Differential contribution of bone marrow derived-monocytes to the lung tissue resident alveolar macrophages and persistent lung inflammation with chronic air pollution exposure
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE143787 | GEO | 2020/09/08
REPOSITORIES: GEO
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Project description:Occupational exposure to crystalline silica results in serious health effects, most notably, silicosis and cancer. A proper understanding of the mechanism(s) underlying the initiation and progression of silica-induced pulmonary toxicity is critical for the intervention and/or prevention of the adverse health effects associated with crystalline silica exposure. Rats were exposed to crystalline silica by inhalation at a concentration of 15 mg/m3, 6 hours/day, 5 days/week for 3, 6 or 12 weeks. At the end of each exposure time point, toxicity and global gene expression changes were determined in the lungs. In general, silica exposure resulted in pulmonary toxicity that was dependent on the duration of silica exposure. A significant and silica exposure time-dependent increase in lactate dehydrogenase activity and accumulation of alveolar macrophages and infiltrating neutrophils in the bronchoalveolar lavage fluid suggested crystalline silica-induced pulmonary toxicity in the rats. Histological changes indicative of pulmonary toxicity were detectable only in the lungs of rats that were exposed to silica for 6- or 12-weeks. Minimal, sub-acute pulmonary inflammation consisting mainly of macrophage accumulation and infiltration of neutrophils was seen in 2 out of 8 rats in the 6-week silica exposure group. Chronic active inflammation, type II pneumocyte hyperplasia, and fibrosis were detected following 12-weeks of silica exposure in all rat lungs. In addition, crystalline silica was visible in the lungs of the rats belonging to the 12-week exposure group. A significant increase in the number of neutrophils seen in the blood indicated silica-induced systemic inflammation in the rats. Microarray analysis of the global gene expression profiles of the rat lungs detected significant differential expression (FDR p <0.05 and fold change >1.5) of 38, 77 and 99 genes in the rats exposed to silica for 3-, 6- and 12-weeks, respectively, compared to the time-matched controls. Bioinformatics analysis of the differentially expressed genes identified significant enrichment of functions, networks and pathways related to inflammation, cancer, oxidative stress, fibrosis and tissue remodeling in the lungs of the silica exposed rats. Collectively, the results of our study provided insights into the molecular mechanisms underlying pulmonary toxicity following sub-chronic exposure to silica in rats.
2014-07-01 | GSE49144 | GEO
Project description:Occupational exposure to crystalline silica results in serious health effects, most notably, silicosis and cancer. A proper understanding of the mechanism(s) underlying the initiation and progression of silica-induced pulmonary toxicity is critical for the intervention and/or prevention of the adverse health effects associated with crystalline silica exposure. Rats were exposed to crystalline silica by inhalation at a concentration of 15 mg/m3, 6 hours/day, 5 days/week for 3, 6 or 12 weeks. At the end of each exposure time point, toxicity and global gene expression changes were determined in the lungs. In general, silica exposure resulted in pulmonary toxicity that was dependent on the duration of silica exposure. A significant and silica exposure time-dependent increase in lactate dehydrogenase activity and accumulation of alveolar macrophages and infiltrating neutrophils in the bronchoalveolar lavage fluid suggested crystalline silica-induced pulmonary toxicity in the rats. Histological changes indicative of pulmonary toxicity were detectable only in the lungs of rats that were exposed to silica for 6- or 12-weeks. Minimal, sub-acute pulmonary inflammation consisting mainly of macrophage accumulation and infiltration of neutrophils was seen in 2 out of 8 rats in the 6-week silica exposure group. Chronic active inflammation, type II pneumocyte hyperplasia, and fibrosis were detected following 12-weeks of silica exposure in all rat lungs. In addition, crystalline silica was visible in the lungs of the rats belonging to the 12-week exposure group. A significant increase in the number of neutrophils seen in the blood indicated silica-induced systemic inflammation in the rats. Microarray analysis of the global gene expression profiles of the rat lungs detected significant differential expression (FDR p <0.05 and fold change >1.5) of 38, 77 and 99 genes in the rats exposed to silica for 3-, 6- and 12-weeks, respectively, compared to the time-matched controls. Bioinformatics analysis of the differentially expressed genes identified significant enrichment of functions, networks and pathways related to inflammation, cancer, oxidative stress, fibrosis and tissue remodeling in the lungs of the silica exposed rats. Collectively, the results of our study provided insights into the molecular mechanisms underlying pulmonary toxicity following sub-chronic exposure to silica in rats. 36 samples were analyzed in this experiment. 6 rats were exposed to crystalline silica by inhalation 15 mg/m3, 6 hours/day, 5 days, 3 weeks. 6 rats were exposed to crystalline silica by inhalation 15 mg/m3, 6 hours/day, 5 days, 6 weeks. 6 rats were exposed to crystalline silica by inhalation 15 mg/m3, 6 hours/day, 5 days, 12 weeks. 18 rats served as controls (6 for each 3 week, 6 week, and 12 week exposure) and were exposed to air during treatment times. Lung gene expression profiling was performed using RNA isolated from rat lung samples.
2014-07-01 | E-GEOD-49144 | biostudies-arrayexpress
Project description:Exposure to particulate matter (PM) is consistently associated with increased morbidity and mortality attributable in part to respiratory illnesses. The alveolar macrophage (AM) is one of the cell types in the lung constantly exposed to and activated by ambient pollutants. Upon contact with environmental particulate pollutants, AM produces reactive oxygen species (ROS) and antioxidant enzymes, but the scope of this oxidative stress response induced by PM remains poorly defined. In this study, we used microarray analysis to determine the gene expression profile in human alveolar macrophages upon exposure to PM and sought to gain more insight into the global response of pro- and anti-oxidant enzymes to PM exposure. Human AM were obtained by bronchoscopy from normal individuals. They were then incubated with Chapel Hill PM2.5 (1 ïg/ml) or vehicle for 4 hours (n = 6 independent samples each). mRNAs were extracted, amplified and hybridized to Agilent Human 1A microarray. Differentially expressed genes were identified by Statistical Analysis for Microarrays (SAM) with a FDR of 10% and a P ⤠0.05. Significant genes were also mapped with Gene Ontology (GO) based on their molecular function. We found 34 and 41 up- and down-regulated genes respectively. Of these, 22 genes (~30%) were involved in metal binding and 14 genes were linked to oxidative stress, including 5 metallothionein-1 (MT1) isoform genes. In lung cells, addition of MT-1F in the medium attenuated PM2.5-induced H2O2 production while knockdown of MT1F gene expression increased H2O2 and IL-6 release induced by PM2.5. Our microarray experiments provided a global view of gene expression after in vitro PM2.5 exposure in human AM. The expression profile was most notable for differential expression of genes related to metal binding and oxidative stress, especially upregulation of MT1 isoform genes. Our findings suggest that metals associated with PM, e.g., zinc, copper, and arsenic, induce MT-1 and may be the primary mediators for PM-induced oxidative stress. Keywords: in vitro exposure, PM2.5 particle treatment, human alveolar macrophages Total RNA was isolated from alveolar macrophages from 6 subjects were treated in vitro with PM2.5 particles or vehicle control for 4 hrs. All particle-treated samples were co-hybridized with the common reference sample (pool of all 6 vehicle-treated samples) twice with Cy3 and Cy5 dyes flipped (12 hybridizations). Three samples were also co-hybridized with its own individual control (vehicle-treatment for the same subject) with Cy3 and Cy5 dyes flipped (6 additional hybridizations).
2008-05-01 | E-GEOD-10394 | biostudies-arrayexpress
Project description:Alveolar macrophages from never smokers and active smokers were isolated by bronchoalveolar lavage and gene expression was measured. Chronic cigarette smoke exposure, as occurs in smoker's lungs, leads to significant changes in gene expression. Of note, RNA was isolated immediately following bronchoscopy. Alveolar macrophage levels were >95%.
2012-10-02 | GSE34517 | GEO
Project description:Background: The tobacco carcinogen urethane causes lung adenocarcinomas (LUAD) in mice. They show high similarity to human LUAD of smokers, including driver KrasQ61R mutations. However, the time line of KRASQ61R mutation acquisition as well as the affected cell lineages are still obscure. Objectives: With this study we aim to identify which cells of the lung gain KrasQ61R mutations and when they occur in response to urethane treatment. Methods: Airway and alveolar GFP-lineage-marked mice received single urethane hits (1 g/Kg). Lungs were harvested at 0, 1, 2, 4, and 8 weeks and LUAD tumors were collected at 16, 24, and 32 weeks post-urethane. The DNA was subjected to digital droplet PCR interrogating the coexistence of GFP and KrasQ61R in the same DNA copy. RNA of tumors was submitted to sequencing for gene expression analysis. Results: Starting from even 1 week post-urethane, both airway and alveolar lineages suffered KrasQ61R mutations (2.57% of copies examined). In airway-labelled cells KrasQ61R mutations increased by 4.06% and 2.55% at 4 and 32 weeks post-urethane, respectively. In contrast, in alveolar-labelled cells KrasQ61R mutations declined by 5.92% and 6.12%. Strikingly, gene expression analysis on tumors revealed an over expression of alveolar markers whereas expression of airway marker genes decreased. Conclusion: After pulmonary tumor initiation by urethane, airway cells accumulate KrasQ61R mutations over time, whereas alveolar cells tend to lose them. However, tumor cells are over expressing alveolar cell markers and lose airway markers. Altogether, these results indicate that smoking-induced LUAD develops from club cells which acquire alveolar cell characteristics. These data provide further insights into the mechanisms underlying LUAD evolution in patients.
2023-11-18 | GSE161806 | GEO
Project description:Alveolar macrophages from never smokers and active smokers were isolated by bronchoalveolar lavage and gene expression was measured. Chronic cigarette smoke exposure, as occurs in smoker's lungs, leads to significant changes in gene expression. Of note, RNA was isolated immediately following bronchoscopy. Alveolar macrophage levels were >95%. 4 never smokers and 4 active smokers were recruited for the study. After bronchoalveolar lavage and RNA isolation, gene expression was measured using Affymetrix Human Exon 1.0 ST arrays.
2012-10-02 | E-GEOD-34517 | biostudies-arrayexpress
Project description:To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer F344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m3 (0.03, 0.06, 0.11, and 0.44 mg Ni/m3) for one and four weeks (6 hours per day, 5 days per week). Results: Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1 week to up-regulation at 4 weeks. Conclusions: These results support a mode of action for Ni3S2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026 mg Ni/m3, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64 M-BM-5g Ni/g lung, for immune/inflammatory signaling. Implications: These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni3S2 toxicity and carcinogenicity. Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer F344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m3 (0.03, 0.06, 0.11, and 0.44 mg Ni/m3) for one and four weeks (6 hours per day, 5 days per week).
2014-07-19 | E-GEOD-59593 | biostudies-arrayexpress
Project description:Empirical evidence from both animals and humans suggest that PM2.5 (particulate matter < 2.5μm) exposure accelerates a variety of non-communicable diseases (NCDs) including Type 2 diabetes. We investigated whether chronic exposure to ambient air pollution (PM2.5), disrupts circadian rhythm to facilitate metabolic insulin resistance and compared the impact of inhaled ambient PM2.5 alone or in combination with continuous light exposure (LL). Exposure to PM2.5 induced peripheral IR, disrupted circadian steroid release, reduced peak oxygen consumption and altered brown adipose 18Ffluorodeoxyglucose uptake on PET imaging. These findings were identical to that seen with LL with no additive interaction between PM2.5 and LL. Transcriptome profiles in the liver revealed a number of differentially expressed circadian genes Bmal1 (Arntl/Npas2), Period (Per) and Cryptochrome (Cry) in response to PM2.5. Alteration in chromatin accessibility in circadian targets was observed with PM2.5 by Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) while chromatin immunoprecipitation (ChIP) analysis, showed a marked difference in promoter occupancy by p300. Our data suggest a previously unrecognized role of particulate air pollution in promoting circadian disruption and metabolic dysfunction through epigenetic regulation of multiple circadian targets
2020-12-01 | GSE145566 | GEO
Project description:Exposure to particulate matter (PM) is consistently associated with increased morbidity and mortality attributable in part to respiratory illnesses. The alveolar macrophage (AM) is one of the cell types in the lung constantly exposed to and activated by ambient pollutants. Upon contact with environmental particulate pollutants, AM produces reactive oxygen species (ROS) and antioxidant enzymes, but the scope of this oxidative stress response induced by PM remains poorly defined. In this study, we used microarray analysis to determine the gene expression profile in human alveolar macrophages upon exposure to PM and sought to gain more insight into the global response of pro- and anti-oxidant enzymes to PM exposure. Human AM were obtained by bronchoscopy from normal individuals. They were then incubated with Chapel Hill PM2.5 (1 ug/ml) or vehicle for 4 hours (n = 6 independent samples each). mRNAs were extracted, amplified and hybridized to Agilent Human 1A microarray. Differentially expressed genes were identified by Statistical Analysis for Microarrays (SAM) with a FDR of 10% and a P ≤ 0.05. Significant genes were also mapped with Gene Ontology (GO) based on their molecular function. We found 34 and 41 up- and down-regulated genes respectively. Of these, 22 genes (~30%) were involved in metal binding and 14 genes were linked to oxidative stress, including 5 metallothionein-1 (MT1) isoform genes. In lung cells, addition of MT-1F in the medium attenuated PM2.5-induced H2O2 production while knockdown of MT1F gene expression increased H2O2 and IL-6 release induced by PM2.5. Our microarray experiments provided a global view of gene expression after in vitro PM2.5 exposure in human AM. The expression profile was most notable for differential expression of genes related to metal binding and oxidative stress, especially upregulation of MT1 isoform genes. Our findings suggest that metals associated with PM, e.g., zinc, copper, and arsenic, induce MT-1 and may be the primary mediators for PM-induced oxidative stress. Keywords: in vitro exposure, PM2.5 particle treatment, human alveolar macrophages
2008-05-01 | GSE10394 | GEO
Project description:We tried to identify growth factor(s) to promote regeneration of type 2 alveolar epitherial cells. To identify such candidates, we compared gene expression profiles of RNAs from lungs of mice of the following four different groups of bone marrow (BM) chimeric mice after diphteria toxin (DT) injection. LL, BM cells of LysM-DTR mice into LysM-DTR mice; WL, BM cells of wild-type mice into LysM-DTR mice; LW, BM cells of LysM-DTR mice into wild-type mice; WW, BM cells of wild-type mice into wild-type mice. Transcriptome analysis revealed that a set of growth factor-related genes was upregulated in the lungs of WL mice compared to LL mice.
2018-07-26 | GSE117630 | GEO