Eicosanoid Networks in Aspirin Hypersensitivity

项目摘要 阿司匹林加重的呼吸系统疾病(AERD)是一种常见的严重的特发性疾病 以哮喘、反复鼻息肉和明显的嗜酸性炎症为特征 鼻窦和支气管壁粘膜。这种疾病一直与明显的 半胱氨酸白三烯产生失调，并伴有隐匿的血小板过度激活。这 提案将侧重于了解这两个特征如何驱动心脏的病理生理 疾病。中心假设是自分泌，LTC4介导的血小板激活途径 在推动与AERD相关的夸大的2型免疫病理中发挥了关键作用， 并且是对ASA的病理性反应的中心。血小板相关的CysLT2R和HMGB1 对于这些功能来说，每个都是必需的。一个必然的假设是，血小板的中和 水杨酸(SA)诱导的HMGB1参与了ASA治疗AERD的疗效。我们 将使用新创造的转基因小鼠，一种新的AERD模型，以及来自 仔细地刻画了人类受试者的特征，以检验这一假设。拟议的研究将揭示 AERD的潜在致病机制并确定可恢复的治疗靶点 正常的动态平衡，并首次将CysLT2R整合到AERD的病理生理学中。

Project Summary Aspirin-exacerbated respiratory disease (AERD) is a common, severe idiopathic disorder characterized by asthma, recurrent nasal polyposis, and marked eosinophilic inflammation of the sinonasal and bronchial mucosa. The disease is consistently associated with markedly dysregulated cysteinyl leukotriene production, and with cryptic over-activation of platelets. This proposal will focus on understanding how these two features drive the pathophysiology of the disease. The central hypothesis is that an autocrine, LTC4-mediated platelet activation pathway plays a critical role in driving the exaggerated type 2 immunopathology associated with AERD, and is central to pathognomonic reactions to ASA. Platelet-associated CysLT2R and HMGB1 are each necessary for these features. A corollary hypothesis is that neutralization of platelet HMGB1 by salicylic acid (SA) contributes to the therapeutic effect of ASA therapy in AERD. We will use newly created transgenic mice, a novel model of AERD, and cells and tissues from carefully characterized human subjects to test the hypothesis. The studies proposed will reveal potential causative mechanisms in AERD and identify therapeutic targets that could restore normal homeostasis, and are the first to integrate CysLT2R into AERD pathophysiology.