Modulation of Asthma by GSNO-based Therapies

基于 GSNO 的疗法调节哮喘

• 批准号: 8438121
• 负责人: Matthew Wolf Foster
• 金额: $ 39.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-07 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438121
• 关键词: Acute; Adrenal Cortex Hormones; Aerosols; Affect; Allergens; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Biochemical; Biological Availability; Breathing; Bronchoconstriction; Bronchodilator Agents; Cell Culture Techniques; Cells; Chronic; Chronic Disease; Development; Dexamethasone; Disease; Donor person; Enzymes; Epithelial Cells; Experimental Models; Extrinsic asthma; Goals; Healthcare; Hematopoietic; Human; In Vitro; Individual; Inflammation; Link; Lung; Measures; Mediating; Metabolism; Methods; Modality; Modeling; Molecular; Mus; NOS2A gene; Nitric Oxide Synthase; Ovalbumin; Oxidoreductase; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Physiological; Prevalence; Property; Protein Isoforms; Proteins; Proteomics; Pyroglyphidae; Risk; Role; S-Nitrosoglutathione; S-Nitrosothiols; Societies; Source; Supplementation; Therapeutic; Toxic effect; Treatment Efficacy; United States; Up-Regulation; aerosolized; airway hyperresponsiveness; airway inflammation; airway obstruction; airway remodeling; asthmatic airway; base; care burden; cell type; in vivo; inhibitor/antagonist; methacholine; mouse model; promoter; protein expression; public health relevance; response; small molecule

DESCRIPTION (provided by applicant): Asthma is a chronic disease characterized by airway inflammation, reversible airway obstruction and airways hyperresponsiveness (AHR). Levels of the endogenous bronchodilator S-nitrosoglutathione (GSNO) are reduced in the airways of asthmatics, and recently, a GSNO-metabolizing enzyme (GSNO reductase; GSNOR) has been identified as a potential modifier of AHR in human asthma. In the lungs of allergen- challenged mice, we observe upregulation of GSNOR and decreased S-nitrosothiols (SNOs), concomitant with increased AHR. We hypothesize that GSNO supplementation via GSNOR inhibition may provide a new avenue for asthma therapy, and in preliminary studies, we have found in mice that inhalation of a small-molecule GSNOR inhibitor (GSNORi) abrogates airway inflammation and protects from allergen-induced AHR. Our specific aims are to: 1) Identify the specific source(s), and levels, of NOS2 that are required for the effects of acute GSNORi administration; 2) Evaluate the therapeutic and potential toxic effects of chronic GSNO/GSNORi versus inhaled corticosteroid (ICS) therapy in a chronic model of HDM challenge; and 3) Identify targets of GSNOR inhibition in primary human airway epithelial cells. Completion of these specific aims will critically advance our understanding of the potential impact and limitations of GSNO- based therapies as acute and chronic treatments for asthma. !

描述（申请人提供）：哮喘是一种以气道炎症、可逆性气道阻塞和气道高反应性（AHR）为特征的慢性疾病。哮喘患者气道中内源性支气管扩张剂 S-亚硝基谷胱甘肽 (GSNO) 的水平降低，最近，GSNO 代谢酶（GSNO 还原酶；GSNOR）已被确定为人类哮喘 AHR 的潜在调节剂。在过敏原攻击小鼠的肺部，我们观察到 GSNOR 上调和 S-亚硝基硫醇 (SNO) 减少，同时 AHR 增加。我们假设通过 GSNOR 抑制补充 GSNO 可能为哮喘治疗提供新途径，并且在初步研究中，我们发现小鼠吸入小分子 GSNOR 抑制剂 (GSNORi) 可以消除气道炎症并防止过敏原诱导的 AHR。我们的具体目标是： 1) 确定急性 GSNORi 给药效果所需的 NOS2 的具体来源和水平； 2) 在 HDM 挑战的慢性模型中评估慢性 GSNO/GSNORi 与吸入皮质类固醇 (ICS) 治疗的治疗作用和潜在毒性作用； 3) 确定原代人气道上皮细胞中 GSNOR 抑制的靶标。完成这些具体目标将极大地促进我们对基于 GSNO 的疗法作为哮喘急性和慢性治疗的潜在影响和局限性的理解。 ！