Kazzaz J A, Xu J, Palaia T A, Mantell L, Fein A M, Horowitz S
CardioPulmonary Research Institute, State University of New York at Stony Brook School of Medicine, Mineola, New York 11501, USA.
J Biol Chem. 1996 Jun 21;271(25):15182-6. doi: 10.1074/jbc.271.25.15182.
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.
所有需氧生物都面临着来自分子氧（O₂）氧化作用的威胁，因此进化出了抗氧化防御机制来应对这一潜在问题。然而，细胞抗氧化剂可能会被氧化损伤所压倒，包括超生理浓度的O₂（高氧）。氧化性细胞损伤涉及活性氧中间体（ROI）对细胞大分子的修饰，常常导致细胞死亡。氧气疗法是挽救生命的重症监护中广泛使用的一部分，但可能会导致肺损伤。一般认为，高氧通过ROI毒性水平的积累来损伤细胞，这些ROI包括过氧化氢（H₂O₂）和超氧阴离子（O₂⁻），而内源性抗氧化防御机制无法充分清除它们。这些氧化剂具有细胞毒性，已被证明可通过凋亡或程序性细胞死亡来杀死细胞。如果高氧诱导的细胞死亡是ROI增加的结果，那么氧气毒性应该通过凋亡来杀死细胞。我们在95%的氧气环境中研究培养的上皮细胞，并使用一种DNA结合荧光染料、DNA原位末端标记和电子显微镜来检测凋亡。使用所有这些方法，我们发现高氧通过坏死而非凋亡来杀死细胞。相比之下，致死浓度的H₂O₂或O₂⁻会导致凋亡。矛盾的是，凋亡是吸入100%氧气而受伤的动物肺部的一个显著现象。这些数据表明，氧气毒性在某种程度上与其他形式的氧化损伤不同，并表明体内凋亡并非氧气的直接作用。
