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Principal Investigator: Alexander Misharin
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $586,846
Funding agency: National Institute of Environmental Health Sciences
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 results would support a novel translational paradigm with important public health implications, and identify
a novel therapeutic strategy to revert the adverse public health effects of O3 exposure.
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Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Stromal Cells><Susceptibility><System><Techniques><Testing><Tissue Expansion><Tissues><Viral><Viral Diseases><Viral Respiratory Tract Infection><Virus Diseases><Work><Wuhan coronavirus><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><autocrine><balance><balance function><biological signal transduction><c-fms Protein><cell type><chronic pulmonary disease><coronavirus disease 2019 associated 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respiratory distress syndrome CoV-2 infection><hCoV19><human subject><immune modulatory intervention><immunointervention><immunological intervention><influenzavirus><lung fibrosis><lung function><lung injury><monocyte><mortality><mouse model><murine model><nCoV2><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ozone exposure><pathogen exposure><pneumonia due to COVID><pneumonia due to COVID-19><pneumonia due to SARS-CoV-2><pneumonia due to coronavirus disease><pneumonia due to coronavirus disease 2019><pneumonia due to severe acute respiratory syndrome coronavirus 2><pneumonia in COVID><pneumonia in COVID-19><pneumonia in SARS-CoV-2><pneumonia in coronavirus disease><pneumonia in coronavirus disease 2019><pneumonia in severe acute respiratory syndrome 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genomics><social role><transcriptomics><viral infection><viral respiratory infection><virus infection><virus-induced disease>