Hyperoxia Inhibits Oxidant-induced Apoptosis in Lung Epithelial Cells

• Published in: The Journal of biological chemistry Vol. 276; no. 1; pp. 569 - 575
• Main Authors: Franek, William R., Horowitz, Stuart, Stansberry, Leah, Kazzaz, Jeffrey A., Koo, Hshi-Chi, Li, Yuchi, Arita, Yuko, Davis, Jonathan M., Mantell, Abraham S., Scott, William, Mantell, Lin L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05-01-2001; American Society for Biochemistry and Molecular Biology
• Subjects: Antioxidants - metabolism; Apoptosis - drug effects; Cytochrome c Group - metabolism; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Flow Cytometry; Fluorescent Antibody Technique; Humans; Hydrogen Peroxide - antagonists & inhibitors; Hydrogen Peroxide - pharmacology; I-kappa B Kinase; I^KB protein; In Situ Nick-End Labeling; Lung - cytology; Lung - drug effects; Lung - metabolism; NF-^KB protein; NF-kappa B - metabolism; Oxidants - antagonists & inhibitors; Oxidants - pharmacology; Oxygen - pharmacology; Oxygen - toxicity; Paraquat - antagonists & inhibitors; Paraquat - pharmacology; Protein-Serine-Threonine Kinases - metabolism; Signal Transduction - drug effects; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - pharmacology; Up-Regulation - drug effects; Xanthine Oxidase - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M004716200

It has previously been shown that hyperoxia induces nonapoptotic cell death in cultured lung epithelial cells, whereas hydrogen peroxide (H2O2) and paraquat cause apoptosis. To test whether pathways leading to oxidative apoptosis in epithelial cells are sensitive to molecular O2, A549 cells were exposed to 95% O2 prior to exposure to lethal concentrations of H2O2. The extent of H2O2-induced apoptosis was significantly reduced in cells preexposed to hyperoxia compared with room-air controls. Preexposure of the hyperoxia-resistant HeLa-80 cell line to 80% O2 also inhibited oxidant-induced apoptosis, suggesting that this inhibition is not due to O2toxicity. Because hyperoxia generates reactive oxygen species and activates the redox-sensitive transcription factor nuclear factor κB (NF-κB), the role of antioxidant enzymes and NF-κB were examined in this inhibitory process. The onset of inhibition appeared to be directly related to the degradation of IκB and subsequent activation of NF-κB (either by hyperoxia or TNF-α), whereas no significant up-regulation of endogenous antioxidant enzyme activities was found. In addition, suppression of NF-κB activities by transfecting A549 cells with a dominant-negative mutant construct of IκB significantly augmented the extent of H2O2-induced apoptosis. These data suggest that hyperoxia inhibits oxidant-induced apoptosis and that this inhibition is mediated by NF-κB.