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

前列腺素 D2：阿司匹林加重呼吸系统疾病的关键介质

• 批准号: 9332401
• 负责人: Tanya Maria Laidlaw
• 金额: $ 44.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332401
• 关键词: Accounting; Acute; Address; Adult; Affect; Anosmia; Arachidonate 5-Lipoxygenase; Aspirin; Asthma; Basophils; Bronchoconstriction; Bronchoconstrictor Agents; Cells; Characteristics; Chemotactic Factors; Chemotaxis; Chronic; Chronic Disease; Clinical; Congestive; Cyclooxygenase Inhibitors; Data; Diagnosis; Disease; Disease Progression; Dose; Effector Cell; Eicosanoids; Etiology; Exanthema; Family; Frequencies; Generations; Human; Hypersensitivity; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Leukotrienes; Leukotrienes A; Life; Life Experience; Lipoxygenase Inhibitors; Lymphoid Cell; Mediating; Mediator of activation protein; Medical; Metabolism; Morbidity - disease rate; Nasal Polyps; Nose; Operative Surgical Procedures; Pain; Patients; Pharmaceutical Preparations; Polyps; Population; Production; Prostaglandin D2; Prostaglandin Production; Pulmonary Function Test/Forced Expiratory Volume 1; Reaction; Receptor Activation; Recruitment Activity; Recurrence; Respiratory System; Respiratory tract structure; Role; Sinus; Source; Stomach; Symptoms; Syndrome; Therapeutic; Tissues; United States; Zileuton; allergic response; aspirin-exacerbated respiratory disease; asthmatic; cell motility; cyclooxygenase 1; cysteinyl-leukotriene; cytokine; defined contribution; desensitization; effective therapy; eicosanoid metabolism; eosinophil; eosinophilic inflammation; falls; improved; inhibitor/antagonist; insight; mast cell; peripheral blood; polyposis; prevent; public health relevance; receptor; respiratory; urinary

 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.

 描述（由适用提供）：阿司匹林过度呼吸道疾病（AERD），也称为Samper的三合会，是一种免疫介导的炎症综合征，影响哮喘患者的7％，患有严重哮喘患者中有14％。患有AERD的患者患有哮喘和严重的慢性鼻窦疾病，伴有侵袭性鼻息肉病，导致鼻阻塞和鼻窦疼痛的持续症状，并且需要多次手术去除息肉。 AERD患者还会对阿司匹林和其他环氧酶-1的其他抑制剂产生过敏性。摄入这些药物会引起急性，偶尔威胁生命，哮喘发作，这是通过增加鼻塞，流鼻涕，有时甚至失速的疼痛和皮疹来实现的。尽管综合征的发病率及其在成年哮喘患者中的频率，但对其病因或潜在机制知之甚少。现有的数据指出了类eicosanoids在AERD中的代谢和作用中的基本异常。 AERD中的气道对白细胞环三烯（Cyslts）的支气管收缩作用过敏，eicosanoid家族的一部分，Cyslts被认为是阿司匹林诱导的反应的主要作用。但是，尽管Cyslt1r拮抗剂和5-脂氧合酶抑制剂Zileuton确实减轻了某些症状，但它们并不均匀，并且不会改变慢性病病程。此外，高剂量阿司匹林疗法是唯一通过降低息肉调节速率来改变疾病进展的药物，对CYSLT的产生没有影响。我们的小组最近表明，除了CYSLT外，与耐阿司匹林耐药哮喘对照相比，AERD的前列腺素D2（PGD2）D2（PGD2）（PGD2）的尿代谢物更高，而PGD-M则在阿司匹林诱导的反应过程中进一步增加，尤其是在具有最严重的临床临床反应的受试者中。 Given these findings, we hypothesize that 1) PGD2 is a crucial effector eicosanoid in AERD that contributes to both the chronic eosinophilic respiratory tissue injection 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 theory benefits由这种疗法提供。为了解决我们的假设，我们提出以下目的：目标1：定义PGD2对AERD患者的慢性病状态和嗜酸性呼吸道感染的贡献。 AIM 2：确定阿司匹林诱导的AERD反应期间急性PGD2释放的生物学和临床后果。 AIM 3：确定阿司匹林诱导的PGD2抑制是否与AERD患者的治疗益处有关。这些目标的完成，包括人类研究和对患者材料的体外研究，将使对PGD2在AERD病因中的免疫病理生理作用有更透彻的了解，并将提供对诊断和治疗该综合征的新方法的见解。