# Immunopathology of Indirect Airway Hyperresponsiveness in Asthma

> **NIH NIH K24** · UNIVERSITY OF WASHINGTON · 2020 · $129,206

## Abstract

Project Summary
Indirect airway hyperresponsiveness (AHR) is a fundamental feature of asthma, yet the immunopathology of
this critical aspect of asthma remains incompletely understood. In contrast to other features of asthma such as
direct AHR to methacholine challenge and airflow obstruction that are present in other lung diseases, indirect
AHR is a unique and specific feature of asthma. We have examined the pathogenesis of exercise-induced
bronchoconstriction (EIB) as a prototypical feature of indirect AHR. In cross sectional studies, EIB is present in
30-50% of subjects with asthma, and can be ascertained precisely by a dry air exercise challenge test. In
addition, subjects with EIB in the absence of other features of asthma have a high risk of progression to other
aspects of the asthma syndrome, further verifying the fundamental relationship between indirect AHR and
asthma. Our research on the pathogenesis of EIB has revealed that subjects with EIB have high levels of
eicosanoids such as leukotrienes (LT) in their airways, as well as epithelial shedding into the airway lumen.
Following exercise challenge, we have identified mast cell (MC) degranulation and sustained release of
eicosanoids. As we have worked to unravel the basis of these alterations in the airway function, we have
identified a secreted phospholipase A2 (sPLA2) that serves as a regulator of eicosanoid synthesis and is
elevated in the airways of subjects with asthma, and discovered infiltration of the airway epithelium with MCs
that have a distinct phenotype in subjects with EIB. Thus, the overall goal my research program is to
understand the alterations in the airways that lead to indirect AHR in humans. Based on our initial
observations, we hypothesize that epithelial-derived sPLA2 group X (sPLA2-X) serves as a key regulator of
innate cells including MCs, leading to the generation of products such as LTs that mediate bronchoconstriction
through the sensory nerves, leading to goblet cell degranulation and smooth muscle constriction. In the first
aim, we use airway samples and primary epithelial cell culture models to examine the regulation and function
of epithelial sPLA2-X. In the second aim, we determine differences in the number and proliferation potential of
MC progenitors in the airways, and whether these cells serve as a critical source of IL-13 in asthma. In the
final aim, we use design-based stereology to examine the cellular and structural basis of indirect AHR in
asthma using airway biopsy samples from informative groups of subjects with and without asthma. These
projects will move the field forward through a better understanding of the structural and molecular basis for
indirect AHR in asthma, and will serve to train the next generation of patient-oriented researchers in this
important area.

## Key facts

- **NIH application ID:** 9838145
- **Project number:** 5K24AI130263-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Teal S. Hallstrand
- **Activity code:** K24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $129,206
- **Award type:** 5
- **Project period:** 2017-01-18 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838145

## Citation

> US National Institutes of Health, RePORTER application 9838145, Immunopathology of Indirect Airway Hyperresponsiveness in Asthma (5K24AI130263-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9838145. Licensed CC0.

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