PHOSPHOLIPASE ACTIVATION IN ASPIRIN INTOLERANT ASTHMA

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DESCRIPTION (Adapted from applicant's abstract) The Candidate: Esther Langmack, M.D., is a Research Fellow in Pulmonary/Critical Care at the University of Colorado. Dr. Langmack's background includes research experience and publication in the areas of enzyme biochemistry, immunology, and asthma. Her overall career goal is to study the role of lipid-derived mediators in the development and perpetuation of inflammation in asthma at a major academic medial center. Her Sponsor is Dr. Sally Wenzel, who has extensive experience studying the role of leukotrienes in asthma. The research Proposal: Cysteinyl leukotrienes (cLTs) are critical to the pathophysiology of asthma, in general, and aspirin-intolerant asthma in particular. However, the initial enzyme (phospholipase(s), 5-lipoxygenase (5-LO)) leading to cLT production in aspirin-intolerant asthma and the mechanisms behind its activation are unknown. The specific hypothesis to be addressed in this proposal is that an increase in arachidonic acid substrate liberation by phospholipases, in the presence of cyclooxygenase inhibition, drives the rapid production of cLTs by 5-LO in aspirin-intolerant asthmatics. Increased arachidonic acid substrate also facilitates the overproduction of other inflammatory lipid mediators which are not 5-LO pathway products, such as HETEs, lipoxins, and platelet activating factor, leading to broad activation of inflammatory pathways. The relative contribution of the two main phospholipases involved in AA release, secretory phospholipase A2 (sPLA2) and cytosolic phospholipase A2 (cPLA2), to AA release and AA-derived mediator production in AIA, will be determined. The in vivo effect of 5-LO inhibition upon the spectrum of AA-derived mediators produced in AIA will be evaluated. This proposal will further understanding of the steps leading to the generation of lipid mediators in inflammatory conditions and the alteration of these mediators which may occur after 5-LO inhibition. These findings will not only improve the understanding of aspirin-intolerant asthma, but will clarify the regulation of lipid mediators in numerous other inflammatory conditions, as well. The Research Environment: National Jewish Medical and Research Center is an internationally recognized institution devoted to research in the areas of allergy, immunology, pulmonary medicine and infectious diseases. Dr. Langmack's collaborators for this project include Dr. Robert Murphy, Dr. Christina Leslie, and Dr. Jay Westcott, who will share their expertise in lipid mediator analysis. (End of Abstract)