MECHANISMS OF TOXICITY OF CARBON MONOXIDE

一氧化碳的毒性机制

• 批准号: 6302221
• 负责人: CLAUDE A PIANTADES
• 金额: $ 24万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302221
• 关键词: antioxidants; brain circulation; brain injury; brain mapping; brain metabolism; carbon monoxide; carbon monoxide poisoning; cellular pathology; cellular respiration; cerebral ischemia /hypoxia; cytotoxicity; excitatory aminoacid; free radical oxygen; free radical scavengers; hyperbaric oxygen therapy; laboratory rat; mitochondria; neural degeneration; neuroprotectants; neurotoxicology; nitric oxide; nonhuman therapy evaluation; oxidative stress; oxygen tension

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.

脑缺氧通过复杂的神经元损伤机制， 不完全理解的机制。 在这个建议中，CO缺氧和重新- 氧合将被用来研究一些病理生理 缺氧性神经元损伤的机制。重点抓好 假设在CO缺氧期间和之后显著的神经元损伤是 由细胞内产生活性氧引起， 特别是来自线粒体来源，这有助于 坏死和程序性细胞死亡（凋亡）。具体目标是：1） 评估ROS产生和氧化应激的程度， 缺氧大鼠缺氧敏感区和耐缺氧区一氧化碳缺氧的研究 2）评估ROS产生和氧化的来源和机制， 低氧敏感性和耐低氧性中CO低氧期间和之后的应激 3）研究大脑区域在体内的程度和机制， 脑PO 2增加改变正常人ROS产生和氧化应激 脑和暴露于体内CO缺氧后，和4）研究影响 一氧化碳缺氧和干预措施，改变氧化应激后， 缺氧对大鼠脑功能和神经病理学的影响。的 预计拟议的研究将证明， 在CO缺氧期间和之后的线粒体来源 脆弱大脑区域的神经元退化， 可以通过药理学上使用高压氧来改善， 最大限度地减少氧化应激的具体干预措施。