Effect of adiponectin deficiency on pulmonary responses to subacute ozone exposure in mice
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Stephanie Shore
PROVIDER: E-GEOD-50183 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Adiponectin is an adipose-derived hormone with anti-inflammatory activity. Following subacute ozone exposure (0.3 ppm for 24-72 h), pulmonary neutrophilic inflammation is augmented in adiponectin deficient mice. The purpose of this study was to use microarrays to examine the impact of adiponectin deficiency on changes in pulmonary gene expression induced by ozone, a common air pollutant.
2013-08-27 | GSE50183 | GEO
Project description:Ozone is a highly toxic air pollutant and global health concern. Mechanisms of genetic susceptibility to ozone-induced lung inflammation are not completely understood. We hypothesized Notch3 and Notch4 are important determinants of susceptibility to ozone-induced lung inflammation. Wild type (WT), Notch3 (Notch3-/-) and Notch4 (Notch4-/-) knockout mice were exposed to ozone (0.3 ppm) or filtered air for 6-72 hours. Ozone increased bronchoalveolar lavage fluid (BALF) protein, a marker of lung permeability, in all genotypes, but significantly greater concentrations were found in Notch4-/- compared to WT and Notch3-/-. Significantly greater mean numbers of BALF neutrophils were found in Notch3-/- and Notch4-/- mice compared to WT mice after ozone. Expression of whole lung Tnf was significantly increased after ozone in all genotypes, and was significantly greater in Notch3-/- mice compared to WT. Statistical analyses of the transcriptome identified differentially expressed gene networks between WT and knockout mice basally and after ozone, and included Trim30, a member of the inflammasome pathway, and Traf6, an inflammatory signaling member. These novel findings are consistent with Notch3 and Notch4 as susceptibility genes for ozone-induced lung injury, and suggest that Notch receptors protect against innate immune inflammation. Wild-type, Notch3 knockout, and Notch4 knockout mice at 7-13 weeks of age were exposed continuously to air or 0.3 ppm ozone for 6, 24, or 48 hours. Three biological replicates from individual animals were included in each exposure group from each genotype and samples hybridized to the GeneChip Mouse Genome 430 2.0 array (Affymetrix).
2015-02-24 | E-GEOD-58244 | biostudies-arrayexpress
Project description:Background: The mechanisms underlying ozone (O3)-induced pulmonary inflammation remain unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators. Objectives: The current study investigated the molecular mechanisms underlying IL-10-mediated attenuation of O3-induced pulmonary inflammation in mice. Methods: Il10-deficient (Il10-/-) and wild type (Il10+/+) mice were exposed to 0.3-ppm O3 or filtered air for 24, 48 or 72 hr. Immediately following exposure, differential cell counts, and total protein (a marker of lung permeability) were assessed from bronchoalveolar lavage fluid (BALF). mRNA and protein levels of cellular mediators were determined from lung homogenates. We also utilized global mRNA expression analyses of lung tissue with Ingenuity Pathway Analyses (IPA) to identify patterns of gene expression through which IL-10 modifies O3-induced inflammation. Results: Mean numbers of BALF polymorphonuclear leukocytes (PMNs) were significantly greater in Il10-/- mice than in Il10+/+ mice after exposure to O3 at all time points tested. O3-enhanced nuclear NF-kB translocation was elevated in the lungs of Il10-/- compared to Il10+/+ mice. Gene expression analyses revealed several key IL-10 and O3-dependent mediators, including IL-6, MIP-2, IL-1 and CD86. Conclusions: Results indicated that IL-10 protects against O3-induced pulmonary neutrophilic inflammation and cell proliferation. Moreover, gene expression analyses identified three response pathways and several novel genetic targets (e.g. Ccr1, Socs3, Il33, Hat1, and Gale) through which IL10 may modulate the innate and adaptive immune response. These novel mechanisms of protection against the pathogenesis of O3-induced pulmonary inflammation may also provide potential therapeutic targets to protect susceptible individuals. PARALLEL study design with 26 samples. Biological replicates: 2 to 3 replicates per group with wild type air exposed animals as controls for each time point (24, 48, 72 hours). Time-Course, Dose-Response, Strain comparison
2011-10-18 | E-GEOD-25095 | biostudies-arrayexpress
Project description:Ozone is a highly toxic air pollutant and global health concern. Mechanisms of genetic susceptibility to ozone-induced lung inflammation are not completely understood. We hypothesized Notch3 and Notch4 are important determinants of susceptibility to ozone-induced lung inflammation. Wild type (WT), Notch3 (Notch3-/-) and Notch4 (Notch4-/-) knockout mice were exposed to ozone (0.3 ppm) or filtered air for 6-72 hours. Ozone increased bronchoalveolar lavage fluid (BALF) protein, a marker of lung permeability, in all genotypes, but significantly greater concentrations were found in Notch4-/- compared to WT and Notch3-/-. Significantly greater mean numbers of BALF neutrophils were found in Notch3-/- and Notch4-/- mice compared to WT mice after ozone. Expression of whole lung Tnf was significantly increased after ozone in all genotypes, and was significantly greater in Notch3-/- mice compared to WT. Statistical analyses of the transcriptome identified differentially expressed gene networks between WT and knockout mice basally and after ozone, and included Trim30, a member of the inflammasome pathway, and Traf6, an inflammatory signaling member. These novel findings are consistent with Notch3 and Notch4 as susceptibility genes for ozone-induced lung injury, and suggest that Notch receptors protect against innate immune inflammation.
2015-02-24 | GSE58244 | GEO
Project description:Ozone is a common pollutant and a potent oxidant in industrialized nations. The mechanisms of ozone-induced lung injury and differential susceptibility are not fully understood. Ozone-induced lung inflammation is mediated, in part, by the innate immune system. We hypothesized that mannose binding lectin (MBL), which has a central role in the activation of the complement pathway of innate immunity, is a necessary component of the pro-inflammatory events caused by ozone-mediated activation of the innate immune system. Wild-type (Mbl+/+) and MBL deficient (Mbl-/-) mice were exposed to ozone (0.3 ppm) for 24, 48, and 72 hours, and bronchoalveolar lavage fluid (BALF) was examined for inflammatory markers. Compared to Mbl+/+ mice, significantly greater mean BALF eosinophils, neutrophils and neutrophil attractants CXCL2 (MIP-2) and CXCL5 (LIX) were found in Mbl-/- mice exposed to ozone. Using genome-wide mRNA microarray analyses, we identified significant differences in expression response profiles and networks at baseline (e.g. NRF2 mediated oxidative stress response) and after exposure (e.g. humoral immune response) between Mbl+/+ and Mbl-/- mice. The microarray data were further analyzed using a pattern recognition analysis for Extracting Patterns and Identifying co-expressed Genes (EPIG), and discovered several informative differential response patterns and subsequent gene sets, including antimicrobial response and inflammatory response. These novel findings demonstrate that targeted deletion of Mbl caused differential expression of inflammation-related gene sets basally and after exposure to ozone, and significantly reduced pulmonary inflammation thus indicating an important innate immunomodulatory role of the gene in this model.
2016-04-25 | GSE68522 | GEO
Project description:Background: Ozone (O3) is the predominant oxidant air pollutant associated with respiratory inflammation, lung dysfunction, and worsening preexisting airway diseases. We determined that TNFR signlaing pathway plays a key role in lung injury and inflammation caused by O3 in mice. However, downstream molecular mechanisms underlying TNFR pathway have not been investigated. Methods: To investigate the role of TNFR pathway in gene expression changes, Tnfr1/2-deficient (Tnfr-/-) and wild-type (Tnfr+/+, C57BL/6J) mice were exposed to air or 0.3-ppm O3. Total RNAs were isolated from lung homogenates and cDNA microarray analyses were performed to elucidate TNFR-directed transcriptomics in basal lungs (air-exposed) as well as in the lung exposed to time course of O3 (24, 48, and 72 hr). Results: O3 caused time-dependent changes in lung gene expressions with the greatest transcriptome changes at 48-72 hr of exposure in Tnfr+/+ mice. At early time of exposure (24 hr), acute phase and inflammatory responses gene as well as redox and lipid metabolism genes were increased by O3 while cell cycle and DNA damage repair genes were markedly increased by O3 at later time points (48-72 hr). Compared to Tnfr+/+ mice, Tnfr-/- mice had lowered expression of inflammatory response and vascular disorder-related genes at baseline (air). After O3 exposure, Tnfr-/- had enhanced expression of immune and inflammatory genes at 24 hr, indicating compensatory or adpative poentiation of immunity in Tnfr-/- mice. At 48 hr of O3 exposure, Tnfr-/- mice showed suppressed expression of genes involved in epithelial proliferation, inflammatory cell influxes and epithelial injury, compared to Tnfr+/+ mice. At 72 hr of O3 exposure, neurodegeneration and neurotransmitter transport genes were suppressed in Tnfr-/- than in Tnfr+/+. Conclusion: Overall, deficiency of TNFR-mediated signaling in mouse lungs altered transcriptomes to protect lungs from O3-induced inflammation, cell proliferation, oxidative stress, and neuronal disorders.
2021-09-29 | GSE166399 | GEO
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.
2025-01-10 | GSE273048 | GEO
Project description:Background: Ozone (O3) is the predominant oxidant air pollutant associated with respiratory inflammation, lung dysfunction, and worsening preexisting airway diseases. We previously determined that lack of NF-kB signlaing pathway suppressed lung injury and inflammation caused by O3 in mice. The current study was to determine transcriptome mechanisms orchestrated by NF-kB during the development of pulmonary O3 injury. Methods: To investigate the role of NF-kB1 pathway in lung gene expression changes, Nfkb1-deficient (Nfkb1-/-) and wild-type (Nfkb1+/+) mice were exposed to air or 0.3-ppm O3. Total RNAs were isolated from lung homogenates and cDNA microarray analyses were performed to elucidate NF-kB1-directed transcriptomics in basal lungs (air-exposed) as well as in the lung exposed to O3 (48 hr). Results: In air-exposed Nfkb1-/- lungs, leukocyte extravasation/adhesion and antigen presentation genes were overexpressed while immunity genes were suppressed, supporting the dual role of Nf-kB1 homodimer as a transcriptional repressor as well as transcriptional activator and the phenotype of Nfkb1-/- mice (defective response to infection and specific antibody production). After O3 exposure. Nfkb1-/- mice showed suppressed expression of lung cell cycle genes and enhanced expression of DNA damage checkpoint regulation pathway genes, compared to Nfkb1+/+ mice. Conclusion: Overall, deficiency of NF-kB1 in mouse lungs altered transcriptomes to protect lungs from O3-induced inflammation, cell proliferation, and DNA damages.
2021-09-29 | GSE166398 | GEO
Project description:Ozone-induced lung injury/inflammation and pulmonary/hypothalamus gene expression are diminished in adrenalectomized (ADREX) rats. Acute ozone exposure induces metabolic alterations concomitant with increases in epinephrine and corticosterone. We hypothesized that adrenal hormones are responsible for observed hepatic ozone effects, and in ADREX rats, these changes would be diminished. Five-seven days after sham or ADREX surgeries, male Wistar-Kyoto rats were exposed to air or 0.8-ppm ozone for 4-hrs. Serum samples were analyzed for metabolites and liver for transcriptional changes immediately post-exposure. Ozone increased circulating triglycerides, cholesterol, free fatty acids, and leptin in sham but not ADREX rats. Ozone-induced inhibition of glucose-mediated insulin release was reversed in ADREX rats. Unlike diminution of hypothalamus and lung mRNA expression changes, ADREX in air-exposed rats (ADREX-air/sham-air) caused differential expression of ~1000 genes in liver. Likewise, ~1000 genes were differentially expressed in ozone-exposed ADREX rats (ADREX-ozone/ADREX-air). Ozone-induced hepatic changes in sham rats reflected enrichment for pathways involving metabolic processes, including acetyl-CoA biosynthesis, TCA cycle, and sirtuins. Upstream predictor analysis identified significant similarity to glucocorticoids and pathways involving CREBBP. These changes were absent in ADREX rats exposed to ozone. However, ozone caused unique changes in ADREX liver mRNA reflecting activation of synaptogenesis, neurovascular coupling, neuroinflammation, and insulin signaling with inhibition of senescence pathways. In these rats, upstream predictor analysis identified numerous microRNAs involved under glucocorticoid insufficiency. These data demonstrate the critical role of adrenal stress hormones in ozone-induced hepatic homeostasis and the need for further research elucidating their role in propagating environmentally driven diseases.
2022-11-02 | GSE196818 | GEO
Project description:Background: The mechanisms underlying ozone (O3)-induced pulmonary inflammation remain unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators. Objectives: The current study investigated the molecular mechanisms underlying IL-10-mediated attenuation of O3-induced pulmonary inflammation in mice. Methods: Il10-deficient (Il10-/-) and wild type (Il10+/+) mice were exposed to 0.3-ppm O3 or filtered air for 24, 48 or 72 hr. Immediately following exposure, differential cell counts, and total protein (a marker of lung permeability) were assessed from bronchoalveolar lavage fluid (BALF). mRNA and protein levels of cellular mediators were determined from lung homogenates. We also utilized global mRNA expression analyses of lung tissue with Ingenuity Pathway Analyses (IPA) to identify patterns of gene expression through which IL-10 modifies O3-induced inflammation. Results: Mean numbers of BALF polymorphonuclear leukocytes (PMNs) were significantly greater in Il10-/- mice than in Il10+/+ mice after exposure to O3 at all time points tested. O3-enhanced nuclear NF-kB translocation was elevated in the lungs of Il10-/- compared to Il10+/+ mice. Gene expression analyses revealed several key IL-10 and O3-dependent mediators, including IL-6, MIP-2, IL-1 and CD86. Conclusions: Results indicated that IL-10 protects against O3-induced pulmonary neutrophilic inflammation and cell proliferation. Moreover, gene expression analyses identified three response pathways and several novel genetic targets (e.g. Ccr1, Socs3, Il33, Hat1, and Gale) through which IL10 may modulate the innate and adaptive immune response. These novel mechanisms of protection against the pathogenesis of O3-induced pulmonary inflammation may also provide potential therapeutic targets to protect susceptible individuals.
2011-10-19 | GSE25095 | GEO