Therapeutic Control of Aspirin-Exacerbated Respiratory Disease

阿司匹林加重性呼吸道疾病（AERD）的特征是严重的鼻窦炎和鼻息肉， 以及通常很严重的哮喘。我们和其他人以前已经证明， AERD的病理生理学涉及来自5-脂氧合酶（5-LO）途径的显著贡献， 特别是半胱氨酰白三烯及其稳定的终产物白三烯（LT）E4。的同事 项目1已经发现，来自个体的血小板和白细胞上的EP 2受体明显缺乏， 与AERD，导致循环血小板-白细胞聚集体（一个潜在的来源， LTC 4产生LTE 4）。在本项目中，我们提出了一个原理验证，双盲，安慰剂对照 普拉格雷（一种广泛使用的P2 Y12受体拮抗剂）治疗AERD的交叉试验， 假设P2 Y12受体，由于其在血小板活化中的作用，一般和LTE 4介导的 特别是肺部炎症是AERD中可行的治疗靶点。此外，我们还表明， 与我们在项目1中的同事一样，来自AERD个体的白细胞表达的 考克斯-2 mRNA和蛋白，并产生较少的考克斯-2依赖性PGE 2相对于白细胞从 非哮喘和阿司匹林耐受性哮喘（ATA）对照受试者。脱敏治疗 阿司匹林2个月可恢复考克斯-2表达和考克斯-2依赖性PGE 2的产生， 细胞水平，同时消除血栓素A2的细胞生成。在本项目的目标2中，我们将使用 阿司匹林脱敏干预确定考克斯-2缺乏的分子基础， 假设考克斯-2衍生的PGE 2缺乏导致AERD中阿司匹林不耐受， 恢复考克斯-2功能是脱敏后阿司匹林有效治疗的机制。这些 迫切需要进行机械干预研究，以开发更好的治疗方法， 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.