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.