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 B (NF-B), the role of antioxidant enzymes and NF-B were examined in this inhibitory process. The onset of inhibition appeared to be directly related to the degradation of IB and subsequent activation of NF-B (either by hyperoxia or TNF-␣), whereas no significant up-regulation of endogenous antioxidant enzyme activities was found. In addition, suppression of NF-B activities by transfecting A549 cells with a dominant-negative mutant construct of IB 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-B.Pulmonary epithelial cell injury is an unfortunate consequence of therapy with supraphysiological concentrations of oxygen (hyperoxia) and a prominent feature of acute inflammatory lung injury (1, 2). Oxidant-induced cell injury and death are generally thought to occur via reactive oxygen species. Although exogenous hydrogen peroxide (H 2 O 2 ) and paraquat induce apoptosis in cultured alveolar epithelial (A549) cells, hyperoxia kills these cells via a mode of cell death that is distinct from apoptosis both morphologically and biochemically (3-5). These observations raise the possibility that hyperoxia actually inhibits apoptosis in pulmonary epithelial cells.There are several possible ways that hyperoxia might inhibit apoptosis in pulmonary epithelial cells. First, one or more enzymes in the apoptotic pathway might be sensitive to direct oxidation by high levels of molecular O 2 , resulting in an irreversible abrogation of the apoptotic pathway in these cells. Alternatively, hyperoxia may activate pathways that inhibit apoptosis. Several laboratories have shown that activation of the transcription factor NF-B can prevent apoptosis induced by chemotherapeutic agents and ionizing radiation in cultured cells (6 -9). In addition, activation of NF-B may be responsible for the protective effect of low-dose amyloid  in neuronal cell death (10) and in the survival and function of hematopoietic stem and progenitor cells (11). We have previously demonstrated that hyperoxia activates NF-B in A549 cells (5). In this report, we examined whether preexposure of cultured epithelial cells to hyperoxia prevents subsequent...
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