Bailey Damian Miles
Hypoxia Research Unit, Department of Physiology, University of Glamorgan, Pontypridd, South Wales, UK.
Adv Exp Med Biol. 2003;543:201-21.
Photosynthesising cyanobacteria breathed life into what was 1000 million years ago considered a reductive atmosphere, thus providing a selective pressure for the evolution of O2-dependent organisms. However, the fact that molecular O2 exists in air as a free radical renders it a double-edged sword, capable of sustaining life in physiologically controlled amounts, yet fatal when in excess. The controlled delivery and stepwise reduction in PO2 from air to mitochondrion may in itself be considered an evolutionary antioxidant to cope with this biological conundrum. The present review will discuss the potential roles, both good and bad, for free radicals during human adaptation to altered environmental PO2. By combining electron paramagnetic resonance spectroscopy with spin-trapping, we provide direct molecular evidence for increased O2 and carbon-centered radical generation at high-altitude which may seem paradoxical in light of the reduced PO2. Radical-mediated contributions to tissue damage and their subsequent role in the pathogenesis of AMS, HAPE and HACE will also be critically examined. Finally, we focus on the sources, mechanisms and functional significance of free radical generation in hypoxia, with a brief consideration of their more positive role as putative signal transductants, capable of adjusting cellular homeostasis and initiating protective adaptation. Our preliminary studies in humans suggest that radical generation by skeletal muscle is exquisitely sensitive to intracellular PO2 which may provide a unifying theory to explain the "free radical paradox" of high-altitude.
进行光合作用的蓝细菌为10亿年前被认为是还原性的大气注入了生命，从而为依赖氧气的生物进化提供了选择压力。然而，分子氧以自由基形式存在于空气中这一事实使其成为一把双刃剑，适量时能维持生命，但过量时则致命。从空气到线粒体的氧分压（PO2）的可控传递和逐步降低本身可被视为一种进化的抗氧化机制，以应对这一生物学难题。本综述将讨论自由基在人类适应环境PO2改变过程中的潜在作用，包括有益和有害的方面。通过将电子顺磁共振光谱与自旋捕获相结合，我们提供了直接的分子证据，表明在高海拔地区氧气和以碳为中心的自由基生成增加，鉴于较低的PO2，这似乎自相矛盾。自由基介导的对组织损伤的作用及其在急性高山病（AMS）、高原肺水肿（HAPE）和高原脑水肿（HACE）发病机制中的后续作用也将受到严格审查。最后，我们关注缺氧时自由基产生的来源、机制和功能意义，并简要考虑它们作为假定信号转导分子的更积极作用，即能够调节细胞内稳态并启动保护性适应。我们在人体中的初步研究表明，骨骼肌产生的自由基对细胞内PO2极为敏感，这可能为解释高海拔地区的“自由基悖论”提供一个统一的理论。
