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: 2229946
• 负责人: JONATHAN S. STAMLER
• 金额: $ 13.74万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-10 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2229946
• 关键词: adduct; amine oxidoreductase; asthma; biochemistry; biological models; bronchodilators; enzyme mechanism; guinea pigs; immunocytochemistry; laboratory mouse; laboratory rat; nitric oxide; nitrogen metabolism; respiratory airflow disorder; respiratory epithelium; respiratory function; respiratory hypersensitivity; respiratory pharmacology; thiols

The airway epithelium secretes relaxing factor(s) that may be important in control of airway tone. The chemical identity 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 identify 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.

气道上皮分泌松弛因子，这可能对 控制气道张力。这些物种的化学特性尚未确定 得到了很好的表征。一氧化氮是一种强大的平滑肌松弛剂 与血压和胃肠道的调节有关 动力。然而，药理学文献阐述了其在 一般而言，气道，并且作为源自上皮的松弛因子， 尤其是有争议的。此外，人们还面临着一项重大的 肺中的悖论，即NO的生物活性需要 与其在富氧环境中已确定的毒性相协调。 我们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的能力 硫醇。这些 S-亚硝基硫醇 (RSNO) 能够抵抗与氧气的反应 并具有平滑肌松弛活性。中心假设为 该提议认为上皮细胞是一氧化氮的丰富来源，并且 与硫醇基团的反应在其细胞中起着至关重要的作用 生物化学和气道药理学。 该项目的具体目标是： 1）承接免疫组化、生化及分子生物学 气道上皮 NO 合酶的特征； 2) 识别和化学表征内源性氮氧化物 和由气道上皮合成的 RSNO 种类； 3）定义RSNO形成和代谢的生化途径 气道上皮细胞；和 4) 确定上皮源性NO和RSNO对气道的影响 在选定的动物模型、正常人类呼吸道和状态下的功能 气道高反应性。 通过证明 NO 在气道上皮细胞中的生理重要性， 对上皮细胞中形成的加合物进行化学表征 分泌到环境中并定义支气管扩张剂活性 内源性 NO 种类，我们期望鉴定出新的药理学 以气道为特征的疾病的治疗方法 过度反应。