Am. J. Respir. Cell Mol. Biol., Volume 25, Number 6, December, 2001 676-684

Ceramide-Mediated Apoptosis in Lung Epithelial Cells Is Regulated by Glutathione

Sophia N. Lavrentiadou, Chris Chan, T'Nay Kawcak, Tommer Ravid, Adili Tsaba, Albert van der Vliet, Reuven Rasooly, and Tzipora Goldkorn

Center for Comparative Respiratory Biology and Medicine, Department of Internal Medicine, University of California, Davis, California

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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