Lipidomic and Transcriptome Signatures in Aspirin-Exacerbated Respiratory Disease

描述（由申请人提供）：阿司匹林加重呼吸系统疾病（AERD）的特征是上呼吸道和下呼吸道持续慢性炎症，导致慢性鼻窦炎、鼻息肉病和哮喘。当患有AERD的个体摄入阿司匹林或其他环加氧酶1抑制剂时，他们的鼻窦炎会急性恶化，并伴有急性支气管收缩，这可能危及生命。约10%的成人哮喘患者患有AERD，但其根本机制尚不清楚。生物化学上，AERD的特征是类二十烷酸生成和功能异常。在基线时，半胱氨酸白三烯的生成增加，并在环加氧酶1的抑制下进一步释放。支气管收缩剂对白三烯E4的反应增强。AERD患者呼吸组织中1型半胱氨酸白三烯受体表达增加，环氧化酶2和前列腺素E2 2型受体表达减少。我们的初步数据表明，AERD患者的呼吸组织将花生四烯酸快速代谢为至少三种主要代谢物，其中一种是15-HETE；另外两种代谢物尚未确定。这种异常的类二十烷酸特征表明，先前未被识别的花生四烯酸代谢物参与了AERD的病理生物学。AERD的类二十烷酸生成和反应性异常缺乏一个连贯的解释，最先进的技术尚未应用于他们的研究。我们建议使用两种最先进的技术来解决AERD的基本机制。我们将使用序列液相色谱/串联质谱法对AERD患者鼻息肉组织产生的脂质介质进行全面分析，并将其与慢性鼻窦炎患者的阿司匹林耐受哮喘患者进行比较。我们将把这与来自同一个体的鼻息肉转录组的全基因组分析结合起来。这种联合方法将使我们能够评估AERD中的基因表达特征，以富集炎症过程和脂质介质生成异常的定义功能基因网络。成功将导致我们对AERD的理解取得重大突破，将刺激AERD新治疗方法的开发，并将允许开发新的诊断工具，这些工具确实依赖于潜在危险的阿司匹林体内激发试验。公共卫生相关性：哮喘是一种常见病，影响了美国约15%的人口，大约十分之一的哮喘成人患者在摄入阿司匹林或类似止痛药后出现危及生命的哮喘发作。这些人患有使人衰弱的鼻窦疾病和严重的哮喘。本提案的目的是利用最先进的对阿司匹林加重呼吸系统疾病患者气道中产生的脂质介质和表达的基因的分析，以便为这种疾病的机制、诊断和治疗提供关键的新见解。

DESCRIPTION (provided by applicant): Aspirin-exacerbated respiratory disease (AERD) is characterized by persistent chronic inflammation of the upper and lower airways leading to chronic rhinosinusitis, nasal polyposis, and asthma. When individuals with AERD ingest aspirin or other inhibitors of cyclooxygenase 1 they develop acute worsening of their rhinosinusitis accompanied by acute bronchoconstriction that may be life-threatening. AERD affects ~10% of adults with asthma, yet the fundamental underlying mechanisms remain unknown. Biochemically, AERD is characterized by abnormalities in eicosanoid generation and function. There is increased generation of cysteinyl leukotrienes at baseline and further release in response to inhibition of cyclooxygenase 1. The bronchoconstrictor response to leukotriene E4 is increased. Respiratory tissues of individuals with AERD show increased expression of the type 1 cysteinyl leukotriene receptor and diminished expression of cyclooxygenase 2 and the type 2 receptor for prostaglandin E2. Our preliminary data indicate that respiratory tissue from individuals with AERD avidly metabolize arachidonic acid to at least three major metabolites, one of which we identified at 15-HETE; the other 2 metabolites have not been identified. This strikingly abnormal eicosanoid profile indicates the involvement of previously unrecognized arachidonate metabolites in the pathobiology of AERD. The abnormalities in eicosanoid generation and responsiveness in AERD lack a coherent explanation, and state-of-the-art technology has not been applied to their investigation. We propose to use two state-of-the-art techniques to address the fundamental mechanisms of AERD. We will use sequential liquid chromatography/tandem mass spectrometry to provide a comprehensive analysis of the lipid mediators generated by nasal polyp tissue from individuals with AERD compared to aspirin-tolerant asthmatics with chronic rhinosinusitis. We will combine this with genome-wide analysis of the transcriptome of nasal polyps from the same individuals. This combined approach will allow us to evaluate the gene expression signature in AERD for enrichment of defined functional gene networks that underlie the inflammatory process and the abnormalities in lipid mediator generation. Success will lead to a significant break-through in our understanding of AERD, will spur the development of new treatments for AERD, and will allow the development of novel diagnostic tools that do rely on potentially dangerous in vivo provocation tests with aspirin. PUBLIC HEALTH RELEVANCE: Asthma is a common disease that affects about 15% of the population of the United States, and about one in every ten adults with asthma develops life-threatening attacks of asthma when they ingest aspirin or similar analgesics. These individuals suffer from debilitating sinus disease and severe asthma. The aim of this proposal is to use state-of-the art analyses of the lipid mediators that are generated and the genes that are expressed in the airways of individuals with aspirin-exacerbated respiratory disease in order to provide key new insights into the mechanisms of this disease, its diagnosis, and its treatment.