CELLULAR OXYGEN-TOXICITY - OXIDANT INJURY WITHOUT APOPTOSIS

All forms of aerobic life are faced with the threat of oxidation from molecular oxygen (O-2) and have evolved antioxidant defenses to cope w ith this potential problem, However, cellular antioxidants can become overwhelmed by oxidative insults, including supraphysiologic concentra tions of O-2 (hyperoxia), Oxidative cell injury involves the modificat ion of cellular macromole cules by reactive oxygen intermediates (ROI) , often leading to cell death, O-2 therapy, which is a widely used com ponent of life-saving intensive care, can cause lung injury, It is gen erally thought that hyperoxia injures cells by virtue of the accumulat ion of toxic levels of ROI, including H2O2 and the superoxide anion (O -2(-)), which are not adequately scavenged by endogenous antioxidant d efenses, These oxidants are cytotoxic and have been shown to kill cell s via apoptosis, or programmed cell death, If hyperoxia-induced cell d eath is a result of increased ROI, then O-2 toxicity should kill cells via ap optosis, We studied cultured epithelial cells in 95% O-2 and a ssayed apoptosis using a DNA-binding fluorescent dye, in situ end-labe ling of DNA, and electron microscopy, Using all approaches we found th at hyperoxia kills cells via necrosis, not apoptosis, In contrast, let hal concentrations of either H2O2 or O-2(-) cause apoptosis, Paradoxic ally, apoptosis is a prominent event in the lungs of animals injured b y breathing 100% O-2. These data indicate that O-2 toxicity is somewha t distinct from other forms of oxidative injury and suggest that apopt osis in vivo is not a direct effect of O-2.