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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE65124 | GEO | 2015/01/21

SECONDARY ACCESSION(S): PRJNA273156

REPOSITORIES: GEO

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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

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

Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease

Project description:For the clinical treatment of chronic obstructive pulmonary disease (COPD), it is important not only to improve the airflow limitation by bronchodilation but also to suppress emphysema by controlling inflammation. In this study, we have screened for compounds that prevent elastase-induced airspace enlargement in mice from medicines already used clinically. Mepenzolate bromide, a muscarinic antagonist used to treat gastrointestinal disorders was selected. Intratracheal administration or inhalation of mepenzolate bromide decreased the severity of elastase-induced airspace enlargement, alteration of lung mechanics and respiratory dysfunction. While mepenzolate bromide showed bronchodilatory activity, most of other muscarinic antagonists tested did not improve the elastase-induced pulmonary disorders. Mepenzolate bromide suppressed elastase-induced pulmonary inflammatory responses and production of superoxide anions, and reduced the level of cigarette smoke-induced airspace enlargement and alteration of lung mechanics. Based on these results, we propose that this drug is therapeutically effective for COPD as a consequence of both its anti-inflammatory and bronchodilatory activities. In order to understand the mechanism governing mepenzolate-dependent decrease in inflammatory responses and oxidative stress, we performed DNA microarray analysis at the lung of mepenzolate-administered (or control) mice. We then analyzed gene sets that were differently expressed at 25 hours after administration of mepenzolate using Gene Set Enrichment Analysis (GSEA).

2013-11-13 | E-GEOD-50836 | biostudies-arrayexpress

Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease

2013-11-13 | GSE50836 | GEO

The role of HHIP in COPD lymphocytic inflammation

Project description:Chronic obstructive pulmonary disease (COPD) is characterized by persistent and amplified inflammation to cigarette smoke in vulnerable subjects. The genetic risk of persistent inflammation is poorly understood. A mouse model targeting hedgehog interacting protein (HHIP)(Hhip+--), a genetic risk factor for COPD, displays progressive, persistent inflammation resembling human cases, providing a valuable model to study the contribution of the genetic risk factor HHIP to inflammation in COPD. By single cell RNA sequencing of Hhip+-- lungs at different disease stages, we identified induction of IFN-gamma in activated CD8+T cells possibly driving the inflammatory phenotype in Hhip+-- lungs. Hhip expression was restricted to lung fibroblasts, which interaction with CD8+T cells were mediated by increased levels of IL-18 from Hhip+-- fibroblasts. Our finding provides insight into how a common genetic variation contributes to the amplified lymphocytic inflammation in COPD.

2021-08-01 | GSE149843 | 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.

2014-12-04 | GSE52509 | 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.

2016-01-01 | GSE57048 | GEO

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

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

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

2014-12-04 | E-GEOD-52509 | biostudies-arrayexpress

Reversal of emphysema by restoration of pulmonary endothelial cells

Project description:Chronic obstructive pulmonary disease (COPD) is a heterogenous disorder marked by small airway inflammation and distal airspace enlargement (emphysema) leading to progressive airflow obstruction and eventual respiratory failure. Current therapies are limited in their ability to halt the pathogenesis of COPD merely relieving symptoms of dyspnea and airflow limitation. Microvasculature dysfunction, an understudied area of investigation, is associated with the severity of COPD. However, it is not known if abnormal lung endothelium drives COPD pathology and/or if correcting endothelial dysfunction has therapeutic potential. Here, we show the centrality of specialized pulmonary endothelial cells to lung pathogenesis in an elastase-induced murine model of COPD. Airspace disease was marked by aberrant endothelial cell loss and dysfunction, which was rescued by intravenous delivery of healthy lung endothelial cells. Airspace injury triggered regulation of a distinct module of maladaptive endothelial transcripts comprising lost endothelial cell function. Endothelial leucine-rich alpha-2-glycoprotein-1 (LRG1) was identified as a key driver of the emphysematous pathology and selective deletion of Lrg1 from endothelial cells rescued elastase-induced defects of pulmonary parenchymal destruction. Hence, targeting lung endothelial cell biology through regenerative methods and/or inhibition of the LRG1 pathway may represent novel therapeutic strategies of immense potential for the treatment of emphysema.

2021-06-22 | GSE140413 | GEO

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