# Mitochondrial DNA Injury is a Key Contributor to the Development of Chemical Lung Injury

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $654,190

## Abstract

Accidental exposure to chlorine (Cl2) causes potentially fatal lung injury accompanied, in survivors, by reactive
airway disease and pulmonary fibrosis resembling symptoms typical of the acute respiratory distress syndrome
(ARDS). Our preliminary data also document that the mitochondrial genome–the integrity of which is critical to
maintenance of normal bioenergetics and mitochondrial signaling activities– displays oxidative damage after Cl2
gas exposure, similar to that detected in other models of acute and chronic lung injury. Against this background,
here we propose to test the hypothesis that an early molecular target in Cl2 gas inhalation is the
mitochondrial (mt) genome, in which oxidative damage functions as a molecular sentinel leading to
activation of pro-inflammatory pathways that drive acute lung injury and progressive lung remodeling.
To address this hypothesis we will perform the following in vivo and in vitro studies outlined in the following three
aims: Aim 1. Define the kinetics of lung oxidative mtDNA damage in mice exposed to Cl2 gas and returned to
room air and test whether a novel agent to augmenting mtDNA injury decreases mortality and the severity of
acute and chronic lung injury. Exp. 1.1 will determine the time course of Cl2 gas-induced lung mtDNA damage
and its relation to lung pathophysiology in global (mitochondrial and nuclear) OGG1 knockout mice (OGG1-/-)
and their wild type (WT) controls (C57BL/6), along with OGG1 KO mice reconstituted with mito-targeted OGG1
(OGG1-/-+OGG1mt), while Exp. 1.2 will test if intranasal administration of mitoOGG1 at selected time points after
termination of Cl2 exposure decreases lung injury pulmonary fibrosis and improves survival. Aim 2: Test the
hypothesis that Cl2 gas-induced lung mtDNA damage triggers mobilization of mtDNA Damage Associated
Molecular Patterns (DAMPs) that drive nucleic acid-dependent inflammation and serve as biomarkers and
causative agents of pneumotoxicity. In Exp. 2.1 will use WT, OGG1-/-, and OGG1-/-+OGG1mt mice to test the
hypothesis that OGG1 activity coordinately regulates Cl2 gas-induced mtDNA DAMP accumulation and activation
of nucleic acid receptor-mediated pro-inflammatory pathways. Aim 3: Determine key cellular mechanisms by
which Cl2 gas causes mtDNA damage-dependent lung cell death and dysfunction. In Exp. 3.1 we will isolate
alveolar macrophages (AM) and lung epithelial type II cells (ATII) from WT, OGG1-/-, and OGG1-/-+OGG1mt
mice, and measure oxygen consumption rate, reactive oxygen species, mitochondrial membrane potential, ion
transport and key indices of cell injury prior to and following exposure to Cl2 gas. Additionally, Exp. 3.2 will define
the mtDNA damage-dependent trafficking of mtDNA DAMPs to cytosolic and extracellular compartments and
determine how these two mtDNA DAMP pools interact to dictate pro-inflammatory nucleic acid receptor
activation. As part of this experiment, we also will determine if exogenous mtDNA DAMPs recapitulate nuclei...

## Key facts

- **NIH application ID:** 10594597
- **Project number:** 2R01HL031197-28A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** MARK N GILLESPIE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $654,190
- **Award type:** 2
- **Project period:** 1987-08-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10594597

## Citation

> US National Institutes of Health, RePORTER application 10594597, Mitochondrial DNA Injury is a Key Contributor to the Development of Chemical Lung Injury (2R01HL031197-28A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10594597. Licensed CC0.

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