Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5).
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ABSTRACT:
SUBMITTER: Walters DM
PROVIDER: S-EPMC3929674 | biostudies-literature | 2014 Mar
REPOSITORIES: biostudies-literature
Publications
Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5).
Walters Dianne M DM White Kevin M KM Patel Ushma U Davis Martin J MJ Veluci-Marlow Roberta M RM Bhupanapadu Sunkesula Solomon Raju SR Bonner James C JC Martin Jessica R JR Gladwell Wes W Kleeberger Steven R SR
FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20131127 3
Interstitial lung diseases (ILDs) are characterized by injury, inflammation, and scarring of alveoli, leading to impaired function. The etiology of idiopathic forms of ILD is not understood, making them particularly difficult to study due to the lack of appropriate animal models. Consequently, few effective therapies have emerged. We developed an inbred mouse model of ILD using vanadium pentoxide (V2O5), the most common form of a transition metal found in cigarette smoke, fuel ash, mineral ores, ...[more]
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Project description:Exposure to vanadium pentoxide (V2O5) is a cause of occupational bronchitis. We evaluated gene expression profiles in cultured human lung fibroblasts exposed to V2O5 in vitro in order to identify candidate genes that could play a role in airway remodeling associated with V2O5-induced bronchitis. Gene expression was measured at various time points over a 24 hr period using the Affymetrix Human Genome U133A 2.0 Array. Expression data were preprocessed using RMA with a log2 transformation. Statistical analysis was performed in R using the affylmGUI package using a linear model with contrasts between untreated control and V2O5-exposed fibroblasts. Genes identified as statistically significant were filtered by selecting only those genes that exhibited a > 2-fold change. Quantitative real-time RT-PCR was utilized to confirm expression of selected genes. More than 2000 genes were significantly changed in response to V2O5 over the time course of our experiment. Genes altered by V2O5 were involved in biologic processes related to cell growth and differentiation, oxidative stress responses, immune regulation, and interferon signaling and apoptosis. In particular, V2O5 induced genes that encode growth factors involved in epithelial repair (HB-EGF) or angiogenesis (VEGF), peroxide generating enzymes (SOD2), pro-inflammatory enzymes (PGHS2), while suppressing genes involved in growth arrest (GAS1, STAT-1) and cell cycle inhibition (CDKN1B). Our study also identified a variety of novel genes that could be used as biomarkers of V2O5-induced bronchitis or could serve as candidate genes for disease progression. Keywords: time course, stress response
2007-01-01 | GSE5339 | GEO
Project description:Exposure to vanadium pentoxide (V2O5) is a cause of occupational bronchitis. We evaluated gene expression profiles in cultured human lung fibroblasts exposed to V2O5 in vitro in order to identify candidate genes that could play a role in airway remodeling associated with V2O5-induced bronchitis. Gene expression was measured at various time points over a 24 hr period using the Affymetrix Human Genome U133A 2.0 Array. Expression data were preprocessed using RMA with a log2 transformation. Statistical analysis was performed in R using the affylmGUI package using a linear model with contrasts between untreated control and V2O5-exposed fibroblasts. Genes identified as statistically significant were filtered by selecting only those genes that exhibited a > 2-fold change. Quantitative real-time RT-PCR was utilized to confirm expression of selected genes. More than 2000 genes were significantly changed in response to V2O5 over the time course of our experiment. Genes altered by V2O5 were involved in biologic processes related to cell growth and differentiation, oxidative stress responses, immune regulation, and interferon signaling and apoptosis. In particular, V2O5 induced genes that encode growth factors involved in epithelial repair (HB-EGF) or angiogenesis (VEGF), peroxide generating enzymes (SOD2), pro-inflammatory enzymes (PGHS2), while suppressing genes involved in growth arrest (GAS1, STAT-1) and cell cycle inhibition (CDKN1B). Our study also identified a variety of novel genes that could be used as biomarkers of V2O5-induced bronchitis or could serve as candidate genes for disease progression. Experiment Overall Design: Experimental Design Experiment Overall Design: Normal adult human lung fibroblasts (ATCC 16 Lu) were purchased from American Type Culture Collection (Rockville, MD). Fibroblasts were seeded into 175 cm2 plastic culture flasks and grown to confluence in 10% fetal bovine serum (FBS)/Dulbeccoâs modified Eagleâs medium (DMEM), then trypsin-liberated, and seeded into 150 mm dishes. Confluent monolayers were rendered quiescent for 24 hrs in serum-free defined medium (SFDM) that consisted of Hamâs F-12 medium with 0.25% BSA with an insulin/transferrin/selenium supplement. Cells were treated with 10 µg/cm2 vanadium pentoxide, V2O5 (Aldrich Chemical, Milwaukee, WI) or SFDM and RNA was harvested from the fibroblast cultures at 1, 4, 8, 12 and 24 hrs post-treatment. RNA from an SFDM control was harvested at each of these time points to normalize the V2O5 treatment at the same corresponding time point. Three replicate chips were analyzed for SFDM and V2O5 treatment groups at each of the five time points tested. Experiment Overall Design: Microarray Hybridizations and Data Analysis Experiment Overall Design: Human lung fibroblast RNA was isolated using RNeasy columns (Qiagen, Valencia, CA). RNA quality was verified by spectrophotometry and gel electrophoresis using the Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA). Probe preparation and hybridization to the microarray was performed in the CIIT Gene Expression Core Facility using standard Affymetrix procedures. Double-stranded cDNA was synthesized from RNA using an oligo-dT24-T7. Biotinylated cRNA was synthesized from an aliquot of the cDNA template using the T7 RNA Transcript Labeling Kit (ENZO Diagnostics, Farmingdale NY). The labeled cRNA was then fragmented, hybridized to Affymetrix Human Genome U133A 2.0 arrays (Affymetrix, Santa Clara, CA), and stained using phycoerythrein-conjugated streptavidin (Molecular Probes, Eugene, OR). Experiment Overall Design: Statistical Analysis and Data Processing Experiment Overall Design: The microarray data were preprocessed using RMA with a log base 2 (log2) transformation. Statistical analysis of the data was performed in R using the affyImGUI package. To identify genes with significant changes in expression following V2O5 exposure, all treatment groups were analyzed using a linear model with contrasts between untreated fibroblasts and V2O5-exposed fibroblasts at each time point. Probability values were adjusted for multiple comparisons using a false discovery rate of 5% (FDR = 0.05). Genes identified as statistically significant were subject to an additional filter by selecting only those genes that exhibited a > 2-fold change from the untreated fibroblasts.
2008-11-22 | E-GEOD-5339 | biostudies-arrayexpress
Project description:Recent genetic findings have identified new targets of investigation in the field of pulmonary fibrosis and have the potential to change clinical care.These findings implicate alterations in host defense, cell-to-cell adhesion, and aging and senescence in the pathophysiology of pulmonary fibrosis. At least one common genetic variant strongly associated with pulmonary fibrosis appears to have prognostic implications for patients.The inherited risk for pulmonary fibrosis is substantial, and recent data suggest that genetic risk for familial and sporadic forms of the disease are similar. Further characterizing this genetic risk will influence clinical practice in terms of categorization, diagnosis, and screening of individuals for this disease.
| S-EPMC4337021 | biostudies-literature
Project description:BACKGROUND: Elevated levels of air pollution are associated with increased risk of lung cancer. Particulate matter (PM) contains transition metals that may potentiate neoplastic development through the induction of oxidative stress and inflammation, a lung cancer risk factor. Vanadium pentoxide (V2O5) is a component of PM derived from fuel combustion as well as a source of occupational exposure in humans. In the current investigation we examined the influence of genetic background on susceptibility to V2O5-induced inflammation and evaluated whether V2O5 functions as a tumor promoter using a 2-stage (initiation-promotion) model of pulmonary neoplasia in mice. RESULTS: A/J, BALB/cJ (BALB), and C57BL/6J (B6) mice were treated either with the initiator 3-methylcholanthrene (MCA; 10 microg/g; i.p.) or corn oil followed by 5 weekly aspirations of V2O5 or PBS and pulmonary tumors were enumerated 20 weeks following MCA treatment. Susceptibility to V2O5-induced pulmonary inflammation was assessed in bronchoalveolar lavage fluid (BALF), and chemokines, transcription factor activity, and MAPK signaling were quantified in lung homogenates. We found that treatment of animals with MCA followed by V2O5 promoted lung tumors in both A/J (10.3 +/- 0.9 tumors/mouse) and BALB (2.2 +/- 0.36) mice significantly above that observed with MCA/PBS or V2O5 alone (P < 0.05). No tumors were observed in the B6 mice in any of the experimental groups. Mice sensitive to tumor promotion by V2O5 were also found to be more susceptible to V2O5-induced pulmonary inflammation and hyperpermeability (A/J>BALB>B6). Differential strain responses in inflammation were positively associated with elevated levels of the chemokines KC and MCP-1, higher NFkappaB and c-Fos binding activity, as well as sustained ERK1/2 activation in lung tissue. CONCLUSIONS: In this study we demonstrate that V2O5, an occupational and environmentally relevant metal oxide, functions as an in vivo lung tumor promoter among different inbred strains of mice. Further, we identified a positive relationship between tumor promotion and susceptibility to V2O5-induced pulmonary inflammation. These findings suggest that repeated exposures to V2O5 containing particles may augment lung carcinogenesis in susceptible individuals through oxidative stress mediated pathways.
| S-EPMC2861012 | biostudies-literature
Project description:Both environmental exposure to vanadium pentoxide (V2O5, V+5 for its ionic counterparts) and fibroblast senescence are associated with pulmonary fibrosis, but whether V+5 causes fibroblast senescence remains unknown. We found in a dose-response study that 2-40 μM V+5 caused human lung fibroblasts (HLF) senescence with increased senescence-associated β-galactosidase activity and p16 expression, while cell death occurred at higher concentration (LC50, 82 μM V+5). Notably, measures of reactive oxygen species (ROS) production with fluorescence probes showed no association of ROS with V+5-dependent senescence. Preloading catalase (polyethylene-conjugated), a H2O2 scavenger, did not alleviate the cellular senescence induced by V+5. Analyses of the cellular glutathione (GSH) system showed that V+5 oxidized GSH, increased GSH biosynthesis, stimulated cellular GSH efflux and increased protein S-glutathionylation, and addition of N-acetyl cysteine inhibited V+5-elevated p16 expression, suggesting that thiol oxidation mediates V+5-caused senescence. Moreover, strong correlations between GSSG/GSH redox potential (Eh), protein S-glutathionylation, and cellular senescence (R2 > 0.99, p < 0.05) were present in V+5-treated cells. Studies with cell-free and enzyme-free solutions showed that V+5 directly oxidized GSH with formation of V+4 and GSSG in the absence of O2. Analyses of V+5 and V+4 in HLF and culture media showed that V+5 was reduced to V+4 in cells and that a stable V+4/V+5 ratio was rapidly achieved in extracellular media, indicating ongoing release of V+4 and reoxidation to V+5. Together, the results show that V+5-dependent fibroblast senescence is associated with a cellular/extracellular redox cycling mechanism involving the GSH system and occurring under conditions that do not cause cell death. These results establish a mechanism by which environmental vanadium from food, dietary supplements or drinking water, can cause or contribute to lung fibrosis in the absence of high-level occupational exposures and cytotoxic cell death.
| S-EPMC9307685 | biostudies-literature
Project description:Susceptibility to fibrotic lung disease differs among people and among inbred strains of mice exposed to bleomycin where C57BL/6J mice are susceptible and C3H/HeJ mice are spared fibrotic disease. Genetic mapping studies completed in offspring derived from these inbred strains revealed the inheritance of C57BL/6J alleles at loci, including the major locus on chromosome 17, called Blmpf1 bleomycin-induced pulmonary fibrosis 1, to be linked to pulmonary fibrosis in treated mice. In the present study, to reduce the interval of Blmpf1, we bred and phenotyped a panel of subcongenic mice with C3H/HeJ alleles in a C57BL/6J background. Subcongenic mice received bleomycin via osmotic minipump and the fibrosis phenotype was measured histologically. Inheritance of C3H/HeJ alleles from 34.31 to 35.02 Mb was revealed to spare bleomycin-induced pulmonary fibrosis of C57BL/6J mice. From database analysis, 40 protein coding genes have been mapped to this reduced Blmpf1 interval, 18 of which contain C57BL/6J:C3H/HeJ sequence polymorphisms predicted to affect protein structure or to confer allele-dependent expression, and by RT-PCR analysis of lung tissue, we show 6 of these genes to differ in expression between C57BL/6J and C3H/HeJ mice. Genes known to regulate T cell numbers and activation (Btnl family, Notch4) are among the limited list of potential causal variants leading to lung disease in this model and the bronchoalveolar lavage of protected subcongenic mice had fewer lymphocytes, post bleomycin, than did C57BL/6J mice. We conclude that Blmpf1genes contributing to the susceptibility to bleomycin-induced pulmonary fibrosis could alter the adaptive immune response of C57BL/6J mice.
| S-EPMC6182746 | biostudies-literature
Project description:Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P < 0.05/12) with ILAs.Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.
| S-EPMC6884045 | biostudies-literature
Project description:The self-healing ability can be imparted to the polymers by different mechanisms. In this study, self-healing polydimethylsiloxane-graft-polyurethane (PDMS-g-PUR)/Vanadium pentoxide (V₂O₅) nanofiber supramolecular polymer composites based on a reversible hydrogen bonding mechanism are prepared. V₂O₅ nanofibers are synthesized via colloidal route and characterized by XRD, SEM, EDX, and TEM techniques. In order to prepare PDMS-g-PUR, linear aliphatic PUR having one ⁻COOH functional group (PUR-COOH) is synthesized and grafted onto aminopropyl functionalized PDMS by EDC/HCl coupling reaction. PUR-COOH and PDMS-g-PUR are characterized by ¹H NMR, FTIR. PDMS-g-PUR/V₂O₅ nanofiber composites are prepared and characterized by DSC/TGA, FTIR, and tensile tests. The self-healing ability of PDMS-graft-PUR and composites are determined by mechanical tests and optical microscope. Tensile strength data obtained from mechanical tests show that healing efficiencies of PDMS-g-PUR increase with healing time and reach 85.4 ± 1.2 % after waiting 120 min at 50 °C. The addition of V₂O₅ nanofibers enhances the mechanical properties and healing efficiency of the PDMS-g-PUR. An increase of healing efficiency and max tensile strength from 85.4 ± 1.2% to 95.3 ± 0.4% and 113.08 ± 5.24 kPa to 1443.40 ± 8.96 kPa is observed after the addition of 10 wt % V₂O₅ nanofiber into the polymer.
| S-EPMC6401741 | biostudies-literature
Project description:The progression of pulmonary fibrosis (PF) entails a complex network of interactions between multiple classes of molecules and cells, which are closely related to the vagus nerve. Stimulation of the vagus nerve increases fibrogenic cytokines in humans, therefore, activation of the nerve may promote PF. The hypothesis was tested by comparing the extent and severity of fibrosis in lungs with and without vagal innervation in unilaterally vagotomized mice. The results show that in vagotomized lungs, there were less collagen staining, less severe fibrotic foci (subpleural, peri-vascular and peri-bronchiolar lesions) and destruction of alveolar architecture; decreased collagen deposition (denervated vs intact: COL1α1, 19.1 ± 2.2 vs 22.0 ± 2.6 ng/mg protein; COL1α2, 4.5 ± 0.3 vs 5.7 ± 0.5 ng/mg protein; p < 0.01, n = 21) and protein levels of transforming growth factor beta and interleukin 4; and fewer myofibroblast infiltration (denervated vs intact: 1.2 ± 0.2 vs 3.2 ± 0.6 cells/visual field; p < 0.05, n = 6) and M2 macrophages [though the infiltration of macrophages was increased (denervated vs intact: 112 ± 8 vs 76 ± 9 cells/visual field; p < 0.01, n = 6), the percentage of M2 macrophages was decreased (denervated vs intact: 31 ± 4 vs 57 ± 9%; p < 0.05, n = 5)]. It indicated that the vagus nerve may influence PF by enhancing fibrogenic factors and fibrogenic cells.
| S-EPMC4542162 | biostudies-other
Project description:Vanadium-based catalysts are used in many technological processes, among which the removal of nitrogen oxides (NOx) from waste gases is one of the most important. The chemical reaction responsible for this selective catalytic reaction (SCR) is based on the reduction of NOx molecules to N2, and a possible reductant in this case is pre-adsorbed NH3. In this paper, NH3 adsorption on Brønsted OH acid centers on low-index surfaces of V2O5 (010, 100, 001) is studied using a theoretical DFT method with a gradient-corrected functional (RPBE) in the embedded cluster approximation model. The results of the calculations show that ammonia molecules are spontaneously stabilized on all low-index surfaces of the investigated catalyst, with adsorption energies ranging from -0.34 to -2 eV. Two different mechanisms of ammonia adsorption occur: the predominant mechanism involves the transfer of a proton from a surface OH group and the stabilization of ammonia as an NH4 (+) cation bonded to surface O atom(s), while an alternative mechanism involves the hydrogen bonding of NH3 to a surface OH moiety. The latter binding mode is present only in cases of stabilization over a doubly coordinated O(2) center at a (100) surface. The results of the calculations indicate that a nondirectional local electrostatic interaction with ammonia approaching a surface predetermines the mode of stabilization, whereas hydrogen-bonding interactions are the main force stabilizing the adsorbed ammonia. Utilizing the geometric features of the hydrogen bonds, the overall strength of these interactions was quantified and qualitatively correlated (R = 0.93) with the magnitude of the stabilization effect (i.e., the adsorption energy).
| S-EPMC3778235 | biostudies-literature