# Mast Cell Activation as a Common Mechanism of Pulmonary Toxicity by Chemical Threat Agents

> **NIH NIH R56** · UNIVERSITY OF COLORADO DENVER · 2023 · $462,501

## Abstract

Project Abstract
The Department of Homeland Security considers numerous chemical threat agents a concern for human health,
specifically those that are acute pulmonary toxicants. In acute lung injury, inflammation is critical thus we propose
that inflammation is a common mechanism of lung injury caused by chemical threat agents due to mast cell
activation through non-IgE mechanisms. We and others have shown mast cell activation to be critical in response
to a wide range of xenobiotics including nitrogen mustard, ozone, diesel exhaust, insecticides/herbicides,
cigarette smoke, heavy metals and nanoparticles as examples. Mast cells are a logical cell type to study in
pulmonary injury from chemical threat agents due to 1) their location at interfaces with the external environment
(e.g., lung); 2) their roles as sensors for initiating both innate and adaptive immune responses; and 3) their
immediate response to danger signals through degranulation and release of preformed mediators. We have
demonstrated that mast cell activation is a major contributor to the pulmonary toxicity and inflammation observed
following nitrogen mustard (NM) exposure, a surrogate of sulfur mustard. Currently there are few shared
mechanisms which have been identified between these chemical threat agents, thus identification of common
pathways would be beneficial for future therapeutic targets and biomarkers of exposure. We propose to examine
common mechanisms using three specific classes of chemicals (alkylating agents (NM), pesticides (chloropicrin),
and industrial chemicals (formaldehyde)). Our overall hypothesis is that activation of mast cells by nitrogen
mustard, formaldehyde, and chloropicrin is a common initiating step in recruitment and propagation of
immune responses in the lung. In aims 1 and 2 we will use mast cell deficient mice to investigate pulmonary
inflammation and injury and in aim 3 a human mast cell line to further examine mechanisms by which these
agents lead to mast cell activation. In aim 1, we will determine the in vivo contribution of mast cells in pulmonary
injury, toxicity, and altered function resulting from chemical threat exposures using WT and mast cell deficient
mice. In aim 2 we will examine bioactive lipid profiles and their contribution to pulmonary injury and toxicity from
chemical threat exposures from aim 1 plasma and bronchoalveolar lavage samples based on published data
with NM that shows increased pro-inflammatory bioactive lipid release upon exposure. Lastly, in aim 3 we will
elucidate the role non-IgE mast cell activation through the Mas-Related G-Protein Coupled Receptor
(MRGPRX2), in mast cells exposed chemical threat exposures using ROSA cells deficient in MRPGRX2 to
identify a novel target. Collectively, our goal is to establish activation of mast cells via MRPGRX2 as a common
mechanism across several chemical classes which are linked with pulmonary toxicity. Secondly, we will identify
novel therapeutic targets for prevention and/...

## Key facts

- **NIH application ID:** 10887265
- **Project number:** 1R56ES034386-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** ALISON K BAUER
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $462,501
- **Award type:** 1
- **Project period:** 2023-08-20 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887265

## Citation

> US National Institutes of Health, RePORTER application 10887265, Mast Cell Activation as a Common Mechanism of Pulmonary Toxicity by Chemical Threat Agents (1R56ES034386-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10887265. Licensed CC0.

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