Therapeutic Control of Aspirin-Exacerbated Respiratory Disease

阿司匹林加重的呼吸系统疾病(AERD)的特征是严重的鼻窦炎和鼻臭， 以及哮喘，这通常是严重的。我们和其他人之前已经证明了 AERD的病理生理学涉及5-脂氧合酶(5-LO)途径的显著贡献， 尤其是半胱氨基白三烯及其稳定的最终产物白三烯(LT)E4。我们的同事在 项目一发现，个体的血小板和白细胞上的EP2受体明显缺乏 在AERD中，导致循环中的血小板-白细胞聚集显著增加(一个潜在的来源 LTC4，这导致了LTE4)。在这个项目中，我们提出了一个原则证明，双盲，安慰剂控制的 普拉格雷(一种广泛使用的P2Y12受体拮抗剂)在AERD中的交叉试验 假设由于P2Y12受体在总体上和LTE4介导的血小板激活中的作用 尤其是肺部炎症，是AERD可行的治疗靶点。此外，我们还展示了 与我们在项目1中的同事一起，来自AERD患者的白细胞表达明显较低水平的 COX-2mRNA和蛋白，并产生比白细胞更少的COX-2依赖的PGE2 非哮喘和阿司匹林耐受哮喘(ATA)对照组。脱敏后治疗 服用阿司匹林2个月可恢复COX-2的表达和COX-2依赖的PGE2的产生 细胞水平，同时取消血栓素A2的细胞产生。在本项目的目标2中，我们将使用 阿司匹林脱敏干预确定COX-2缺陷的分子基础并测试 假设COX-2衍生的PGE2缺陷是AERD患者阿司匹林不耐受的原因，并且 恢复COX-2功能是阿司匹林治疗脱敏后疗效的机制之一。这些 迫切需要机械干预研究，以发展改进的治疗方法并确定原因 AERD的机制。

Aspirin exacerbated respiratory disese (AERD) is characterized by severe rhinosinusitis and nasal polposis, as well as asthma that is often severe. We and others have previously demonstrated that the pathophysiology of AERD involves a marked contribution from the 5-lipoxygenase (5-LO) pathway, particularly the cysteinyl leukotrienes and their stable end-product, leukotriene (LT)E4. Our colleagues in Project 1 have found that EP2 receptors are markedly deficient on platelets and leukocytes from individuals with AERD, resulting in markedly increased circulating platelet-leukocyte aggregates (a potential source of LTC4 that gives rise to LTE4). In this Project, we propose a proof-of-principle, double-blind, placebocontrolled crossover trial of prasugrel (a widely used P2Y12 receptor antagonist) in AERD to test the hypothesis that P2Y12 receptors, due to their role in platelet activation in general and LTE4-mediated pulmonary inflammation in particular, are viable therapeutic targets in AERD. In addition, we have shown with our colleagues in Project 1 that leukocytes from individuals with AERD express markedly lower levels of COX-2 mRNA and protein, and generate less COX-2-dependent PGE2 relative to leukocytes from nonasthmatic and aspirin tolerant asthmatic (ATA) control subjects. Desensitization followed by treatment with aspirin for 2 months restores both COX-2 expression and COX-2-dependent PGE2 production on a cellular level, while abrogating the cellular generation of thromboxane A2. In Aim 2 of this project, we will use an intervention with aspirin desensitiztion determine the molecular basis for COX-2 defciency and to test the hypothesis that a deficiency in COX-2-derived PGE2 accounts for aspirin intolerance in AERD, and that restoring COX-2 function is a mechanism for the efficacy treatment with aspirin after desensitization. These mechanistic intervention studies are urgently needed to develop improved treatment and identify causal mechanisms for AERD.