Eicosanoid Networks in Aspirin Exacerbated Respiratory Disease

描述（由申请方提供）：阿司匹林加重的呼吸道疾病（AERD）是一种严重的疾病，其特征为哮喘、复发性鼻息肉病和鼻窦和支气管粘膜显著的嗜酸性粒细胞炎症。它约占哮喘的5%，在严重哮喘中的比例不成比例（约30%）。由于对疾病发病机制缺乏了解，治疗选择受到限制。迄今为止尚未报道合适的动物模型。该建议使用一种新的小鼠模型的AERD测试压倒一切的假设，即AERD出现在主机谁是倾向于异常功能的任何一个几个相互关联的控制点的脂质介质层次。这些异常导致前列腺素（PG）E2-EP 2受体系统无法控制半胱氨酰白三烯（cys-LT）的合成和效应作用。一个叠加的炎症损伤导致显着夸大的嗜酸性呼吸道炎症与增强的下游致病作用的血栓烷A2（TXA 2）-T前列腺素（TP）受体系统作为一个最终的共同途径。我们发现，屋尘螨处理的ptges-/-小鼠（缺乏通过诱导型考克斯-2酶产生PGE 2的能力），而非WT对照，在吸入赖氨酸-阿司匹林（Lys-ASA）激发时支气管收缩，并产生比WT对照高约3倍的cys-LT。值得注意的是，TP受体的基因缺失或药理学阻断完全保护ptges-/-小鼠免受支气管嗜酸性粒细胞增多、Th 2细胞因子产生和肺ICAM-1诱导，尽管持续高水平的肺cys-LT产生。现在，我们试图精确地确定如何在个别控制点的脂质介质层次的扰动导致AERD的表型。因为我们的数据表明TP受体可能是AERD的主要治疗靶点，我们还将寻求确定解释其功能的机制。这些研究将揭示AERD的潜在致病机制，并确定可以恢复正常稳态的治疗靶点。

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.