TOXIC AND THERAPEUTIC EFFECTS OF OXYGEN

本申请是一个计划项目补助金，以研究在 分子氧、活性氧（ROS） 和一氧化氮（NO.）在生理和病理条件下。 决定氧的命运并调节其相互作用的因素 和组织硫醇池是四个研究主题 包括提案的项目。 项目1，一氧化碳中毒期间和之后的大脑代谢研究 (CO)缺氧，提出线粒体ROS的产生在不同的 脑区域是神经元损伤的重要来源。的 研究人员将ROS的产生与兴奋性毒性NO的变化联系起来。 生产和O2可用性。ROS生成，包括NO生成 将与神经病理学和功能的变化相关， 了解它们在神经元损伤中的作用。 下一个项目研究一氧化氮在细胞内的作用， 肺部呼吸道的生物化学。它解决了一个主要的矛盾， 肺，即，NO的生物活性与 它在富氧环境中的毒性的答案 显然矛盾将寻求在能力不。经历 氧化还原反应，决定与 位于细胞外和细胞内的蛋白质巯基部分。 蛋白硫醇NO.加合物或S-亚硝基硫醇，其对 与分子氧反应，具有强大的生物活性。 项目3将评估分离的内皮细胞对一氧化氮的反应 环氧NO.的作用机制，它与各种 细胞靶点，将通过糖酵解酶GAPDH进行研究。 努力还将集中在内皮细胞中NO形成的机制， 细胞，NO形成的调节，以及长期暴露的影响 重点是细胞蛋白巯基库的变化。 最后一个项目将评估细胞外超氧化物的作用 SOD在调节肺气道和血管功能中的作用。是 基于重要的发现，EC-SOD，这是高度组成型 在肺中表达，被定位在细胞外空间， 在气道和肺血管中的平滑肌细胞周围。 的 将检验EC-SOD是NO的关键生物调节剂的假设。 活动 EC-SOD和NOS。将在多个组织中共定位， 探讨EC-SOD与O_2、NO之间的函数关系。 气道和血管结构。

This application is for a Program Project Grant to study relationships at the cellular level between molecular oxygen, reactive oxygen species (ROS) and nitric oxide (NO.) under physiological and pathological conditions. Factors that determine the fate of oxygen and regulate its interactions with NO. and tissue thiol pools is the investigative theme for the four projects that comprise the proposal. Project 1, a study of brain metabolism during and after carbon monoxide (CO) hypoxia, proposes that mitochondrial ROS generation in different brain regions is a significant source of neuronal injury. The investigators will relate ROS production to changes in excitotoxicity, NO. production and O2 availability. ROS production including NO. production will be correlated with changes in neuropathology and function to better understand their roles in neuronal injury. The next project studies the role of nitric oxide in the cellular biochemistry of the airways of the lungs. It addresses a major paradox in the lung, i.e., that the biological activity of NO. is in conflict with its established toxicity in an oxygen-rich environment. Answers to this apparent paradox will be sought in the capacity of NO. to undergo oxidation-reduction reactions that determine the formation of adducts with protein thiol moieties located both extracellularly and intracellularly. Protein thiol NO. adducts, or S-nitrosothiols, which are resistant to reactions with molecular oxygen, possess potent biological activity. Project 3 will evaluate responses of isolated endothelial cells to nitric oxide. The mechanisms of action of NO., which interacts with a variety of cellular targets, will be investigated via the glycolytic enzyme, GAPDH. Efforts also will focus on mechanisms of NO. formation in endothelial cells, regulation of NO. formation, and the effects of prolonged exposure of cells to NO. with emphasis on changes in cellular protein thiol pools. The last project will evaluate the role of extracellular superoxide dismutase (EC-SOD) in modulating lung airway and vascular function. It is based on the important finding that EC-SOD, which is highly constitutively expressed in the lungs, has been localized in the extracellular spaces around smooth muscle cells in airways and in pulmonary vasculature. The hypothesis will be tested that EC-SOD is a key bioregulator of NO. activity. Both EC-SOD and NOS. will be colocalized in several tissues and the functional relationships of EC-SOD, O2 and NO. will be explored in both airway and vascular structures.