Pathophysiologic and Therapeutic Mechanisms in Aspirin Exacerbated Respiratory Disease

摘要 这个哮喘和过敏性疾病合作研究中心(AADCRC)继续关注 阿司匹林加重的呼吸系统疾病(AERD)的机制基础，一种独特的临床综合征 在严重哮喘和复发性鼻息肉患者中占不成比例的比例。 AERD与肥大细胞(MC)的异常/持续性激活和半胱氨酸基的产生有关 白三烯(CysLts)。这两个特征在病态临床反应中明显地进一步诱发。 阿司匹林或其他非选择性环氧合酶(COX)抑制剂，反映体内平衡受损 前列腺素E_2合成系统。在当前的支持期间，我们发现了以下关键角色 血小板和T前列腺素(TP)受体在AERD发病机制中的作用 MC来源的PGD2和血栓烷(TX)A2在驱动持续性呼吸道炎症中的作用 这种疾病。我们现在发现，来自激活的结构细胞的细胞因子的表达显著增加 AERD患者鼻组织中IL-33和胸腺间质淋巴生成素的变化 与AT控制系统相比。此外，我们发现CysLTs在体内作用于(A)孟鲁司特耐药受体(S)。 为了推动IL-33的过度生产，AERD中的MC激活通过一种独特的IL-33驱动的机制发生，并且 IL-33和TSLP诱导MC来源的PG作为效应器放大2型炎症。一支高素质的团队 具有互补技能的有成就的研究人员将应用细胞、分子和整个动物 策略，结合概念验证临床试验，以确定这些发现的机制基础， 它们与疾病病理生理学的相关性，以及它们对治疗的适应性。项目1(J.Boyce，Pi)专注于 IL-33、TSLP和PGE2改变鼻息肉MC功能的机制及生理作用 后果。项目2(N.Barrett，Pi)将确定驱动肺IL-33的细胞类型和cysLT受体 并将确定IL-33和PGE2在确定转录图谱中的作用。 AERD环境中的小鼠和人类MC。项目3(E.以色列，PI)将确定TP受体的疗效 阻断阿司匹林临床反应的严重性，并将确定TP阻断是否阻断 致病前馈循环。这些项目由各自的行政核心(核心A)支持， 基因组学/信息学/统计学(核心B)和样本生物库和分析(核心C)。

Abstract This Asthma and Allergic Disease Cooperative Research Center (AADCRC) continues its focus on the mechanistic basis of aspirin-exacerbated respiratory disease (AERD), a distinctive clinical syndrome that accounts for a disproportionate percentage of individuals with severe asthma and recurrent nasal polyps. AERD is associated with aberrant/persistent mast cell (MC) activation and generation of the cysteinyl leukotrienes (cysLTs). Both features are markedly further induced during pathognomonic clinical reactions aspirin or other nonselective inhibitors of cyclooxygenase (COX), reflecting impairements in the homeostatic prostaglandin (PG)E2 synthetic system. In the current period of support, we discovered critical roles for platelets and T prostanoid (TP) receptors in AERD pathogenesis, and uncovered a strong contribution from MC-derived PGD2 and thromboxane (TX)A2 in driving the persistent respiratory inflammation associated with the disease. We now find remarkably increased expressions of cytokines derived from activated structural cells (interleukin 33 (IL-33) and thymic stromal lymphopoietin (TSLP)) in the nasal tissue of subjects with AERD compared to AT controls. Additionally, we found that cysLTs act in vivo at (a) montelukast-resistant receptor(s) to drive IL-33 overproduction, that MC activation in AERD occurs by a unique IL-33-driven mechanism, and that IL-33 and TSLP elicit MC-derived PGs as effectors to amplify type 2 inflammation. A team of highly accomplished investigators with complementary skills will apply cellular, molecular, and whole animal strategies, combined with a proof-of-concept clincal trial to determine the mechanistic basis for these findings, their relevance to disease pathophysiology, and their amenability to therapy. Project 1 (J. Boyce, PI) focuses on the mechanisms and by which IL-33, TSLP, and PGE2 alter MC function in nasal polyps, and the physiolgic consequences. Project 2 (N. Barrett, PI) will determine the cell types and cysLT receptors that drive lung IL-33 in murine AERD, and will define the contributions of IL-33 and PGE2 in determinng the transcriptional profile of mouse and human MCs in the AERD milieu. Project 3 (E. Israel, PI) will determine the efficacy of TP receptor blockade on the severity of clinical reactions to aspirin, and will determine whether TP blockade interrupts a pathogenic feed-forward loop. The Projects are supported by respective Cores for Adminstration (Core A), Genomics/Informatics/Statistics (Core B), and Sample Biorepository and Analysis (Core C).