative stress. LPS also increased the lactate/pyruvate ratio, attenuated SOD2 protein levels, and decreased ATP levels in the mouse lung indicative of mitochondrial dysfunction. Again, GSH-EE treatment preserved the mitochondrial function. Finally, our studies showed that LPS induced an increase in the mitochondrial translocation of Bax, caspase 3 activation, and nuclear DNA fragmentation and these parameters were all prevented with GSH-EE. Thus, this study suggests that GSH-EE supplementation may reduce the mitochondrial dysfunction associated with ALI.
急性肺损伤（ALI）是一种危及生命的病症，与低氧血症、弥漫性肺泡损伤、炎症及肺功能丧失相关。革兰氏阴性菌外膜的脂多糖（LPS；内毒素）是参与ALI发生发展的主要毒力因子。LPS导致细胞内和细胞外重要的保护性抗氧化剂谷胱甘肽（GSH）耗竭，这是导致活性氧增加的一个重要事件。恢复GSH稳态是否能有效改善ALI中的线粒体功能障碍和细胞凋亡尚不清楚，因此，这是本研究的重点。在LPS处理的小鼠外周肺组织中，过氧化氢和蛋白质硝化水平显著升高。用谷胱甘肽乙酯（GSH-EE）预处理可防止氧化应激的这种增加。LPS还增加了小鼠肺中的乳酸/丙酮酸比值，降低了超氧化物歧化酶2（SOD2）蛋白水平，并降低了ATP水平，表明存在线粒体功能障碍。同样，GSH-EE处理可保留线粒体功能。最后，我们的研究表明，LPS诱导Bax的线粒体易位增加、半胱天冬酶3激活和核DNA片段化，而这些参数均被GSH-EE阻止。因此，本研究表明补充GSH-EE可能会减轻与ALI相关的线粒体功能障碍。
