GSNO Reductase, S-Nitrosothiols, and Asthma

GSNO 还原酶、S-亚硝基硫醇和哮喘

• 批准号: 7574462
• 负责人: Loretta G Que
• 金额: $ 35.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7574462
• 关键词: Acute; Adrenergic Agents; Adult; Agonist; Allergens; Allergic; Animals; Applications Grants; Asthma; Breathing; Bronchoconstriction; Bronchodilator Agents; Child; Chronic; Coupled; Cystic Fibrosis; Data; Disease; Enzymes; Epithelial Cells; Equilibrium; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic; Genetic Polymorphism; Health; Homeostasis; Human; Hypersensitivity; Inflammation; Liquid substance; Literature; Lung; Lung diseases; Mammalian Cell; Metabolism; Modeling; Molecular Weight; Mus; Muscle Tonus; Nitric Oxide; Oxidoreductase; P-2; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Play; Production; Proteins; Research Personnel; Respiratory Failure; Rest; Role; Smooth Muscle; Source; Tachyphylaxis; Testing; Tissues; Wild Type Mouse; adrenergic; airway hyperresponsiveness; airway obstruction; asthmatic airway; base; cohort; desensitization; enzyme activity; homologous recombination; human subject; methacholine; new therapeutic target; programs; respiratory smooth muscle; response

DESCRIPTION (provided by applicant): In humans, S-nitrosoglutathione (GSNO), an endogenous bronchodilator, is depleted in the airway of asthmatics. GSNO reductase (GSNOR), an enzyme widely expressed across tissues including lung, regulates levels of lung GSNO levels. Wild-type mice develop increased GSNOR activity and decreased lung S-nitrosothiol (SNO) concentration following allergen challenge and suffer from increased airway hypersensitivity. In contrast, mice with a genetic deletion of GSNOR have increased lung SNO levels after allergen challenge and are protected from airway hyperreactivity. GSNOR deficient mice also have lower basal bronchial tone than normal animals and do not desensitize after repeated stimulation with (2 agonist therapy suggesting that endogenous SNOs regulate smooth muscle tone. These results provide genetic evidence in mice that dynamic SNO turnover is a critical mechanism of NO function in health and disease. In this grant application, we will test the hypothesis that depletion of the endogenous bronchodilator, GSNO, from the airway increases airway hyperresponsiveness to methacholine and decreases response to inhaled (2 agonists in human asthma. We will first determine if GSNOR activity is increased in human asthma and correlates with airway SNO expression (Aim 1). We will next determine if GSNOR activity predicts responsiveness to inhaled ((2 agonist therapy and if the presence of polymorphisms of GSNOR predicts enzyme activity, airway SNO concentration, and response to (2 agonists in asthmatic as compared to control subjects (Aim 2). Finally, we plan to determine whether repletion of SNO in subjects with mild asthma confers protection against methacholine induced bronchoconstriction and desensitization to an inhaled (2 agonist (Aim 3). This proposal will further our understanding of GSNOR and SNOs in asthma, how they function as homeostatic agents in asthma, and how repletion of SNO provides a novel therapeutic target.

描述（由申请人提供）：在人类中，S-亚硝基谷胱甘肽（GSNO）是一种内源性支气管扩张剂，在哮喘患者的气道中被耗尽。 GSNO 还原酶 (GSNOR) 是一种在包括肺在内的组织中广泛表达的酶，可调节肺 GSNO 水平。野生型小鼠在过敏原攻击后，GSNOR 活性增加，肺 S-亚硝基硫醇 (SNO) 浓度降低，并且气道过敏性增加。相比之下，GSNOR 基因缺失的小鼠在过敏原攻击后肺部 SNO 水平增加，并且免受气道高反应性的影响。 GSNOR 缺陷小鼠的基础支气管张力也比正常动物低，并且在重复刺激 (2 激动剂治疗后不会脱敏，表明内源性 SNO 调节平滑肌张力。这些结果为小鼠提供了遗传证据，表明动态 SNO 周转是健康和疾病中 NO 功能的关键机制。在这项拨款申请中，我们将检验以下假设：内源性支气管扩张剂的消耗， 来自气道的 GSNO 会增加气道对乙酰甲胆碱的高反应性，并降低对人类哮喘吸入 (2 激动剂) 的反应。我们将首先确定 GSNOR 活性是否在人类哮喘中增加并与气道 SNO 表达相关（目标 1）。接下来我们将确定 GSNOR 活性是否预测对吸入 ((2 激动剂治疗) 的反应性以及是否存在 GSNOR 可以预测哮喘患者与对照受试者相比的酶活性、气道 SNO 浓度以及对 (2 激动剂) 的反应（目标 2）。最后，我们计划确定轻度哮喘受试者补充 SNO 是否可以预防乙酰甲胆碱引起的支气管收缩以及对吸入 (2 激动剂) 的脱敏（目标 3）。该提案将进一步加深我们对哮喘患者中 GSNOR 和 SNO 的理解。 哮喘、它们如何作为哮喘中的稳态剂发挥作用，以及 SNO 的补充如何提供新的治疗靶点。