Spatial analysis of young and old murine lungs exposed to ozone and fibrogenic stress [spatial_ozone]
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ABSTRACT:
PROVIDER: PRJNA1139846 | ENA |
REPOSITORIES: ENA
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Project description:Ozone (O3) is a ubiquitous pollutant known to produce acute and transient inflammation through oxidative injury and inflammation. These effects are exacerbated in susceptible populations, such as the elderly and those exhibiting genetic mutations in central nodes of pulmonary function. To comprehend the impact of these predisposing factors, the present study examines structural, mechanical, and immunological responses to single acute O3 exposure (0.8 ppm, 3h) in young (12 week old) and old (80 week old) mice. We therefore examined the impact of ozone in a surfactant competent and mutant murine line. The latter models a clinically relevant mutation in the gene encoding for the alveolar epithelial type 2 specific surfactant protein C. Ozone exposure produced focal injury localized at the terminal bronchiole-to-alveolar junctions and enlarged alveoli in aged SP-C mutant lungs. This histological feature was used to select regions of interest for spatial transcriptomics. Paraffin sections of 4 mice were prepared: a young/12wk SP-C wild type air control, a young/12wk SP-C wild type ozone (0.8 ppm, 3h), a young/12wk SP-C mutant ozone, and an old/80wk ozone. Immunofluorescence for DNA, CD45, CD68 was performed to identify macrophages (CD45+CD68+) and non-immune ("other", DNA+CD45-) cells within healthy (air control only), peri-injured and injured regions of the lung. A total of 24 regions (680um x 700um in size) were selected from CD68+ macrophages and CD45- non immune/"other" cells. RNA sequencing was then performed. Principal component and pathway analysis revealed spatial heterogeneity in response to ozone, as well as a senescence signature in the aging lungs. These results illustrate regional and age dependent heterogeneity in immune and non-immune cells of the lung during an acute exposure to air pollution.
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Project description:Spatial analysis of murine lungs exposed to fibrogenic stress
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Project description:Ozone is known to cause lung injury and resident cells of the respiratory tract, i.e., epithelial cells and macrophages, respond to inhaled ozone in a variety of ways that affect their survival, morphology, and functioning. However, complete understanding of sex-associated and cell type-specific gene expression changes in response to ozone exposure is still limited. Through transcriptome profiling, we aimed to analyze gene expression alterations and biological pathways enrichment in three distinct cell type-enriched compartments of ozone-exposed murine lungs. We chronically exposed adult males and females to 0.8ppm ozone or filtered air. RNA-Seq was performed on airway epithelium-enriched airways, parenchyma, and purified airspace macrophages. Differential gene expression and biological pathway analyses were performed and supported by cellular and immunohistochemical analyses. While majority of differentially expressed genes (DEGs) in ozone-exposed versus air-exposed groups were common between both sexes, sex-specific DEGs were also identified in all the three tissue compartments. As compared to ozone-exposed males, ozone-exposed females had significant alterations in gene expression in three compartments. Pathways relevant to cell division and DNA repair were enriched in the ozone-exposed airways indicating ozone-induced airway injury and repair which was further supported by immunohistochemical analyses. In addition to cell division and DNA repair pathways, inflammatory pathways were also enriched within the parenchyma supporting contribution by both epithelial and immune cells. Finally, immune response and cytokine-cytokine receptor interactions were enriched in macrophages, indicating ozone-induced macrophage activation. Lastly, our analyses also revealed the overall upregulation of mucoinflammation and mucous cell metaplasia-associated pathways.
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Project description:Ozone is a very common environmental pollutant and has been associated with the exacerbation of cardiopulmonary diseases like asthma. In this study the molecular mechanisms underlying the effect of ozone on airways hyperpermability were investigated. Two strains of mice, HeJ (Tlr4 mutant) and OuJ (wildtype) were exposed continuously to air or 0.3ppm of ozone. Lungs were removed and RNA was collected to generate expression profiles.
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Project description:Acute inflammatory exacerbations (AIEs) represent immune-driven deteriorations of many chronic lung conditions, including COPD, asthma, and pulmonary fibrosis (PF). The first line of therapy is represented by broad-spectrum immunomodulation. To better study immune cell heterogeneity during AIE-PF, this work leverages a clinically relevant model of inflammatory exacerbations triggered by mutation in the alveolar epithelial type 2 cell Surfactant Protein-C gene [SP-CI73T]. SP-CI73T mice received corn oil (controls) or tamoxifen (175 mg/kg, orally) to excise a neomycin cassette placed on the surfacant protein C gene locus, hence inducing the expression of the mutant transcript. We have previously shown that a complex inflammatory response arises by 14 days post tamoxifen administration. Paraffin sections of murine lungs were therefore collected in controls and 14 days post induction. Immunofluorescence for DNA, CD45, CD68 was performed to identify macrophages (CD45+CD68+) and non-immune ("other", DNA+CD45-) cells within healthy, peri-injured and injured regions of the lung. A total of 12 regions (680um x 700um in size) were selected and macrophages and "other" cells isolated. RNA sequencing was then performed. Principal component and pathway analysis revealed spatial heterogeneity with an hyperactive peri-injured compartment (extracellular matrix remodeling, innate and adaptive immunity, senescence). Cells isolated from injured areas of the lung were relatively quiescent. These results illustrate regional heterogeneity in immune and non-immune cells of the lung during fibrogenic stress.
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Project description:Ozone is a very common environmental pollutant and has been associated with the exacerbation of cardiopulmonary diseases like asthma. In this study the molecular mechanisms underlying the effect of ozone on airways hyperpermability were investigated. Two strains of mice, HeJ (Tlr4 mutant) and OuJ (wildtype) were exposed continuously to air or 0.3ppm of ozone. Lungs were removed and RNA was collected to generate expression profiles. Keywords: other
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Project description:ILC2 cells from young and old mouse lungs were analysed and revealed altered transcriptome of old ILC2 compared to the young.
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Project description:Transcriptome profiling of lungs from young and aged hamster
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Project description:Ozone is a major air pollutant in highly populated areas. High levels of ambient ozone have been associated with decreased lung function and increased exacerbations of asthma in children and adults. However, the effects of ozone on the newborn’s lung are largely unknown. This study was aimed at profiling the newborn lung response to ozone at the transcriptome level to define the impact of ozone pollutant on the developing postnatal lung. Newborn mice were exposed to ozone or filtered normal air for 3 h. Total RNA was isolated from lung tissues at 6 and 24 h after completion of exposure and was subjected to gene expression analysis using Whole Mouse Genome Gene Expression 4X44K Microarrays (G2519F-014868, Agilent Technologies). Transcriptome analysis of the postnatal lung indicated that 455 genes were down-regulated and 166 genes were up-regulated by at least 1.5 fold at 6 h post-ozone exposure (t-test, p<0.05). At 24 h post exposure, 543 genes were down-regulated and 323 genes were up-regulated in the lungs of ozone-exposed newborn mice, compared to filtered air-exposed newborn mice (t-test, p<0.05). After controlling for false discovery rate, 50 genes were significantly down-regulated and only 4 genes were up-regulated at 24 h post ozone-exposure (q<0.05). Gene ontology enrichment analysis revealed that cell cycle-associated functions including cell division/proliferation, cellular assembly and organization were the predominant pathways negatively regulated by ozone exposure. These findings suggest that elevated ozone pollution may interfere with lung development and growth in the early age.
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Project description:Single cell RNA sequencing from lungs of young (2-3 month old) and aged (20-22 month old) mice.
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