Therapeutic Control of Aspirin-Exacerbated Respiratory Disease

阿司匹林加剧的呼吸系统疾病的治疗控制

• 批准号: 8195751
• 负责人: Elliot Israel
• 金额: $ 48.48万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195751
• 关键词: Accounting; Adenosine Diphosphate; Arachidonate 5-Lipoxygenase; Aspirin; Asthma; Attenuated; Blood Platelets; Breathing; Cells; Characteristics; Chemicals; Clinical; Cross-Over Studies; Cyclooxygenase Inhibitors; Defect; Development; Dinoprostone; Disease; Dose; Double-Blind Method; Drug usage; Eosinophilia; Exhibits; Failure; Functional disorder; G-Protein-Coupled Receptors; Generations; Homeostasis; In Vitro; Individual; Inflammation; Inflammatory; Ingestion; Intervention; Intervention Studies; Lead; Leukocytes; Leukotriene C4; Leukotriene E4; Link; Lung diseases; Mediating; Messenger RNA; Metabolism; Molecular; Mus; Myocardial Infarction; Nose; Obstruction; Oral; Pathway interactions; Patients; Placebo Control; Platelet Activation; Play; Pneumonia; Production; Prostaglandin E Receptor; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Prostaglandins E; Proteins; Pulmonary Eosinophilia; Reaction; Receptor Signaling; Relative (related person); Respiratory physiology; Role; Severities; Source; Stroke; Testing; Therapeutic; Thromboxane A2; Tissues; Treatment Efficacy; base; cyclooxygenase 1; cyclooxygenase 2; cysteinyl-leukotriene; desensitization; double-blind placebo controlled trial; effective therapy; improved; in vivo; inhibitor/antagonist; mouse model; peripheral blood; polyposis; prevent; prostaglandin EP2 receptor; receptor; respiratory; response; rhinosinusitis; therapeutic target; urinary

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.

阿司匹林加剧的呼吸道疾病（AERD）的特征是严重的鼻 - 鼻炎和鼻polposis， 以及通常严重的哮喘。我们和其他人以前已经证明了 AERD的病理生理涉及5-脂氧合酶（5-LO）途径的明显贡献， 特别是半胱氨酸白细胞及其稳定的终产物白细胞（LT）E4。我们的同事们 项目1发现，EP2受体显着缺乏个体的血小板和白细胞 使用AERD，导致循环血小板 - 白细胞骨料显着增加（潜在的来源 LTC4产生LTE4）。在这个项目中，我们提出了原则证明，双盲，安慰剂控制 Prasugrel（一种广泛使用的P2Y12受体拮抗剂）的跨试验，以测试 假设P2Y12受体，由于其在血小板激活中的作用一般和LTE4介导的作用 尤其是肺部炎症，是AERD中可行的治疗靶标。此外，我们已经显示 在项目1中，我们的同事来自AERD Express的个人的白细胞明显较低 Cox-2 mRNA和蛋白质，相对于来自白细胞的Cox-2依赖性PGE2较少 非哮喘和阿司匹林耐受性哮喘（ATA）控制受试者。脱敏然后进行治疗 阿司匹林持续2个月，在A上恢复COX-2表达和COX-2依赖性PGE2的产生 细胞水平，同时废除了血栓烷A2的细胞产生。在该项目的目标2中，我们将使用 与阿司匹林脱感干预确定COX-2缺乏症的分子基础，并测试 假设COX-2衍生的PGE2缺乏对AIRD中的阿司匹林不耐受性说明，并且 恢复COX-2功能是脱敏后阿司匹林疗效治疗的一种机制。这些 迫切需要进行机械干预研究以开发改进的治疗并确定因果关系 AERD机制。