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Glutathione (GSH) is an essential antioxidant tripeptide that protects mammalian cells against oxidants and xenobiotics. Patients with fibrotic lung disorders have very low levels of GSH in their alveolar epithelial lining fluid (ELF), whereas transforming growth factor (TGF)-β is overexpressed in their alveolar epithelial cells. We observed that TGF-β₁ increased susceptibility of the human alveolar epithelial cell line A549 to H₂O₂-mediated cytotoxicity (P < 0.05), decreased the activities of the antioxidant enzymes glutathione reductase and catalase by 31%, and markedly decreased GSH content in A549 cells (P < 0.01). GSH depletion was associated with an equivalent decrease in the activity of the rate-limiting enzyme in GSH synthesis, γ-glutamylcysteine synthetase (γ-GCS) (P < 0.01). Western blot analysis confirmed that the loss of γ-GCS activity was associated with a marked decrease in γ-GCS heavy subunit (γ …