This Project will determine the role of T prostanoid (TP) receptors in the pathophysiology of aspirin exacerbated respiratory disease (AERD). TP receptors bind thromboxane A2 (TXA2) with high affinity, and also mediate bronchoconstriction induced by prostaglandin (PG)D2. Using a double blinded, placebo controlled crossover trial of ifetroban, a potent and selective TP receptor antagonist, we will test the central hypothesis that TP receptor signaling on platelets, endothelial cells, and airway smooth muscle promotes persistent eosinophilic respiratory inflammation, drives cysteinyl leukotriene (cysLT) overproduction, facilitates release of innate type 2 cytokines downstream of cysLTs and platelets, and mediates bronchoconstriction in response to TXA2 and PGD2 released by mast cells (MCs) during reactions to aspirin in AERD. As such, TP receptor blockade will interfere with both the cysLT-dependent and -independent features of AERD pathophysiology and interrupt a feed-forward loop that drives the disease.
Aim 1 will determine the efficacy of ifetroban as a treatment for patients with AERD.
Aim 2 will determine the relevance of TP receptor signaling, and the effect of TP receptor blockade, on platelet and MC activation, mediator generation, release of IL-33, and cell recruitment in subjects with AERD at baseline and during clinical reactions to aspirin. The studies are central to the AADCRC, as they seek to validate central hypothetical disease-causing mechanisms inferred by the other two projects, while providing cells and tissues necessary for the completion of these projects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI095219-07
Application #
9294923
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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