Endothelial NAD[P]H oxidase in hyperoxic lung injury

高氧性肺损伤中的内皮 NAD[P]H 氧化酶

• 批准号: 6877196
• 负责人: VISWANATHAN NATARAJAN
• 金额: $ 34.31万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6877196
• 关键词: NAD(P)H dehydrogenase; antisense nucleic acid; biological signal transduction; cytoskeleton; enzyme induction /repression; free radical oxygen; gene expression; green fluorescent proteins; hyperoxia; intermolecular interaction; laboratory mouse; lung injury; molecular pathology; phosphatidate; phospholipase D; protein kinase; protein structure function; radiotracer; respiratory epithelium; tissue /cell culture; vascular endothelium permeability

DESCRIPTION (provided by applicant): Administration of supraphysiological concentration of oxygen (hyperoxia) is a common clinical practice in the management of premature babies and adults with respiratory failures. However, prolonged exposure to hyperoxia is toxic to lung tissue, causing injury and mortality. The mechanisms of hyperoxic lung injury are not well defined, however, elevated levels of reactive oxygen species (ROS) and reactive nitrogen species with decreased alveolar glutathione may account for the pulmonary toxicity, endothelial damage, and vascular leakiness. Damage to the endothelium results likely from ROS generated by neutrophil-dependent and neutrophil-independent enzymatic pathways of NAD(P)H oxidase, xanthine oxidase, cycloxygenase/lipoxygenase, and mitochondrial electron transport. We have identified activation of endothelial NAD(P)H oxidase and enhanced production of ROS in hyperoxia, however, there remains several unanswered questions regarding the role and regulation of endothelial NAD(P)H oxidase in vascular injury and leakiness. It is hypothesized that acute lung injury and barrier dysfunction due to hyperoxia are mediated by ROS generated by the activation of endothelial NAD(P)H oxidase system. To test this hypothesis, we will investigate the effect of hyperoxia in NAD(P)H oxidase activation ROS generation, cytoskeletal changes and barrier dysfunction in human endothelial cells and in animal models. SA1: To characterize hyperoxia-mediated O2/ROS generation by endothelial NAD (P)H oxidase. SA2: To investigate the role of protein kinases in hyperoxia-induced NAD(P)H oxidase activation. SA3: To characterize the role of phospholipase D/phosphatidic acid in hyperoxia-mediated NAD(P)H oxidase activation. SA4: To determine the role of hyperoxia-mediated NAD(P)H oxidase in cytoskeletal re-arrangement and endothelial barrier dysfunction/vascular leakiness. Further understanding the role and regulation of endothelial NAD(P)H oxidase activation in hyperoxia will allow development of targeted therapies to attenuate ROS-induced lung injury and reverse endothelial dysfunction.

描述（由申请人提供）：超生理学的管理 氧气浓度（高氧）是一种常见的临床实践 早产儿和患有呼吸衰竭的成人的管理。然而， 长时间暴露在高氧环境中对肺组织有毒，导致损伤和 死亡。高氧性肺损伤的机制尚不明确， 然而，活性氧 (ROS) 和活性氮水平升高 肺泡谷胱甘肽减少的物种可能是肺损伤的原因 毒性、内皮损伤和血管渗漏。内皮损伤 结果可能是由中性粒细胞依赖性和中性粒细胞产生的ROS产生的 NAD(P)H 氧化酶、黄嘌呤氧化酶的中性粒细胞独立酶途径 环加氧酶/脂氧合酶和线粒体电子传递。我们有 确定了内皮 NAD(P)H 氧化酶的激活并增强了 然而，高氧条件下的 ROS 仍然存在一些未解答的问题： 内皮NAD(P)H氧化酶在血管损伤中的作用及调控 泄漏。据推测，急性肺损伤和屏障功能障碍 由于高氧是由内皮细胞激活产生的ROS介导的 NAD(P)H 氧化酶系统。为了检验这个假设，我们将研究其效果 高氧对 NAD(P)H 氧化酶激活、ROS 生成、细胞骨架变化的影响 以及人内皮细胞和动物模型中的屏障功能障碍。 SA1： 表征内皮 NAD (P)H 介导的高氧介导的 O2/ROS 生成 氧化酶。 SA2：研究蛋白激酶在高氧诱导的中的作用 NAD(P)H 氧化酶激活。 SA3：表征磷脂酶的作用 高氧介导的 NAD(P)H 氧化酶激活中的 D/磷脂酸。 SA4：至 确定高氧介导的 NAD(P)H 氧化酶在细胞骨架中的作用 重新排列和内皮屏障功能障碍/血管渗漏。更远 了解内皮 NAD(P)H 氧化酶激活的作用和调节 在高氧状态下将允许开发靶向疗法来减弱 ROS 诱导的肺损伤并逆转内皮功能障碍。