Prostaglandin D2: A Key Mediator of Aspirin-Exacerbated Respiratory Disease

 描述（由申请人提供）： 阿司匹林急性呼吸道疾病（AERD），也称为Samter三联征，是一种免疫介导的炎症综合征，影响7%的成人哮喘患者和14%的严重哮喘患者。AERD患者发生哮喘和严重的慢性鼻窦疾病，伴有侵袭性鼻息肉病，导致持续的鼻阻塞和鼻窦疼痛症状，并且需要多次手术切除息肉是常见的。AERD患者还对阿司匹林和其他环氧合酶-1抑制剂过敏。摄入这些药物会引发急性哮喘发作，偶尔危及生命，伴有鼻塞、流鼻涕加重，有时胃痛和皮疹。尽管该综合征的发病率及其在成人哮喘人群中的频率，但对其病因或潜在机制知之甚少。现有的数据表明，AERD中类花生酸的代谢和作用存在根本性异常。AERD患者的气道对类花生酸家族的一部分半胱氨酰白三烯（cysLT）的支气管收缩作用过敏，cysLT被认为是阿司匹林诱导反应的主要效应物。然而，尽管CysLT 1 R拮抗剂和5-脂氧合酶抑制剂齐留通确实减轻了一些症状，但它们并不是一致有效的，也不能改变慢性疾病的病程。此外，高剂量阿司匹林治疗，唯一的药物治疗，以修改疾病的进展，通过降低息肉再生率，对生产cysLT没有影响。我们的研究小组最近表明，除了cysLT，前列腺素D2（PGD 2）的尿代谢产物PGD-M在AERD中比阿司匹林耐受性哮喘对照组更高，并且PGD-M在阿司匹林诱导的反应期间进一步增加，特别是在具有最严重临床反应的受试者中。鉴于这些发现，我们假设：1）PGD 2是AERD中一种关键的效应类花生酸，可导致慢性嗜酸性呼吸组织炎症和摄入阿司匹林后发生的严重超敏反应; 2）高浓度的阿司匹林可抑制PGD 2的产生，剂量的阿司匹林治疗防止效应细胞迁移到呼吸道，因此是这种治疗所提供的治疗益处的机制的基础。疗法为了解决我们的假设，我们提出了以下目的：目的1：确定PGD 2对AERD患者慢性疾病状态和嗜酸性呼吸道炎症的贡献。目的2：确定阿司匹林诱导的AERD反应期间PGD 2急性释放的生物学和临床后果。目的3：确定阿司匹林诱导的PGD 2抑制是否与AERD患者的治疗获益有关。这些目标的完成，包括人体研究和患者材料的体外研究，将导致对PGD 2在AERD病因学中的免疫病理生理作用的更透彻的理解，并将提供对诊断和治疗这种综合征的新方法的见解。

 DESCRIPTION (provided by applicant): Aspirin-Exacerbated Respiratory Disease (AERD), also referred to as Samter's Triad, is an immune-mediated inflammatory syndrome that affects 7% of adults with asthma and 14% of those with severe asthma. Patients with AERD develop asthma and severe chronic sinus disease with aggressive nasal polyposis that causes constant symptoms of nasal blockage and sinus pain, and a need for multiple surgeries to remove polyps is common. Patients with AERD also develop a hypersensitivity to aspirin and other inhibitors of cyclooxygenase-1. Ingestion of these medications elicits an acute, occasionally life-threatening, asthma attack accompanied by increasing nasal congestion, runny nose, and sometimes stomach pain and rash. Despite the morbidity from the syndrome and its frequency in the adult population of asthmatics, little is known about its etiology or underlying mechanisms. Existing data point to fundamental abnormalities in the metabolism and action of eicosanoids in AERD. The airways in AERD are hypersensitive to the bronchoconstrictor effects of cysteinyl leukotrienes (cysLTs), part of the eicosanoid family and cysLTs were thought to be the main effectors of aspirin-induced reactions. However, although CysLT1R antagonists and the 5-lipoxygenase inhibitor zileuton do alleviate some symptoms they are not uniformly effective and do not modify the chronic disease course. Moreover, high-dose aspirin therapy, the only medical therapy shown to modify the progression of the disease by decreasing the rate of polyp regrowth, has no effect on the production of cysLTs. Our group has recently shown that in addition to cysLTs, a urinary metabolite of prostaglandin D2 (PGD2), PGD-M, is higher in AERD compared to aspirin-tolerant asthmatic controls, and PGD-M further increases during aspirin-induced reactions, especially in subjects with the most severe clinical reactions. Given these findings, we hypothesize that 1) PGD2 is a crucial effector eicosanoid in AERD that contributes to both the chronic eosinophilic respiratory tissue inflammation and the severe hypersensitivity reactions that occur upon ingestion of aspirin and 2) the suppression of PGD2 generation by high-dose aspirin therapy prevents effector cell migration into the respiratory tract and thus underlies the mechanism of therapeutic benefit afforded by this therapy. To address our hypotheses we propose the following Aims: AIM 1: Define the contribution of PGD2 to the chronic disease state and the eosinophilic respiratory inflammation in patients with AERD. AIM 2: Determine the biologic and clinical consequences of acute PGD2 release during aspirin-induced reactions in AERD. AIM 3: Determine if the aspirin-induced suppression of PGD2 relates to the therapeutic benefit in patients with AERD. Completion of these aims, including both human studies and in vitro studies of patient material, will result in a more thorough understanding of the immunopathophysiologic role of PGD2 in the etiology of AERD and will provide insight into new ways of diagnosing and treating this syndrome.