# Immunopathology of Indirect Airway Hyperresponsiveness in Asthma

> **NIH NIH K24** · UNIVERSITY OF WASHINGTON · 2024 · $134,071

## Abstract

K24: Immunopathology of Indirect Airway Hyperresponsiveness in Asthma
Project Summary
Indirect or "endogenous" airway hyperresponsiveness (AHR) is a fundamental feature of asthma that is not
fully understood. In contrast to other features of asthma such as airflow obstruction or the response to an
exogenous bronchoconstrictor such as methacholine, endogenous AHR is specific for asthma and replicates
many of the common triggers for asthma including the response to cold/dry air, hypertonic aerosols and
allergens in individuals who are appropriately sensitized. We have focused on exercise-induced
bronchoconstriction (EIB) as a prototypical feature of endogenous AHR because it is a common trigger for
symptoms, has been associated with risk of asthma progression, does not require allergic sensitization and
can be precisely measured in the laboratory. Recent studies from our lab have revealed a shift in the precise
location of mast cells (MCs) in the airways from the submucosa to the epithelium and that MCs and eosinophils
(Eos) interact with the airway epithelium in a manner that serves to propagate airway inflammation. We have
also identified alterations in phospholipid metabolism and a specific enzyme called secreted phospholipase A2
group 10 (sPLA2-X) that is strongly associated with AHR and contributes to the dysregulated lipid mediator
metabolism present in asthmatic airways. The overall goal of my research program is to understand the
underlying alterations in the airways that lead to endogenous AHR in humans. We hypothesize that MCs
and Eos act in concert with the epithelium to promote airway inflammation and that alterations in phospholipid
metabolism play a key role through generation of mediators that serve to activate the sensory nerves. In the
first aim, we determine differences in the number and proliferation potential of MC progenitors in the airways
and utilize ex vivo models to examine how interactions among MCs, Eos and airway epithelial cells (AECs)
serve to propagate airway inflammation. In the second aim, we examine the function of sPLA2-X in innate
immune cells and explore the therapeutic potential of an extracellular inhibitor of this enzyme in a model of
EIB. In the final aim, we use design-based stereology to examine the precise location of cells and structures in
the airway wall and integrate this information with transcriptomic analyses of airway epithelial brushings to
identify the underpinnings of AHR in asthma. These projects move the field forward through a better
understanding of the basis for AHR in asthma and will support the career development of the next generation
of patient-oriented researchers interested in the immunopathology of asthma.

## Key facts

- **NIH application ID:** 10873340
- **Project number:** 5K24AI130263-08
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Teal S. Hallstrand
- **Activity code:** K24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $134,071
- **Award type:** 5
- **Project period:** 2017-01-18 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873340

## Citation

> US National Institutes of Health, RePORTER application 10873340, Immunopathology of Indirect Airway Hyperresponsiveness in Asthma (5K24AI130263-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873340. Licensed CC0.

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