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

 描述(申请人提供)：阿司匹林加重呼吸系统疾病(AERD)，也被称为Samter‘s Triad，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患者患有哮喘和严重的慢性鼻窦病，并伴有侵袭性鼻息肉，导致持续的鼻塞和鼻窦疼痛症状，需要多次手术切除息肉是常见的。AERD患者还会对阿司匹林和其他环氧合酶-1抑制剂产生过敏反应。摄入这些药物会引起急性哮喘发作，有时会危及生命，并伴有日益严重的鼻塞、流鼻涕，有时还会出现胃痛和皮疹。尽管这种综合征的发病率及其在成人哮喘患者中的频率，但对其病因或潜在机制知之甚少。现有数据表明，在AERD中，二十烷类化合物的代谢和作用存在根本性的异常。AERD的呼吸道对半胱氨酸白三烯(CysLts)的支气管收缩作用非常敏感，CysLTs是二十烷基类化合物家族的一部分，被认为是阿司匹林诱导反应的主要效应者。然而，尽管CysLT1R拮抗剂和5-脂氧合酶抑制剂齐鲁通确实缓解了一些症状，但它们并不是一致有效的，也不能改变慢性病的病程。此外，大剂量阿司匹林疗法是唯一被证明可以通过降低息肉再生率来改变疾病进展的药物，对CysLT的产生没有影响。我们的研究小组最近发现，与阿司匹林耐受的哮喘对照组相比，AERD患者除CysLTs外，还存在前列腺素D2(PGD2)的尿代谢物PGD-M，并且在阿司匹林诱导的反应期间，尤其是在临床反应最严重的受试者中，PGD-M进一步增加。鉴于这些发现，我们假设1)PGD2是AERD中一个关键的效应器二十烷类化合物，导致慢性嗜酸性呼吸道组织炎症和摄入阿司匹林后发生的严重超敏反应，以及2)大剂量阿司匹林治疗抑制PGD2的产生阻止效应细胞迁移到呼吸道，从而奠定了该疗法治疗益处的机制。为了解决我们的假设，我们提出了以下目标：目标1：确定PGD2在AERD患者的慢性疾病状态和嗜酸性呼吸道炎症中的作用。目的2：确定急性前列腺素D2释放在阿司匹林诱导的急性呼吸窘迫综合征中的生物学和临床后果。目的3：确定阿司匹林对前列腺素D2的抑制是否与急性呼吸窘迫综合征患者的疗效有关。完成这些目标，包括对患者材料的人体研究和体外研究，将使人们更彻底地了解PGD2在AERD病因中的免疫病理生理学作用，并将为诊断和治疗这种综合征的新方法提供洞察力。

 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.