BIOLOGY OF NITRIC OXIDE DERIVED FROM AIRWAY EPITHELIUM

气道上皮来源的一氧化氮的生物学

• 批准号: 6110010
• 负责人: JONATHAN S. STAMLER
• 金额: $ 24万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6110010
• 关键词: adduct; aminothiol; asthma; bronchodilators; enzyme activity; enzyme structure; glutathione; guinea pigs; human tissue; immunocytochemistry; isozymes; laboratory mouse; laboratory rabbit; laboratory rat; nitric oxide; nitric oxide synthase; nitroso compounds; oxidation reduction reaction; oxidative stress; respiratory epithelium; thiols

The airway epithelium secretes relaxing factor(s) that may be important in control of airway tone. The chemical identify of these species has not been well characterized. Nitric oxide is a powerful smooth muscle relaxant implicated in the regulation of blood pressure and gastrointestinal motility. However, the pharmacological literature addressing its role in the airways in general, and as a relaxing factor derived from epithelium, in particular, is controversial. Moreover, one is faced with a major paradox in the lung, namely, that the biological activity of NO needs to be reconciled with its established toxicity in an oxygen-rich environment. We have proposed that answers to paradox lie in the redox chemistry of NO, specifically its capacity to form adducts with both amino acid and protein thiols. These S-nitrosothiols (RSNO) are resistant to reaction with oxygen and possess smooth muscle relaxant activity. The central hypothesis of this proposal is that the epithelium is a rich source of NO, and that reactions with thiol groups play a critical role in its cellular biochemistry and airway pharmacology. The Specific Aims of this project are: 1) to undertake the immunohistochemical, biochemical and molecular characterization of the airway epithelial NO synthase(s); 2) to identity and chemically characterize the endogenous nitrogen oxides and RSNO species synthesized by airway epithelium; 3) to define the biochemical pathways of RSNO formation and metabolism in airway epithelial cells; and 4) to determine the effects of epithelial-derived NO and RSNO on airway function in selected animal models, normal human airways and states of airway hyperreactivity. By demonstrating the physiological importance of NO in airway epithelium, chemically characterizing the adducts formed in epithelial cells and secreted into their environment and defining the bronchodilator activities of endogenous NO species, we expect to identify novel pharmacological approaches for treatment of diseases characterized by airway hyperreactivity.

气道上皮细胞分泌舒张因子，其可能在 控制气道张力。这些物种的化学鉴定还没有 被很好地描述了。一氧化氮是一种强大的平滑肌松弛剂 参与调节血压和胃肠道 能动性 然而，药理学文献讨论了其在 一般来说，作为来自上皮的松弛因子， 尤其是有争议的。此外，一个人面临着一个主要的 肺中的悖论，即NO的生物活性需要 与其在富氧环境中的既定毒性相一致。 我们已经提出，悖论的答案在于NO的氧化还原化学， 特别是它与氨基酸和蛋白质形成加合物能力 硫醇这些S-亚硝基硫醇（RSNO）可抵抗与氧气的反应 并具有平滑肌松弛活性。的中心假设 该建议是上皮是NO的丰富来源，并且 与硫醇基团的反应在其细胞中起着关键作用， 生物化学和气道药理学。 该项目的具体目标是： 1)进行免疫组化、生化和分子生物学 气道上皮NO合酶的表征; 2)确定和化学表征内源性氮氧化物 呼吸道上皮合成RSNO; 3)确定RSNO形成和代谢的生化途径， 气道上皮细胞;和 4)确定上皮来源的NO和RSNO对气道的影响， 功能在选定的动物模型，正常的人气道和状态 气道高反应性 通过证明NO在气道上皮中的生理重要性， 化学表征上皮细胞中形成的加合物， 分泌到它们的环境中并定义支气管扩张活性 内源性NO物种，我们希望确定新的药理学 用于治疗以气道为特征的疾病的方法 反应过度