Modulation of Asthma by GSNO-based Therapies

基于 GSNO 的疗法调节哮喘

• 批准号: 8601946
• 负责人: Matthew Wolf Foster
• 金额: $ 38.47万
• 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/8601946
• 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（由申请人提供）：哮喘是一种慢性疾病，其特征是气道炎症、可逆性气道阻塞和气道高反应性（AHR）。内源性支气管扩张剂S-亚硝基谷胱甘肽（GSNO）的水平在哮喘患者的气道中降低，最近，GSNO代谢酶（GSNO还原酶; GSNOR）已被确定为人类哮喘中AHR的潜在调节剂。在过敏原激发的小鼠的肺中，我们观察到GSNOR的上调和S-亚硝基硫醇（SNO）的减少，伴随着AHR的增加。我们假设通过GSNOR抑制补充GSNO可能为哮喘治疗提供新的途径，并且在初步研究中，我们在小鼠中发现吸入小分子GSNOR抑制剂（GSNORI）消除气道炎症并保护免受过敏原诱导的AHR。我们的具体目标是：1）鉴定急性GSNORi施用的作用所需的NOS 2的特定来源和水平; 2）在HDM激发的慢性模型中评价慢性GSNO/GSNORi相对于吸入性皮质类固醇（ICS）疗法的治疗和潜在毒性作用;和3）鉴定原代人气道上皮细胞中GSNOR抑制的靶标。这些具体目标的完成将极大地促进我们对基于GSNO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。!