# Research Project III - Vesicant-Induced Lung Injury

> **NIH NIH U54** · RBHS-SCHOOL OF PUBLIC HEALTH · 2020 · $1,125,015

## Abstract

Research Project 3. Vesicant-induced Lung Injury
Key Personnel:
Debra L. Laskin, Ph.D., Distinguished Professor, Rutgers University School of Pharmacy
Jeffrey D. Laskin, Ph.D., Professor, Rutgers University School of Public Health
Project Summary/Abstract
Sulfur mustard (SM) and nitrogen mustard are high priority chemical threats that cause debilitating damage to
the respiratory system resulting in both acute and chronic effects. As this is the major cause of morbidity and
mortality in exposed victims, it is essential to identify effective strategies to mitigate pulmonary toxicity caused
by these vesicants. Our studies are focused on macrophages and inflammatory mediators as key to both
acute lung injury and fibrosis induced by vesicants.
We discovered that following mustard exposure, distinct subset of macrophages with proinflammatory/
cytotoxic activity (M1) and profibrotic (M2) activity sequentially appear in the lung. Our objective is to elucidate
the contribution of these macrophage subsets to mustard-induced lung injury and fibrosis, with the overall goal
of identifying new targets for therapeutic intervention. This mechanistic research is essential as macrophages
are known to release numerous cytotoxic and profibrotic mediators; thus, targeting only one product or
macrophage subset is unlikely to be effective in completely mitigating vesicant-induced lung injury. We
hypothesize that M1 macrophages contribute to injury by generating cytotoxic oxidants and TNFα, which cause
lung damage and promote lipid oxidation; oxidized lipids and TNFα upregulate macrophage scavenger
receptors stimulating lipid uptake and the development of M2 macrophage foam cells, which play a key role in
fibrogenesis. To test this hypothesis plans are to (1) elucidate the origin of M1 and M2 inflammatory
macrophages responding to vesicant-induced lung injury and mechanisms mediating their accumulation in the
lung; (2) Evaluate the role of oxidized lipids and M1 and M2 macrophages in foam cell formation and vesicant-
induced fibrosis, and (3) Assess the contribution of TNFα to vesicant-induced acute lung injury and lung
fibrosis. An innovative combination of strategies will be used for our studies including lineage tracking, the
generation of chimeric mice, adoptive transfer and monocyte/ macrophage depletion. We will also work closely
with the Center's Pharmaceutics and Medicinal Chemistry Support Core to refine a microparticle lung drug
delivery system designed to specifically target profibotic M2 macrophages and with the Pharmacology and
Drug Development Support Core to move one of our lead countermeasures for vesicant-induced lung injury
into advanced drug development. Successful completion of our proposed studies will result in a more precise
understanding of the specific roles of macrophages in vesicant-induced toxicity, their origin, and mechanisms
mediating their accumulation in the lung. This will have significant implications for the development of more
effica...

## Key facts

- **NIH application ID:** 9982785
- **Project number:** 5U54AR055073-15
- **Recipient organization:** RBHS-SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** Debra L Laskin
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,125,015
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982785

## Citation

> US National Institutes of Health, RePORTER application 9982785, Research Project III - Vesicant-Induced Lung Injury (5U54AR055073-15). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9982785. Licensed CC0.

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