Cellular oxygen toxicity. Oxidant injury without apoptosis.
All forms of aerobic life are faced with the threat of oxidation from molecular oxygen (O2) and have evolved antioxidant defenses to cope with this potential problem. However, cellular antioxidants can become overwhelmed by oxidative insults, including supraphysiologic concentrations of O2 (hyperoxia). Oxidative cell injury involves the modification of cellular macromolecules by reactive oxygen intermediates (ROI), often leading to cell death. O2 therapy, which is a widely used component of life-saving intensive care, can cause lung injury. It is generally thought that hyperoxia injures cells by virtue of the accumulation of toxic levels of ROI, including H2O2 and the superoxide anion (O2-), which are not adequately scavenged by endogenous antioxidant defenses. These oxidants are cytotoxic and have been shown to kill cells via apoptosis, or programmed cell death. If hyperoxia-induced cell death is a result of increased ROI, then O2 toxicity should kill cells via apoptosis. We studied cultured epithelial cells in 95% O2 and assayed apoptosis using a DNA-binding fluorescent dye, in situ end-labeling of DNA, and electron microscopy. Using all approaches we found that hyperoxia kills cells via necrosis, not apoptosis. In contrast, lethal concentrations of either H2O2 or O2- cause apoptosis. Paradoxically, apoptosis is a prominent event in the lungs of animals injured by breathing 100% O2. These data indicate that O2 toxicity is somewhat distinct from other forms of oxidative injury and suggest that apoptosis in vivo is not a direct effect of O2.
Kazzaz
J A
JA
CardioPulmonary Research Institute, State University of New York at Stony Brook School of Medicine, Mineola, New York 11501, USA.
Xu
J
J
Palaia
T A
TA
Mantell
L
L
Fein
A M
AM
Horowitz
S
S
D000230:Adenocarcinoma; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D004848:Epithelium; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018496:Hyperoxia; D008168:Lung / Q000187:drug effects / Q000473:pathology; D055370:Lung Injury; D008175:Lung Neoplasms; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009336:Necrosis; D018384:Oxidative Stress; D010100:Oxygen / Q000633:toxicity*; D017382:Reactive Oxygen Species; D014407:Tumor Cells, Cultured
D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D010100:Oxygen