Ceramide-mediated apoptosis in lung epithelial cells is regulated by glutathione

被引:92
作者
Lavrentiadou, SN [1 ]
Chan, C [1 ]
Kawcak, T [1 ]
Ravid, T [1 ]
Tsaba, A [1 ]
van der Vliet, A [1 ]
Rasooly, R [1 ]
Goldkorn, T [1 ]
机构
[1] Univ Calif Davis, Sch Med, Dept Internal Med, Ctr Comparat Resp Biol & Med, Davis, CA 95616 USA
关键词
D O I
10.1165/ajrcmb.25.6.4321
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Reactive oxygen species (ROS) are mediators of lung injury, and glutathione (GSH) is the major nonprotein antioxidant that protects the cell from oxidative stress. We have recently shown that H2O2 induces ceramide-mediated apoptosis in human lung epithelial cells. We hypothesized that ROS-mediated depletion of GSH plays a regulatory role in ceramide generation, and thus in the induction of apoptosis. Our present studies demonstrate that GSH at physiologic concentrations (1 to 10 mM) inhibits ceramide production in a time- and dose-dependent manner in A549 human alveolar epithelial cells. On the other hand, buthionine-sulfoximine-mediated depletion of intracellular GSH induces elevation of ceramide levels and apoptosis. In addition, GSH blocks H2O2-mediated induction of intracellular ceramide generation and apoptosis. These effects were not mimicked by oxidized GSH (GSSG) or other thiol antioxidants, such as dithiothreitol and 2-mercaptoethanol. Moreover, increase of intracellular H2O2, mediated by inhibition of catalase by aminotriazole, also induces ceramide generation and apoptosis. These effects were blocked by N-acetylcysteine. Our results suggest that GSH depletion may be the link between oxidative stress and ceramide-mediated apoptosis in the lung.
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页码:676 / 684
页数:9
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