Eicosanoid Networks in Aspirin Exacerbated Respiratory Disease

描述(由申请人提供)：阿司匹林加重的呼吸系统疾病(AERD)是一种严重的疾病，其特征是哮喘、反复发作的鼻息肉以及鼻窦和支气管粘膜明显的嗜酸性炎症。它占哮喘的5%，在严重哮喘中占不成比例的份额(约30%)。由于缺乏对疾病发病机制的了解，治疗选择受到限制。到目前为止还没有合适的动物模型的报道。这项建议使用一种新的AERD小鼠模型来检验压倒一切的假设，即AERD发生在宿主身上，这些宿主倾向于脂质介体体系中几个相互关联的控制点中的任何一个的异常功能。这些异常导致前列腺素(PG)E2-EP2受体系统无法控制半胱氨酰白三烯(Cys-LTs)的合成和效应作用。叠加的炎性损伤可导致嗜酸性呼吸道炎症显著加重，血栓素A2(TXA2)-T前列腺素(TP)受体系统的下游致病作用增强是最终的共同途径。我们发现，室内粉尘染尘小鼠(缺乏通过可诱导的COX-2酶产生PGE2的能力)，但不是WT对照组，在吸入赖氨酸-阿司匹林(Lys-ASA)时，支气管收缩，并产生比WT对照组高约3倍的Cys-LT。值得注意的是，TP受体的基因缺失或药物阻断完全保护pTGES/-小鼠免受支气管嗜酸性粒细胞增多症、Th2细胞因子的产生和肺ICAM-1的诱导，尽管肺内持续高水平产生Cys-LT。我们现在试图准确地确定在脂质介体层级中个别控制点的扰动如何导致AERD的表型。由于我们的数据表明TP受体可能是AERD的主要治疗靶点，我们也将寻求确定其功能的机制(S)。建议的研究将揭示AERD的潜在致病机制，并确定可以恢复正常内稳态的治疗靶点。

DESCRIPTION (provided by applicant): Aspirin-exacerbated respiratory disease (AERD) is a severe disorder characterized by asthma, recurrent nasal polyposis, and marked eosinophilic inflammation of the sinonasal and bronchial mucosa. It accounts for ~5% of asthma, and for a disproportionate share (~30%) of severe asthma. Therapeutic options are limited by a lack of understanding of disease pathogenesis. No suitable animal model has been reported to date. This proposal uses a novel mouse model of AERD to test the overriding hypothesis that AERD arises in hosts who are predisposed to abnormal function of any one of several interconnected control points of a lipid mediator hierarchy. These abnormalities result in failure of the prostaglandin (PG)E2-EP2 receptor system to control the synthesis and effector actions of cysteinyl leukotrienes (cys-LTs). A superimposed inflammatory insult results in markedly exaggerated eosinophilic respiratory tract inflammation with augmented downstream pathogenetic effects of the thromboxane A2 (TXA2)-T prostanoid (TP) receptor system as a final common pathway. We have found that house dust mite-treated ptges-/- mice (which lack the capacity to produce PGE2 through the inducible COX-2 enzyme), but not WT controls, bronchoconstrict when challenged by inhalation with inhaled lysine-aspirin (Lys-ASA), and generate ~3-fold higher quantities of cys-LTs than do WT controls. Remarkably, genetic deletion or pharmacologic blockade of TP receptors completely protect ptges-/- mice from bronchial eosinophilia, Th2 cytokine generation, and pulmonary ICAM-1 induction despite persistent high level pulmonary cys-LT production. We now seek to determine precisely how perturbations at individual control points in a lipid mediator hierarchy lead to the phenotype of AERD. Because our data suggest that TP receptors may be major therapeutic targets in AERD, we will also seek to identify the mechanism(s) that account for their functions. The studies proposed will reveal potential causative mechanisms in AERD and identify therapeutic targets that could restore normal homeostasis.