The role of NOXO1 in the mouse model of cigarette smoke-induced emphysema and pulmonary hypertension
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE112287 | GEO | 2020/03/01
REPOSITORIES: GEO
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Project description:Chronic Obstructive Pulmonary Disease, which is comprised of chronic bronchitis and emphysema, is a leading cause of morbidity and mortality. Because tissue destruction is the prominent characteristic of emphysema, extracellular proteinases, particularly those with elastolytic ability, are often considered to be key drivers in this disease. Several human and mouse studies have implicated roles for matrix metalloproteinases (MMPs), particularly macrophage-derived proteinases, in COPD pathogenesis. MMP28 is expressed by the pulmonary epithelium and macrophage, and we have found that it regulates macrophage recruitment and polarization. We hypothesized that MMP28 would have contributory roles in emphysema via alteration of macrophage numbers and activation. Because of the established association of emphysema pathogenesis to macrophage influx, we evaluated the inflammatory changes and lung histology of Mmp28-/- mice exposed to 3 and 6 months of cigarette smoke. At earlier time-points, we found altered macrophage polarization in the smoke-exposed Mmp28-/- lung consistent with other published findings that MMP28 regulates macrophage activation. At both 3 and 6 months, Mmp28-/- mice had blunted inflammatory responses more closely resembling non-smoked mice, with a reduction in neutrophil recruitment and CXCL1 chemokine expression. By 6 months, Mmp28-/- mice were protected from emphysema. These results highlight a previously unrecognized role for MMP28 in promoting chronic lung inflammation and tissue remodeling induced by cigarette smoke and highlight another potential target to modulate COPD.
2017-02-18 | GSE93898 | GEO
Project description:HIV1+ smokers develop emphysema at an earlier age and with a higher incidence than HIV1- smokers. Based on the knowledge that human alveolar macrophages (AM) are capable of producing proteases that degrade extracellular matrix components, we hypothesized that upregulation of AM matrix metalloproteinases may be associated with the emphysema of HIV1+ smokers. To test this hypothesis, microarray analysis was used to screen which MMP genes were expressed by AM isolated by bronchoalveolar lavage (BAL) of HIV1+ smokers with early emphysema. For each of the MMP genes observed to be expressed (MMP-1, -2, -7, -9, -10, -12 and -14), TaqMan PCR was used to quantify the relative expression in AM from 4 groups of individuals: HIV1 healthy nonsmokers, HIV1- healthy smokers, HIV1- smokers with early emphysema and HIV1+ smokers with early emphysema. Strikingly, while AM gene expression of MMPs was higher in HIV1- individuals with emphysema in comparison with HIV1- healthy smokers, for the majority of the MMPs (-1, -7, -9, -10, -12), AM expression from HIV1+ smokers with early emphysema was significantly higher than HIV1- smokers with early emphysema. Consistent with these observations, HIV1+ individuals with early emphysema had higher levels of epithelial lining fluid MMPs (-2, -7, -9,-12) than the 3 HIV1 groups. Interestingly, the active forms of MMP-2, -9 and -12 were detected in epithelial lining fluid from HIV1+ individuals with early emphysema, but not in any of the other groups. Considering that the substrate specificity of the upregulated AM MMPs includes collagenases, gelatinases, matrilysins and elastase, these data suggest that upregulated AM MMP genes and activation of MMP proteins may contribute to the emphysema of HIV1+ individuals who smoke. Keywords: expression study Asymptomatic HIV+ smokers with early emphysema
2016-03-24 | E-GEOD-10038 | biostudies-arrayexpress
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:HIV1+ smokers develop emphysema at an earlier age and with a higher incidence than HIV1- smokers. Based on the knowledge that human alveolar macrophages (AM) are capable of producing proteases that degrade extracellular matrix components, we hypothesized that upregulation of AM matrix metalloproteinases may be associated with the emphysema of HIV1+ smokers. To test this hypothesis, microarray analysis was used to screen which MMP genes were expressed by AM isolated by bronchoalveolar lavage (BAL) of HIV1+ smokers with early emphysema. For each of the MMP genes observed to be expressed (MMP-1, -2, -7, -9, -10, -12 and -14), TaqMan PCR was used to quantify the relative expression in AM from 4 groups of individuals: HIV1 healthy nonsmokers, HIV1- healthy smokers, HIV1- smokers with early emphysema and HIV1+ smokers with early emphysema. Strikingly, while AM gene expression of MMPs was higher in HIV1- individuals with emphysema in comparison with HIV1- healthy smokers, for the majority of the MMPs (-1, -7, -9, -10, -12), AM expression from HIV1+ smokers with early emphysema was significantly higher than HIV1- smokers with early emphysema. Consistent with these observations, HIV1+ individuals with early emphysema had higher levels of epithelial lining fluid MMPs (-2, -7, -9,-12) than the 3 HIV1 groups. Interestingly, the active forms of MMP-2, -9 and -12 were detected in epithelial lining fluid from HIV1+ individuals with early emphysema, but not in any of the other groups. Considering that the substrate specificity of the upregulated AM MMPs includes collagenases, gelatinases, matrilysins and elastase, these data suggest that upregulated AM MMP genes and activation of MMP proteins may contribute to the emphysema of HIV1+ individuals who smoke. Keywords: expression study
2016-03-24 | GSE10038 | GEO
Project description:To assess the mechanism which caused emphysema in the IQOS group, we performed microarray analysis using homogenate lung tissue that were exposed to fresh air, IQOS aerosol, or cigarette smoke for 6 months. In microarray-based analysis, gene expressions to the air group were different in the IQOS and CS group, and apoptosis-related pathways were enhanced in the IQOS group. Apoptosis-related protein (cytochrome c, cleaved caspase-3, and cleaved PARP1) expression in the IQOS group were higher than air group in homogenete lungs. More single-stranded DNA and TUNEL positive alveolar cells were found in the IQOS group than control significantly.
2022-12-31 | GSE161869 | GEO
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. Expression data of mice treated with cigarette smoke. Lung tissue was analysed at four and six months of age.
2014-12-04 | E-GEOD-52509 | biostudies-arrayexpress
Project description:In this study, an α2(VI) deficient mouse (Col6α2-KO) model was used to examine the role of Type VI collagen in oral tissues. To examine bone properties, µCT was employed, and bone volume and bone mineral density (BMD) was measured in oral tissues. To further investigate its molecular basis, proteome analysis was performed using protein extracted from alveolar bone. In addition, alveolar bone loss progression was evaluated with a periodontitis induced model. µCT analysis showed the Col6α2- KO mice had less volume of alveolar bone, dentin and dental pulp, while the width of periodontal ligament (PDL) was greater than WT. The BMD in alveolar bone and dentin were elevated in Col6α2-KO mice compared with WT. Our proteome analysis showed significant changes in proteins related to ECM organization and elevation of proteins associated with biomineralization in the Col6α2-KO mice. In induced periodontitis, Col6α2-KO mice had greater alveolar bone loss compared to WT. In conclusion, Type VI collagen has role in controlling biomineralization in alveolar bone and that changes in the ECM of alveolar bone could be associated with greater bone loss from periodontitis.
2022-11-21 | PXD037422 | Pride
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:Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. We have demonstrated that paladin has a predominant vascular expression pattern and shifts from endothelial to mural cells during mouse development. We have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice displayed an emphysema-like phenotype with increased alveolar air spaces and impaired lung function with obstructive changes. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that paladin is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.
Proteomic analysis of Pald1 wild type and knock-out mice reveal that most of the protein expression differences are related to sex and not genotype, supporting the notion that sex can be a major factor for lung development and disease. In addition, Pald1 wild type and knock-out mice exhibit differential expression of HPGD, hydroxyprostaglandin dehydrogenase 15 (NAD), the major enzyme for degradation of prostaglandins.
2017-11-01 | PXD005625 | JPOST Repository
Project description:Patients with chronic obstructive pulmonary disease (COPD) having higher blood eosinophil levels exhibit worse lung function and more severe emphysema, implying the potential role of eosinophils in emphysema development. However, the specific mechanism underlying eosinophil-mediated emphysema development is not fully elucidated. In this study, single-cell RNA sequencing was used to identify eosinophil subgroups in mouse models of asthma and emphysema and analyze their functions. Analysis of the accumulated eosinophils revealed differential transcriptomes between the mouse lungs of elastase-induced emphysema and ovalbumin-induced asthma., Eosinophil depletion alleviated elastase-induced emphysema. Notably, eosinophil-derived cathepsin L (CTSL) degraded the extracellular matrix (ECM), causing emphysema in the pulmonary tissue. Eosinophils were positively correlated with serum CTSL levels, which were increased in patients with emphysema than in those without emphysema. Collectively, these results suggest that CTSL expression in eosinophils plays an important role in ECM degradation and remodeling and is related to emphysema in patients with COPD. Therefore, eosinophil-derived CTSL may serve as a potential therapeutic target for patients with emphysema.
2023-10-17 | GSE237749 | GEO