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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. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE57048 | GEO | 2016/01/01

SECONDARY ACCESSION(S): PRJNA245321

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 | GSE57073 | 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

Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring

Project description:BACKGROUND: The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about how HHIP contributes to COPD pathogenesis. METHODS: Here, we exposed Hhip haploinsufficient mice (Hhip+/-) to cigarette smoke (CS) for 6 months to model the biological consequences caused by CS in human COPD risk-allele carriers at the HHIP locus. Gene expression profiling in murine lungs was performed followed by an integrative network inference analysis, PANDA (Passing Attributes between Networks for Data Assimilation) analysis. RESULTS: We detected more severe airspace enlargement in Hhip+/- mice vs. wild-type littermates (Hhip+/+) exposed to CS. Gene expression profiling in murine lungs suggested enhanced lymphocyte activation pathways in CS-exposed Hhip+/- vs. Hhip+/+ mice, which was supported by increased numbers of lymphoid aggregates and enhanced activation of CD8+ T cells after CS-exposure in the lungs of Hhip+/- mice compared to Hhip+/+ mice. Mechanistically, results from PANDA network analysis suggested a rewired and dampened Klf4 signaling network in Hhip+/- mice after CS exposure. CONCLUSIONS: In summary, HHIP haploinsufficiency exaggerated CS-induced airspace enlargement, which models CS-induced emphysema in human smokers carrying COPD risk alleles at the HHIP locus. Network modeling suggested rewired lymphocyte activation signaling circuits in the HHIP haploinsufficiency state. Total RNA was obtained from the lung tissue of C57BL/6J mice exposed to cigarette smoke (CS) or filtered air (air) for 6 months. Six mice from each of four groups with different genotypes (Hhip+/+ or Hhip+/-) and treatments (air or CS) were randomly chosen for gene expression profiling

2015-01-21 | E-GEOD-65124 | biostudies-arrayexpress

Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring

2015-01-21 | GSE65124 | GEO

Cigarette smoke-induced iBALT mediates macrophage activation in a B cell-dependent manner in COPD

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

Cigarette smoke-induced iBALT mediates macrophage activation in a B cell-dependent manner in COPD

2014-12-04 | GSE52509 | 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

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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