Cellular Oxygen Toxicity

Abstract

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 (O⁻₂), 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 O⁻₂ 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.