# Pathophysiologic and Therapeutic Mechanisms in Aspirin Exacerbated Respiratory Disease

> **NIH NIH U19** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $1,543,357

## Abstract

Abstract
This Asthma and Allergic Disease Cooperative Research Center (AADCRC) continues its focus on the
mechanistic basis of aspirin-exacerbated respiratory disease (AERD), a distinctive clinical syndrome that
accounts for a disproportionate percentage of individuals with severe asthma and recurrent nasal polyps.
AERD is associated with aberrant/persistent mast cell (MC) activation and generation of the cysteinyl
leukotrienes (cysLTs). Both features are markedly further induced during pathognomonic clinical reactions
aspirin or other nonselective inhibitors of cyclooxygenase (COX), reflecting impairements in the homeostatic
prostaglandin (PG)E2 synthetic system. In the current period of support, we discovered critical roles for
platelets and T prostanoid (TP) receptors in AERD pathogenesis, and uncovered a strong contribution from
MC-derived PGD2 and thromboxane (TX)A2 in driving the persistent respiratory inflammation associated with
the disease. We now find remarkably increased expressions of cytokines derived from activated structural cells
(interleukin 33 (IL-33) and thymic stromal lymphopoietin (TSLP)) in the nasal tissue of subjects with AERD
compared to AT controls. Additionally, we found that cysLTs act in vivo at (a) montelukast-resistant receptor(s)
to drive IL-33 overproduction, that MC activation in AERD occurs by a unique IL-33-driven mechanism, and
that IL-33 and TSLP elicit MC-derived PGs as effectors to amplify type 2 inflammation. A team of highly
accomplished investigators with complementary skills will apply cellular, molecular, and whole animal
strategies, combined with a proof-of-concept clincal trial to determine the mechanistic basis for these findings,
their relevance to disease pathophysiology, and their amenability to therapy. Project 1 (J. Boyce, PI) focuses
on the mechanisms and by which IL-33, TSLP, and PGE2 alter MC function in nasal polyps, and the physiolgic
consequences. Project 2 (N. Barrett, PI) will determine the cell types and cysLT receptors that drive lung IL-33
in murine AERD, and will define the contributions of IL-33 and PGE2 in determinng the transcriptional profile of
mouse and human MCs in the AERD milieu. Project 3 (E. Israel, PI) will determine the efficacy of TP receptor
blockade on the severity of clinical reactions to aspirin, and will determine whether TP blockade interrupts a
pathogenic feed-forward loop. The Projects are supported by respective Cores for Adminstration (Core A),
Genomics/Informatics/Statistics (Core B), and Sample Biorepository and Analysis (Core C).

## Key facts

- **NIH application ID:** 9973135
- **Project number:** 5U19AI095219-10
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Joshua A Boyce
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,543,357
- **Award type:** 5
- **Project period:** 2011-07-15 → 2021-07-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973135

## Citation

> US National Institutes of Health, RePORTER application 9973135, Pathophysiologic and Therapeutic Mechanisms in Aspirin Exacerbated Respiratory Disease (5U19AI095219-10). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9973135. Licensed CC0.

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