Pathophysiologic and Therapeutic Mechanisms in Aspirin Exacerbated Respiratory Disease

摘要 哮喘和过敏性疾病合作研究中心（AADCRC）继续关注 阿司匹林加剧的呼吸道疾病（AERD）的机制基础，一种独特的临床综合征， 在患有严重哮喘和复发性鼻息肉的个体中占不成比例的比例。 AERD与异常/持续性肥大细胞（MC）活化和半胱氨酰半胱氨酸的产生相关。 白三烯（cysLTs）。这两个特征在特异性临床反应中明显进一步诱导 阿司匹林或其他非选择性环氧合酶（考克斯）抑制剂，反映了体内平衡的损害 前列腺素（PG）E2合成系统。在当前的支持期间，我们发现了以下方面的关键作用： 血小板和T前列腺素（TP）受体在AERD发病机制中的作用，并揭示了来自 MC衍生的PGD 2和血栓烷（TX）A2在驱动与哮喘相关的持续性呼吸道炎症中的作用 这种疾病我们现在发现来自活化结构细胞的细胞因子的表达显著增加 （白细胞介素33（IL-33）和胸腺基质淋巴细胞生成素（TSLP）） 与对照组相比。此外，我们发现cysLT在体内作用于（a）孟鲁司特耐药受体， 为了驱动IL-33过度产生，AERD中的MC活化通过独特的IL-33驱动机制发生， IL-33和TSLP引发MC衍生的PG作为效应物放大2型炎症。有团队高 具有互补技能的熟练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顺应性。项目1（J.博伊斯，PI）侧重于 IL-33、TSLP和PGE 2改变鼻息肉MC功能的机制，以及鼻息肉MC的生理功能。 后果项目2（北）Barrett，PI）将确定驱动肺IL-33的细胞类型和cysLT受体 在小鼠AERD中，并将确定IL-33和PGE 2在确定 小鼠和人MCs在AERD环境中。项目3（E.以色列，PI）将确定TP受体的疗效 阻断对阿司匹林的临床反应的严重程度，并将确定是否TP阻断中断 致病性前馈循环这些项目由各自的管理核心（核心A）支持， 基因组学/信息学/统计学（核心B）和样品生物储存和分析（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).