Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Role of Notch receptors in ozone induced lung injury in mice

ABSTRACT: 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).

ORGANISM(S): Mus musculus

SUBMITTER: Dr. Steven Kleeberger

PROVIDER: E-GEOD-58244 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Novel Roles for Notch3 and Notch4 Receptors in Gene Expression and Susceptibility to Ozone-Induced Lung Inflammation in Mice.

Verhein Kirsten C KC McCaw Zachary Z Gladwell Wesley W Trivedi Shweta S Bushel Pierre R PR Kleeberger Steven R SR

Environmental health perspectives 20150206 8

<h4>Background</h4>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 that Notch3 and Notch4 are important determinants of susceptibility to ozone-induced lung inflammation.<h4>Methods</h4>Wild-type (WT), Notch3 (Notch3-/-), and Notch4 (Notch4-/-) knockout mice were exposed to ozone (0.3 ppm) or filtered air for 6-72 hr.<h4>Results</h4>Relative to air-exposed contr ...[more]

PMID: 25658374

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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

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 newbornM-bM-^@M-^Ys 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. Three-day old BALB/c mice were exposed for 3 h to ozone (1000 parts per billion). Age-matching littermate controls were exposed for 3 h to filtered normal air. Whole lung tissue was collected 6 and 24 h after completion of exposure to ozone or filtered air and was subjected to microarray analysis. Each time point was performed separately with its own filtered air littermate controls. Pups were cross-fostered during exposure so that all pups were with a dam during exposure. A total of 6-8 mice were initially included in each group and time point. Of these, n=4 mouse lungs were randomly selected for use in gene expression analysis.

Dataset Information

Role of Notch receptors in ozone induced lung injury in mice

Publications

Novel Roles for Notch3 and Notch4 Receptors in Gene Expression and Susceptibility to Ozone-Induced Lung Inflammation in Mice.

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