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Irp2 mediates cigarette smoke-induced bronchitis and emphysema via regulation of cytochrome c oxidase and mitochondrial iron loading

ABSTRACT: Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death globally, is influenced by both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as a candidate COPD susceptibility gene based on genetic association studies, with IRP2 increased in the lungs of COPD patients. Here we demonstrate that mice deficient in IRP2 are protected from cigarette smoke (CS)-induced COPD. Using RIP-Seq, RNA-Seq, gene expression and pathway analysis, we identify IRP2 as a regulator of mitochondrial function in the lung. We show that an increase in IRP2 results in a cytochrome c oxidase (COX)-dependent alteration in oxidative capacity and mitochondrial-iron dysfunction involving frataxin. We demonstrate that mice with impaired COX or frataxin activity have altered responses to CS and show that overexpressing IRP2 in vivo alters mitochondrial dynamics. These data suggest a critical role of the mitochondria-iron axis in mediating the pathogenesis of COPD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57073 | GEO | 2016/01/01

SECONDARY ACCESSION(S): PRJNA245391

REPOSITORIES: GEO

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Irp2 mediates cigarette smoke-induced bronchitis and emphysema via regulation of cytochrome c oxidase and mitochondrial iron loading.

2016-01-01 | GSE57048 | GEO

Irp2 mediates cigarette smoke-induced bronchitis and emphysema via regulation of cytochrome c oxidase and mitochondrial iron loading.

Project description:Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death globally, is influenced by both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as a candidate COPD susceptibility gene based on genetic association studies, with IRP2 increased in the lungs of COPD patients. Here we demonstrate that mice deficient in IRP2 are protected from cigarette smoke (CS)-induced COPD. Using RIP-Seq, RNA-Seq, gene expression and pathway analysis, we identify IRP2 as a regulator of mitochondrial function in the lung. We show that an increase in IRP2 results in a cytochrome c oxidase (COX)-dependent alteration in oxidative capacity and mitochondrial-iron dysfunction involving frataxin. We demonstrate that mice with impaired COX or frataxin activity have altered responses to CS and show that overexpressing IRP2 in vivo alters mitochondrial dynamics. These data suggest a critical role of the mitochondria-iron axis in mediating the pathogenesis of COPD. We used microarrays to compare the global programme of gene expression in the lungs of WT mice compared ot the lungs harvested from Irp2-/- mice. n=6 Wildtype C57/BL6 mice (n=3 males, 3 females), n=5 (n=2 males, n =3 females) Irp2-/- C57/BL6 mice, approx 28-32 weeks were sacrificied, lungs removed and snap forzen. RNA isolated after one freeze thaw cycle using the Qiagen RNeasy Kit.

2016-07-03 | E-GEOD-57048 | biostudies-arrayexpress

Irp2 mediates cigarette smoke-induced bronchitis and emphysema via regulation of cytochrome c oxidase and mitochondrial iron loading

Project description:Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death globally, is influenced by both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as a candidate COPD susceptibility gene based on genetic association studies, with IRP2 increased in the lungs of COPD patients. Here we demonstrate that mice deficient in IRP2 are protected from cigarette smoke (CS)-induced COPD. Using RIP-Seq, RNA-Seq, gene expression and pathway analysis, we identify IRP2 as a regulator of mitochondrial function in the lung. We show that an increase in IRP2 results in a cytochrome c oxidase (COX)-dependent alteration in oxidative capacity and mitochondrial-iron dysfunction involving frataxin. We demonstrate that mice with impaired COX or frataxin activity have altered responses to CS and show that overexpressing IRP2 in vivo alters mitochondrial dynamics. These data suggest a critical role of the mitochondria-iron axis in mediating the pathogenesis of COPD. 1.5 X106 Beas2B cells (purchased from ATCC) with or without 10 Î¼M DFO (16 h) (15 cm2 dishes) were washed with ice cold PBS and collected into 2 ml eppendorfs by scraping. RNA immunoprecipitation was carried out using the Magna RIPâ?¢ RNA-Binding Protein Immunoprecipitation Kit (Millipore, Billerica, MA). 4 Î¼g of Irp2 (7H6: sc-33682, Santa Cruz, Dallas, Texas) or 4 Î¼g of IgG rabbit control antibody (sc-2749, Santa Cruz) were added to supernatants and incubated overnight at 4Â°C. RNA was extracted from Magna RIPâ?¢ beads by Trizol extraction. Samples were prepared for RNA-Seq using the TruSeq RNA-Seq Lib Prep Reagent (Illumina, San Diego, CA) and performed on the Illumina HiSeq2000 platform.

2016-07-03 | E-GEOD-57073 | biostudies-arrayexpress

The protective role of hydrogen sulfide and its impact on gene expression profiling in rat model of COPD

Project description:To investigate the role of H2S in Chronic obstructive pulmonary disease (COPD), a rat model of COPD was established by cigarette smoking (CS) and intratracheal instillation of lipopolysaccharide (LPS). Rats were randomly divided into 4 groups: Control, CS+LPS, CS+LPS+NaHS and CS+LPS+propargylglycine (PPG). Transcription profiling of lung tissue comparing Control with CS+LPS, CS+LPS with CS+LPS+NaHS, and CS+LPS with CS+LPS+PPG. The goal was to determine the impact of H2S on gene expression profiling in rat model of COPD.

2021-09-24 | GSE184693 | GEO

Wistar rat model of COPD: Cigarette smoking exposure and fine particulate matter (PM2.5) exposure vs. control.

Project description:Genome-wide analysis of lncRNA expression profiles in COPD rat model exposed by cigarette smoking (CS) and fine particulate matter (PM2.5). Goal was to explore the differences and similarities lncRNAs expression in rats model of COPD exposed by CS and PM2.5.

2021-06-21 | GSE178513 | GEO

Identification of miRNAs in Mouse lung epithelial cells (MLE12) expression of which is altered by exposure to cigarette-smoke extracts

Project description:Our study aimed to identify miRNAs expression of which is affected by exposure to cigarette smoke (CS) in alveolar type-II cells. Identification and delineation of their modes of action is important for understanding CS-induced failure of repair mechanisms in COPD pathogenesis

2020-05-01 | GSE131188 | GEO

Transcriptomic analysis of lung tissue from cigarette smoke induced emphysema murine models and human COPD show shared and distinct pathways

Project description:Although cigarette smoke (CS) is the primary risk factor for COPD, the underlying molecular mechanisms for the significant variability in developing COPD in response to CS are incompletely understood. We performed lung gene expression profiling of two different wild-type murine strains (C57BL/6J, NZW/LacJ) and two genetic models with mutations in COPD GWAS genes (HHIP, FAM13A) after 6 months of chronic CS exposure and compared the results to human COPD lung tissues. We identified gene response patterns that correlate with severity of emphysema in mouse and human lungs. Xenobiotic metabolism and Nrf2-mediated oxidative stress response were commonly regulated molecular response patterns across C57BL/6J, Hhip +/- and Fam13a -/- murine models upon chronic CS exposure and human COPD subjects. The CS resistant Fam13a -/- mouse and NZW/LacJ strain revealed an opposite pattern of gene expression response, suggesting distinct molecular pathways for resistance against emphysema. There were few genes commonly modulated between mouse and humans. Our study suggests gene expression responses to CS may be largely species and model dependent, yet shared pathways could provide biologically significant insights underlying individual susceptibility to CS

2017-09-05 | GSE87292 | GEO

Fibroblast growth factor (FGF) 10 is essential for lung morphogenesis

Project description:Fibroblast growth factor (FGF) 10 is essential for lung morphogenesis and polymorphisms in the Fgf10 region are linked with higher susceptibility towards COPD in human patients. We found that FGF10 signaling is impaired in lung septal wall compartment from COPD patients. Mice with impaired FGF10 signaling (Fgf10+/-) were more prone to develop cigarette smoke (CS)-induced emphysema and pulmonary hypertension (PH). Furthermore, FGF10 overexpression could successfully reverse cigarette smoke-induced emphysema and PH in mice.

2024-04-01 | GSE230854 | GEO

Intermittent exposure to whole cigarette smoke alters the differentiation of primary small airway epithelial cells in the air-liquid interface culture

Project description:Cigarette smoke (CS) is the leading cause to develop COPD. Therefore, we investigated the pathologic effects of whole CS on the differentiation of primary small airway epithelial cells (SAEC), from three healthy donors and three COPD patients, cultured under ALI (air-liquid interface) conditions. The analysis of the epithelial physiology demonstrated that CS impaired barrier formation and reduced cilia beat activity. Although, COPD-derived ALI cultures preserved some features known from COPD patients, the CS-induced effects were similarly pronounced in ALI cultures from patients compared to healthy controls. A RNA sequencing analysis revealed the deregulation for marker genes for basal cells and secretory cells upon CS exposure. The comparison between gene signatures obtained from our in vitro model (CS vs. air) with a published data set from human epithelial brushes (smoker vs. non-smoker) reveals a high degree of similarity between the deregulated genes and pathways. ALI culture has been generated utilising cells obtained from 3 COPD and 3 healthy subjects. Subsequently cultures have been treated with CS and air respectively for 33 days. Gene expression profiles were generated using next generation sequencing.

2019-12-31 | GSE135188 | GEO

DNA methylation profiling in lungs tissues of smokers and patients with COPD

Project description:Epigenetics changes have been shown to be affected by cigarette smoking. It is possible that cigarette smoke (CS)-mediated DNA methylation would affect several cellular and pathophysiological processes, acute exacerbations, and comorbidity in lungs of patients with chronic obstructive pulmonary disease (COPD). We sought to determine whether genome-wide lung DNA methylation profiles of smokers and patients with COPD were significantly different from non-smokers. We isolated DNA from lung tissues of patients including 8 lifelong non-smokers, 8 current smokers, and 8 patients with COPD, and subsequently analyzed the samples using the Illumina’s Infinium HumanMethylation450 BeadChip.

2017-06-12 | GSE92511 | GEO

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