Gene expression profiling of human fibroblast MRC5 cells exposed to cigarette smoke condensate (CSC)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE252801 | GEO | 2024/01/15
REPOSITORIES: GEO
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Project description:We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells (HBEC) for transformation by a single oncogene. The smoke-induced, chromatin changes include initial repressive polycomb marking of genes later manifesting abnormal DNA methylation by 10 months. At this time, cells manifest epithelial to mesenchymal changes, anchorage-independent growth and upregulated RAS/MAPK signaling with silencing of hyper-methylated genes normally inhibiting these pathways and which are associated with smoking related NSCLC. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adeno-squamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation.
2017-10-21 | GSE101673 | GEO
Project description:We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells (HBEC) for transformation by a single oncogene. The smoke-induced, chromatin changes include initial repressive polycomb marking of genes later manifesting abnormal DNA methylation by 10 months. At this time, cells manifest epithelial to mesenchymal changes, anchorage-independent growth and upregulated RAS/MAPK signaling with silencing of hyper-methylated genes normally inhibiting these pathways and which are associated with smoking related NSCLC. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adeno-squamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation.
2017-10-21 | GSE101863 | GEO
Project description:We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells (HBEC) for transformation by a single oncogene. The smoke-induced, chromatin changes include initial repressive polycomb marking of genes later manifesting abnormal DNA methylation by 10 months. At this time, cells manifest epithelial to mesenchymal changes, anchorage-independent growth and upregulated RAS/MAPK signaling with silencing of hyper-methylated genes normally inhibiting these pathways and which are associated with smoking related NSCLC. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adeno-squamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation.
2017-10-21 | GSE101862 | GEO
Project description:Cigarette smoke (CS)-induced airway inflammation is an important pathologic feature of chronic obstructive pulmonary disease (COPD). Recent studies suggest a potential role of JunD in the regulation of inflammation, but its role in CS-induced airway inflammation has not been reported. This study aimed to determine its role in CS-induced airway inflammation through bioinformatics analysis and in vitro and in vivo experiments. Data from the Gene Expression Omnibus (GEO) database (GSE37147) were analyzed using weighted gene co-expression network analysis (WGCNA) and key driver analysis (KDA), and these analyses were validated using the GSE47460 dataset. The effect of CS on JunD expression was examined in lung tissues of COPD patients and CS-exposed mice and in CS extract (CSE)-exposed BEAS-2B cells. The effects of CSE on airway epithelial inflammatory injury after JunD knockdown or overexpression were also investigated. mRNA-seq and chromatin immunoprecipitation (ChIP)-seq were used to explore the mechanism of JunD-mediated CS-induced airway inflammation. Mice were injected with adeno-associated virus serotype 9 (AAV9)-JunD vector or control vector and then exposed to CS for 4 weeks, and lung tissue morphology and airway inflammation were evaluated. KDA of the lung function-related gene modules in GSE37147 revealed a potential role of JunD in COPD, which was validated in GSE47460. JunD was downregulated in lung tissues of COPD patients and CS-exposed mice and in BEAS-2B cells. JunD knockdown aggravated CSE-induced tumor necrosis factor (TNF)-α and interleukin (IL)-1β release by BEAS-2B cells, while JunD overexpression attenuated these effects. mRNA-seq and ChIP-seq identified several JunD-regulated genes, which are involved in the immune response and TNF signaling pathway and are commonly dysregulated in cell models of airway inflammation. In vivo, JunD overexpression attenuated the CS-induced inflammatory cell infiltration and inflammatory cytokine release in mouse lungs. Thus, JunD is involved in CS-induced airway inflammation and JunD-based therapy may be useful in CS-induced airway disorders.
2020-12-09 | GSE162902 | GEO
Project description:Chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality, is primarily caused by prolonged exposures to cigarette smoke (CS) and the disease may persist or progress even after smoking cessation. To provide novel insight the mechanisms of COPD development we investigated temporal patterns of lung transcriptome expression in response to chronic CS exposure that also persist following CS cessation, using next generation sequencing techniques. Whole lung RNA-seq data was analyzed from C57Bl/6 mice exposed to CS for 1 day, 7 days, 1 month, 3 months, 6 months, and 9 months as well as for 6 months followed by 3 months of cessation. Age-matched littermate mice exposed to ambient air were used as control (AC). Differential gene expression and pathway analyses revealed consistent upregulation of genes involved in glutathione metabolism, a pathway previously implicated in lung responses to chronic CS and in COPD, that was reversible upon cessation. In addition, novel patterns in mouse-model pathways such as pyrimidine metabolism and phosphatidylinositol signaling system and have been recognized. Genes in these pathways encoding for enzymes controlling metabolic functions were significantly altered by CS exposures and were associated with congruent abnormalities in contemporaneous plasma metabolomic profiles. The bioinformatics integration of lung tissue genomics and plasma metabolomics uncovered that changes in lung gene expression induced by CS exposures are translated in systemic metabolic signatures, with potential implication in the development of COPD.
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Project description:Chronic obstructive pulmonary disease (COPD) is characterized by a progressive decline in lung function, caused by exposure to exogenous particles, mainly cigarette smoke (CS). COPD pathogenesis is initiated and perpetuated by an abnormal CS-induced inflammatory response of the lungs, involving both innate and adaptive immunity. Specifically, B cells organized in iBALT structures, as well as macrophages, accumulate in the lungs and contribute to CS-induced emphysema, but the mechanisms thereof remain unclear. Here, we demonstrate that B cell-deficient mice are significantly protected against CS-induced emphysema. Chronic CS exposure led to increased lung compliance, total lung capacity, and mean linear chord length in WT, but not B cell-deficient mice, associated with an increased size and number of iBALT structures. The increased accumulation of macrophages around iBALT and in emphysematous alveolar areas in CS-exposed WT mice coincided with upregulated MMP12 expression. In vitro co-culture experiments using B cells and macrophages demonstrated that B cell-derived IL-10 drives macrophage activation and MMP12 upregulation. In summary, B cell function in iBALT formation in CS-induced emphysema provides a new innovative mechanism, which could be explored as a target for therapeutic intervention in COPD patients.
2014-12-04 | GSE52509 | GEO
Project description:Although smoking cessation shows clear cardiovascular risk benefits, lung-related disease risk remains higher in former smokers than in never smokers. To better understand the factors involved in this phenomenon, ApoE-/- mice were exposed to mainstream cigarette smoke (CS) or a smoking cessation-mimicking protocol for up to six months. Analysis of bronchoalveolar lavage fluid (BALF) from CS-exposed ApoE-/- mice revealed the presence of high concentrations of mediators involved in functions ranging from inflammation to cell proliferation and tissue remodeling. Gene expression levels for many analytes found elevated in BALF were also increased in lung tissue, indicating that the inflammatory response was the result of local tissue activation and the contribution of recruited inflammatory cells. Gene set enrichment analysis (GSEA) of expression data from lungs of CS-exposed mice showed activation of pathways involved in cell proliferation and tissue remodeling and a progressive deactivation upon smoke exposure cessation. Distinct activation patterns of inflammation, complement, and xenobiotic metabolism pathways were found in nasal epithelium and lung parenchyma during CS exposure and smoking cessation. Exposure of ApoE-/- mice to CS for up to 6 months induced adaptive and inflammatory responses in the respiratory tract that were partially deactivated upon cessation. We were able to reveal molecular perturbations accompanying these changes during CS exposure and cessation. Differential CS-mediated responses of pulmonary and nasal tissues reflect common mechanisms but also the varying degrees of epithelial functional specialization along the respiratory tract. These findings provide novel clues for the identification of markers of COPD progression.
2013-10-19 | E-MTAB-1390 | biostudies-arrayexpress
Project description:The lymphatic vasculature is critical for lung function, but defects in lymphatic functionin the pathogenesis of lung disease is understudied. To further assess the contribution of lymphatics to the pathogenesis of lung emphysema we used a mouse model of cigarette smoke (CS)-induced emphysema, and analyzed lung lymphatics using immunohistochemistry, functional assays, and confocal microscopy. Additionally, we further harvested thoracic lymph from CS-exposed mice for proteomic analysis. In this presented section of our research, we highlight the label free quantitative DIA proteomics approaches used to profile the proteomic and peptidomics changes in the lymph from cigarette smoke (CS)-mice as compared with the lymph proteome from mice exposed to room air. Label free quantitative DIA proteomics analysis of lymph confirmed upregulation of coagulation and inflammatory pathways in the lymphatics of CS-exposed mice compared to control mice.
2022-05-10 | PXD031413 | Pride
Project description:Chronic obstructive pulmonary disease (COPD) is a complex pulmonary disorder primarily induced by cigarette smoking, and characterized by persistent airflow limitation. The mouse represents an important model for studying COPD pathologies such as lung emphysema. In this respect, a number of mechanistic studies have been performed, however the approaches were mostly focused on single gene analysis or characterization of cellular, inflammatory or histopathological changes without attempting a more comprehensive interpretation. In the present study we aimed at applying systems biology approach to identify genome-wide molecular mechanisms indicative of cigarette smoke (CS)-induced lung emphysema. The lung transcriptomes of five mouse models (C57BL/6, ApoE-/-, A/J, CD1, and Nrf2-/-), that are known to be susceptible to CS-induced emphysema development, were analyzed following prolonged (5-6 months) CS exposure. The investigation resulted in the confirmation of many existing mechanistic explanations underlying smoke-induced lung emphysema, including increased transcriptional activity of NF-?B, and increased levels of TNF-a, IFN-g, and IL-1b. More importantly, we predicted mechanisms without currently well-documented roles, including increased transcriptional activity of PU.1, STAT1, C/EBP, FOXM1, YY1 and N-cor, and increased IL-17 cytokine expression, and reduced protein expression of ITGB6 and CFTR. We also corroborated, by using targeted proteomic approaches, several predictions such as reduced expression of ITGB6 and increased expression of BRCA1, C/EBPs, PU.1, TNF-a, IL-1b or CSF2. We believe this study will provide more insights into better understanding of CS-induced molecular processes underlying emphysema development in mice that may eventually be relevant in humans.
2014-11-28 | E-MTAB-2756 | biostudies-arrayexpress
Project description:We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells (HBEC) for transformation by a single oncogene. The smoke-induced, chromatin changes include initial repressive polycomb marking of genes later manifesting abnormal DNA methylation by 10 months. At this time, cells manifest epithelial to mesenchymal changes, anchorage-independent growth and upregulated RAS/MAPK signaling with silencing of hyper-methylated genes normally inhibiting these pathways and which are associated with smoking related NSCLC. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adeno-squamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation.
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