Aspirin-exacerbated respiratory disease (AERD) is a common, severe idiopathic disorder characterized by asthma, recurrent nasal polyposis, and marked eosinophilic inflammation of the sinonasal and bronchial mucosa. The disease is consistently associated with markedly dysregulated cysteinyl leukotriene production, and with cryptic over-activation of platelets. This proposal will focus on understanding how these two features drive the pathophysiology of the disease. The central hypothesis is that an autocrine, LTC4-mediated platelet activation pathway plays a critical role in driving the exaggerated type 2 immunopathology associated with AERD, and is central to pathognomonic reactions to ASA. Platelet-associated CysLT2R and HMGB1 are each necessary for these features. A corollary hypothesis is that neutralization of platelet HMGB1 by salicylic acid (SA) contributes to the therapeutic effect of ASA therapy in AERD. We will use newly created transgenic mice, a novel model of AERD, and cells and tissues from carefully characterized human subjects to test the hypothesis. The studies proposed will reveal potential causative mechanisms in AERD and identify therapeutic targets that could restore normal homeostasis, and are the first to integrate CysLT2R into AERD pathophysiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI136041-06
Application #
9607566
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Dong, Gang
Project Start
2017-12-04
Project End
2022-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
6
Fiscal Year
2019
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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Pan, Dingxin; Buchheit, Kathleen M; Samuchiwal, Sachin K et al. (2018) COX-1 mediates IL-33-induced extracellular signal-regulated kinase activation in mast cells: Implications for aspirin sensitivity. J Allergy Clin Immunol :
Kondeti, Vinay; Al-Azzam, Nosayba; Duah, Ernest et al. (2016) Leukotriene D4 and prostaglandin E2 signals synergize and potentiate vascular inflammation in a mast cell-dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3. J Allergy Clin Immunol 137:289-298