Integrative analysis reveals mouse strain-dependent responses to acute ozone exposure associated with airway macrophage transcriptional activity

Acute ozone (O ) exposure is associated with multiple adverse cardiorespiratory outcomes, the severity of which varies across individuals in human populations and inbred mouse strains. However, molecular determinants of response, including susceptibility biomarkers that distinguish who will develop...

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Bibliographic Details
Published in:American journal of physiology. Lung cellular and molecular physiology 2022-01, Vol.322 (1), p.L33-L49
Main Authors: Tovar, Adelaide, Crouse, Wesley L, Smith, Gregory J, Thomas, Joseph M, Keith, Benjamin P, McFadden, Kathryn M, Moran, Timothy P, Furey, Terrence S, Kelada, Samir N P
Format: Article
Language:English
Subjects:
Animals
Biomarkers
Chromatin
Chromatin - metabolism
Cytokines - metabolism
Exposure
Female
Gene expression
Gene Expression Regulation - drug effects
Human populations
Immune system
Inbreeding
Inflammation
Inflammation - genetics
Inflammation - pathology
Inhalation
Injuries
Inspection
Lung - pathology
Macrophages
Macrophages - drug effects
Macrophages - metabolism
Male
Mice
Mice, Inbred C57BL
Neutrophilia
Ozone
Ozone - adverse effects
Phenotype
Respiration
Respiratory tract
RNA, Messenger - genetics
RNA, Messenger - metabolism
Transcription
Transcription, Genetic - drug effects
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Summary:Acute ozone (O ) exposure is associated with multiple adverse cardiorespiratory outcomes, the severity of which varies across individuals in human populations and inbred mouse strains. However, molecular determinants of response, including susceptibility biomarkers that distinguish who will develop severe injury and inflammation, are not well characterized. We and others have demonstrated that airway macrophages (AMs) are an important resident immune cell type that are functionally and transcriptionally responsive to O inhalation. Here, we sought to explore influences of strain, exposure, and strain-by-O exposure interactions on AM gene expression and identify transcriptional correlates of O -induced inflammation and injury across six mouse strains, including five Collaborative Cross (CC) strains. We exposed adult mice of both sexes to filtered air (FA) or 2 ppm O for 3 h and measured inflammatory and injury parameters 21 h later. Mice exposed to O developed airway neutrophilia and lung injury with strain-dependent severity. In AMs, we identified a common core O transcriptional response signature across all strains, as well as a set of genes exhibiting strain-by-O exposure interactions. In particular, a prominent gene expression contrast emerged between a low- (CC017/Unc) and high-responding (CC003/Unc) strain, as reflected by cellular inflammation and injury. Further inspection indicated that differences in their baseline gene expression and chromatin accessibility profiles likely contribute to their divergent post-O exposure transcriptional responses. Together, these results suggest that aspects of O -induced respiratory responses are mediated through altered AM transcriptional signatures and further confirm the importance of gene-environment interactions in mediating differential responsiveness to environmental agents.
ISSN:1040-0605
1522-1504
DOI:10.1152/ajplung.00237.2021