# Pathophysiological Mechanisms of Chemical-Induced Acute Lung Injury

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2024 · $483,848

## Abstract

Project Summary
The overall goal of this application is to determine the sequence of key events that leads to the pathological
progression elicited after acrolein and phosgene inhalation. Chemically-induced acute lung injury (CIALI) is a
form of acute respiratory distress syndrome (ARDS). ARDS is characterized by loss of alveolar barrier function
that leads to increased protein and neutrophil infiltration into the alveolar air space. Currently, ARDS therapy is
mainly limited to managed mechanical ventilation, and the mortality rate remains high. Mortality is influenced by
sex, age, and genetic susceptibility in patients, which can be experimentally modeled in mice. A major CIALI risk
factor is smoke inhalation and the main irritant in smoke is acrolein. Death can be immediate or delayed resulting
from a complex cellular and pulmonary responses that progress with time and dictate the severity of the injury.
Another chemical that can induce delayed pulmonary edema is phosgene, which was develop as a chemical
weapon in World War I. Currently, it is unknown whether acrolein and phosgene produce CIALI by the same
overlapping mechanisms or by mechanisms unique to each chemical. To develop effective therapeutic
interventions, more studies are needed to understand the disease-progression and injury-resolution mechanisms
underlying severity of injury and mortality. This proposal has the following Specific Aims: 1. Determine the
temporal events of sensitivity and resistance to acrolein-induced acute lung injury, 2. Delineate critical pathways
in acrolein-induced CIALI progression and resolution using multiomic analyses, and 3. Compare and contrast
the progression of phosgene-induced CIALI to that of acrolein-induced CIALI. Detailed time course analyses will
evaluate bronchoalveolar lavage, lung histopathology, spatial lipidomics, spatial metabolomics and single-cell
and spatial transcriptomics following acrolein or phosgene exposure. Strain- and sex-specific responses will be
investigated. Determining the sequence of key pathological events controlling the progression and resolution of
acute lung injury elicited by acrolein and phosgene should provide a mechanistic basis for the development of
therapy.

## Key facts

- **NIH application ID:** 10910056
- **Project number:** 5R01ES034490-02
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** George Douglas Leikauf
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $483,848
- **Award type:** 5
- **Project period:** 2023-08-20 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10910056

## Citation

> US National Institutes of Health, RePORTER application 10910056, Pathophysiological Mechanisms of Chemical-Induced Acute Lung Injury (5R01ES034490-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10910056. Licensed CC0.

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