Modulation of Asthma by GSNO-based Therapies

描述（由申请人提供）：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。内源性支气管扩张剂s -亚硝基谷胱甘肽（GSNO）水平在哮喘患者气道中降低，最近，一种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。在致敏原刺激小鼠的肺中，我们观察到GSNOR上调，s -亚硝基硫醇（SNOs）降低，同时AHR升高。我们假设通过抑制GSNOR补充GSNO可能为哮喘治疗提供新的途径，并且在初步研究中，我们发现在小鼠中吸入小分子GSNOR抑制剂（GSNORi）可以消除气道炎症并保护过敏原诱导的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)评估慢性GSNO/GSNORi与吸入皮质类固醇（ICS）治疗在慢性HDM挑战模型中的治疗和潜在毒性作用；3)确定GSNOR在人气道上皮细胞中的抑制靶点。完成这些特定目标将极大地促进我们对基于GSNO的治疗作为急性和慢性哮喘治疗的潜在影响和局限性的理解。

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.