MECHANISMS OF TOXICITY OF CARBON MONOXIDE

脑缺氧通过复合体和神经细胞引起选择性神经元损伤 不完全理解的机制。在这项提议中，一氧化碳缺氧和重新- 氧合作用将被用于研究一些病理生理学。 缺氧性神经元损伤的机制。我们将重点关注 一氧化碳缺氧期和缺氧后显著神经元损伤的假说 是由细胞内产生的活性氧引起的， 尤其是线粒体来源，这对两者都有贡献 坏死性和程序性细胞死亡(细胞凋亡)。具体目标是：1) 评估体内和术后ROS的产生和氧化应激的程度 大鼠脑内低氧敏感区和耐缺氧区一氧化碳的变化 体内，2)评估ROS产生和氧化的来源和机制 一氧化碳缺氧期和缺氧后应激对缺氧的敏感性和抵抗力 活体脑区，3)研究脑损伤的程度和机制 正常人群脑氧分压升高改变ROS生成和氧化应激 脑和一氧化碳暴露后的体内低氧，以及4)观察其影响 一氧化碳缺氧及改变一氧化碳后氧化应激的干预 低氧对大鼠脑功能和神经病理改变的影响。这个 拟议中的研究有望证明，来自 一氧化碳缺氧期和缺氧后线粒体来源有很大贡献 与脆弱脑区的神经元退化有关，而这种效应 可通过高压氧的药理使用和 将氧化应激降至最低的具体干预措施。

Cerebral hypoxia causes selective neuronal damage by complex and incompletely understood mechanisms. In this proposal, CO hypoxia and re- oxygenation will be used to study some of the pathophysiological mechanisms involved in hypoxic neuronal injury. We will focus on the hypothesis that significant neuronal damage during and after CO hypoxia is caused by intracellular production of reactive oxygen species, particularly from mitochondrial sources, which contributes to both necrotic and programmed cell death (apoptosis). The Specific Aims are: 1) Assess the extent of ROS production and oxidative stress during and after CO hypoxia in hypoxia sensitive and resistant brain regions in the rat in vivo, 2) Assess sources and mechanisms of ROS production and oxidative stress during and after CO hypoxia in hypoxia sensitive and resistant brain regions in vivo, 3) Investigate the extent and mechanisms by which increases in brain PO2 alter ROS production and oxidative stress in normal brain and after exposure to CO hypoxia in vivo, and 4) Investigate effects of CO hypoxia and interventions which alter oxidative stress after CO hypoxia on changes in brain function and neuropathology in the rat. The proposed studies are expected to demonstrate that oxidative stress from mitochondrial sources during and after CO hypoxia contribute substantially to neuronal degeneration in vulnerable brain regions, and that this effect can be ameliorated by pharmacological use of hyperbaric oxygen and specific interventions that minimize oxidative stress.