Aspirin exacerbated respiratory disese (AERD) is characterized by severe rhinosinusitis and nasal polposis, as well as asthma that is often severe. We and others have previously demonstrated that the pathophysiology of AERD involves a marked contribution from the 5-lipoxygenase (5-LO) pathway, particularly the cysteinyl leukotrienes and their stable end-product, leukotriene (LT)E4. Our colleagues in Project 1 have found that EP2 receptors are markedly deficient on platelets and leukocytes from individuals with AERD, resulting in markedly increased circulating platelet-leukocyte aggregates (a potential source of LTC4 that gives rise to LTE4). In this Project, we propose a proof-of-principle, double-blind, placebocontrolled crossover trial of prasugrel (a widely used P2Y12 receptor antagonist) in AERD to test the hypothesis that P2Y12 receptors, due to their role in platelet activation in general and LTE4-mediated pulmonary inflammation in particular, are viable therapeutic targets in AERD. In addition, we have shown with our colleagues in Project 1 that leukocytes from individuals with AERD express markedly lower levels of COX-2 mRNA and protein, and generate less COX-2-dependent PGE2 relative to leukocytes from nonasthmatic and aspirin tolerant asthmatic (ATA) control subjects. Desensitization followed by treatment with aspirin for 2 months restores both COX-2 expression and COX-2-dependent PGE2 production on a cellular level, while abrogating the cellular generation of thromboxane A2.
In Aim 2 of this project, we will use an intervention with aspirin desensitiztion determine the molecular basis for COX-2 defciency and to test the hypothesis that a deficiency in COX-2-derived PGE2 accounts for aspirin intolerance in AERD, and that restoring COX-2 function is a mechanism for the efficacy treatment with aspirin after desensitization. These mechanistic intervention studies are urgently needed to develop improved treatment and identify causal mechanisms for AERD.
AERD is a severe disease for which there are few effective treatments. This project will test the effect of a new treatment for AERD, prasugrel, which is a drug used commonly to prevent heart attack and stroke, and will determine why cells from patients with AERD do not generate sufficient amounts of a chemical called PGE2. These studies will lead to new treatments for AERD and asthma.
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