TY - JOUR
T1 - Hyperoxia-induced apoptosis does not require mitochondrial reactive oxygen species and is regulated by Bcl-2 proteins
AU - Scott Budinger, G. R.
AU - Tso, May
AU - McClintock, David S.
AU - Dean, David A.
AU - Sznajder, Jacob I.
AU - Chandel, Navdeep S.
PY - 2002/5/3
Y1 - 2002/5/3
N2 - Exposure of animals to hyperoxia results in lung injury that is characterized by apoptosis and necrosis of the alveolar epithelium and endothelium. The mechanism by which hyperoxia results in cell death, however, remains unclear. We sought to test the hypothesis that exposure to hyperoxia causes mitochondria-dependent apoptosis that requires the generation of reactive oxygen species from mitochondrial electron transport. Ratla cells exposed to hyperoxia underwent apoptosis characterized by the release of cytochrome c, activation of caspase-9, and nuclear fragmentation that was prevented by the overexpression of Bcl-XL. Murine embryonic fibroblasts from bax-/- bak-/- mice were resistant to hyperoxia-induced cell death. The administration of the antioxidants manganese (III) tetrakis (4-benzoic acid) porphyrin, ebselen, and N-acetylcysteine failed to prevent cell death following exposure to hyperoxia. Human fibrosarcoma cells (HT1080) lacking mitochondrial DNA (ρ0 cells) that failed to generate reactive oxygen species during exposure to hyperoxia were not protected against cell death following exposure to hyperoxia. We conclude that exposure to hyperoxia results in apoptosis that requires Bax or Bak and can be prevented by the overexpression of Bcl-XL. The mitochondrial generation of reactive oxygen species is not required for cell death following exposure to hyperoxia.
AB - Exposure of animals to hyperoxia results in lung injury that is characterized by apoptosis and necrosis of the alveolar epithelium and endothelium. The mechanism by which hyperoxia results in cell death, however, remains unclear. We sought to test the hypothesis that exposure to hyperoxia causes mitochondria-dependent apoptosis that requires the generation of reactive oxygen species from mitochondrial electron transport. Ratla cells exposed to hyperoxia underwent apoptosis characterized by the release of cytochrome c, activation of caspase-9, and nuclear fragmentation that was prevented by the overexpression of Bcl-XL. Murine embryonic fibroblasts from bax-/- bak-/- mice were resistant to hyperoxia-induced cell death. The administration of the antioxidants manganese (III) tetrakis (4-benzoic acid) porphyrin, ebselen, and N-acetylcysteine failed to prevent cell death following exposure to hyperoxia. Human fibrosarcoma cells (HT1080) lacking mitochondrial DNA (ρ0 cells) that failed to generate reactive oxygen species during exposure to hyperoxia were not protected against cell death following exposure to hyperoxia. We conclude that exposure to hyperoxia results in apoptosis that requires Bax or Bak and can be prevented by the overexpression of Bcl-XL. The mitochondrial generation of reactive oxygen species is not required for cell death following exposure to hyperoxia.
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U2 - 10.1074/jbc.M109317200
DO - 10.1074/jbc.M109317200
M3 - Article
C2 - 11877388
AN - SCOPUS:0037013272
SN - 0021-9258
VL - 277
SP - 15654
EP - 15660
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 18
ER -