Hyperoxia inhibits oxidant-induced apoptosis in lung epithelial cells.
It has previously been shown that hyperoxia induces nonapoptotic cell death in cultured lung epithelial cells, whereas hydrogen peroxide (H(2)O(2)) and paraquat cause apoptosis. To test whether pathways leading to oxidative apoptosis in epithelial cells are sensitive to molecular O(2), A549 cells were exposed to 95% O(2) prior to exposure to lethal concentrations of H(2)O(2). The extent of H(2)O(2)-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% O(2) also inhibited oxidant-induced apoptosis, suggesting that this inhibition is not due to O(2) toxicity. Because hyperoxia generates reactive oxygen species and activates the redox-sensitive transcription factor nuclear factor kappa B (NF-kappa B), the role of antioxidant enzymes and NF-kappa B were examined in this inhibitory process. The onset of inhibition appeared to be directly related to the degradation of I kappa B and subsequent activation of NF-kappa B (either by hyperoxia or TNF-alpha), whereas no significant up-regulation of endogenous antioxidant enzyme activities was found. In addition, suppression of NF-kappa B activities by transfecting A549 cells with a dominant-negative mutant construct of I kappa B significantly augmented the extent of H(2)O(2)-induced apoptosis. These data suggest that hyperoxia inhibits oxidant-induced apoptosis and that this inhibition is mediated by NF-kappa B.
Franek
W R
WR
CardioPulmonary Research Institute, Winthrop University Hospital, SUNY-Stony Brook School of Medicine, Mineola, New York 11501, USA.
Horowitz
S
S
Stansberry
L
L
Kazzaz
J A
JA
Koo
H C
HC
Li
Y
Y
Arita
Y
Y
Davis
J M
JM
Mantell
A S
AS
Scott
W
W
Mantell
L L
LL
D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D003574:Cytochrome c Group / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051550:I-kappa B Kinase; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D016877:Oxidants / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology* / Q000633:toxicity; D010269:Paraquat / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism
D000975:Antioxidants; D003574:Cytochrome c Group; D016328:NF-kappa B; D016877:Oxidants; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D014969:Xanthine Oxidase; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D010269:Paraquat; D010100:Oxygen