# Monocyte-derived alveolar macrophage drives inflammatory response to lung ozone exposure

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $630,363

## Abstract

Abstract:
Morbidity and mortality associated with ozone (O3) exposures are a substantial public health concern. Unlike
other environmental exposures, O3-related morbidity and mortality, is largely linked to respiratory causes and
associated with pre-existing respiratory conditions. However, specific mechanisms underlying this phenomenon
are poorly understood. Understanding how prior lung injury drives susceptibility to subsequent O3 exposure is
particularly important in the context on viral lung injury, such as pneumonia caused by seasonal influenza virus
or SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic. Our overall hypothesis is that this is
driven by distinct alveolar macrophage (AMØ) subsets. During the past decade, work from several groups,
including ours, has demonstrated that long-living, self-maintaining, tissue-resident AMØ are the dominant
immune cell type in normal mouse and human lung. Tissue-resident AMØ are essential to lung homeostasis and
direct responses to pathogens and environmental exposures, including O3. We have previously reported that
murine O3 exposure expands tissue-resident AMØ, and their loss exacerbates O3-induced lung injury.
Conversely, monocyte-derived AMØ, recruited during lung injury (e.g. viral infection), augment inflammation. Our
group previously showed that monocyte-derived AMØ recruited after lung injury persist in the lung via autocrine
M-CSF/M-CSF receptor (M-CSF-R), maintain an activated phenotype, and drive chronic lung diseases.
Extending this to humans, we demonstrate that the abundance and activation state of monocyte-derived AMØs
negatively correlate with pulmonary function in patients with early pulmonary fibrosis. Cumulatively, our
published and preliminary data support that distinct AMØ subsets direct the balance between ongoing
inflammation and its resolution and suggest that AMØ composition, particularly the baseline presence and
activation of monocyte-derived AMØ, prior to exposure can enhance severity and persistence of O3-induced lung
injury. This baseline condition is particularly important as respiratory viral infections, including influenza and
SARS-CoV2, induce the recruitment of monocyte-derived AMØs. Leveraging mechanistic mouse models, state-
of-the-art lineage-tracing systems, single-cell genomics, and serial sampling in controlled human O3 exposures,
we will test the hypothesis that the abundance and activation state of monocyte-derived AMØs drive O3-
induced lung inflammatory responses via autocrine M-CSF/M-CSF-R signaling. Our specific aims are: Aim
1: To determine the role of autocrine monocyte-derived alveolar macrophage M-CSF/M-CSF-R signaling in
maintaining lung inflammation in mouse models of O3-exposure. Aim 2: To determine whether the abundance
and activation status of monocyte-derived AMØ predicts lung physiological and inflammatory responses in
controlled acute O3 exposures in normal human subjects and in individuals with prior SARS-CoV2 infection.
These ...

## Key facts

- **NIH application ID:** 10498403
- **Project number:** 1R01ES034350-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Alexander Misharin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $630,363
- **Award type:** 1
- **Project period:** 2022-08-24 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498403

## Citation

> US National Institutes of Health, RePORTER application 10498403, Monocyte-derived alveolar macrophage drives inflammatory response to lung ozone exposure (1R01ES034350-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10498403. Licensed CC0.

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