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)：哮喘是一种慢性疾病，以呼吸道炎症、可逆性呼吸道阻塞和呼吸道高反应(AHR)为特征。哮喘患者呼吸道中内源性支气管扩张剂S-亚硝基谷胱甘肽(GSNO)水平降低，最近发现一种GSNO代谢酶(GSNO还原酶；GSNOR)是哮喘患者AHR的潜在修饰物。在过敏原攻击小鼠的肺中，我们观察到GSNOR的上调和S-亚硝硫醇(SNO)的减少，伴随着AHR的增加。我们假设，通过抑制GSNOR补充GSNO可能为哮喘治疗提供一种新的途径，在初步研究中，我们在小鼠身上发现，吸入小分子GSNOR抑制剂(GSNORi)可以消除呼吸道炎症，保护过敏原诱导的AHR。我们的具体目标是：1)确定急性给予GSNORi所需的NOS2的特定来源(S)和水平；2)在HDM慢性模型中评估GSNO/GSNORi与吸入皮质类固醇(ICS)治疗的疗效和潜在毒性；以及3)确定原代人类呼吸道上皮细胞GSNOR抑制的靶点。完成这些具体目标将极大地促进我们对以GSNO为基础的疗法作为哮喘的急性和慢性治疗的潜在影响和局限性的理解。好了！