Evaluation of microRNA expression in sheep model for lung fibrosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Ovis aries
PROVIDER: GSE166682 | GEO | 2021/02/13
REPOSITORIES: GEO
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Project description:Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-β1 exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, administration of Ogg1-targetting siRNA, mitigated bleomycin-induced pulmonary fibrosis in mice, thereby highlighting OGG1 as a tractable target in lung fibrosis. The novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and associated pro-fibrotic markers in fibroblast cells. In addition, TH5487 decreased pro-inflammatory cytokine production, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation, with both increased in fibrotic murine and IPF patient lung tissue. Taken together, these data strongly suggest that TH5487 is a potent, specific, and clinically-relevant treatment for IPF. This DIA-MS dataset entails the raw data and peptide-centric DIA-NN search results of both, lung tissue and bronchoalveolar lavage fluid of n=5 mice profiled across the treatment groups bleomycin combined with TH (BTH), dexamethasone (DEX), TH alone (TH) and vehicle control (V) relative to bleomycin alone (B) as control. Different animals within protein groups were considered biological replicates of the respective treatment condition.
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Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis and limited treatment options. Efforts to identify effective treatments are thwarted by limited understanding of IPF pathogenesis and poor translatability of available preclinical models. To address these limitations, we generated spatially resolved transcriptome maps of human IPF and bleomycin-induced mouse lung fibrosis.
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Project description:Intratracheal application of bleomycin is known to induce inflammatory and fibrotic reactions in the lung within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Because some of these features are found in patients with idiopathic pulmonary fibrosis (IPF), the bleomycin-induced lung fibrosis animal model is commonly used. However, exploratory treatments that were successfully used in this animal model and progressed to clinical trials lacked significant efficacy in humans. Here, the bleomycin-induced rat lung fibrosis model was studied using whole genome expression data that was collected at various time points and the relevance to human disease was evaluated through comparison with whole genome expression data from IPF patient-derived lung biopsies. The highest gene expression correlation between both species was observed in animals 7 days after bleomycin instillation. These gene expression signatures helped to identify a set of twelve novel disease-relevant translational gene markers that were able to separate IPF patients from controls. Furthermore, three Wnt/-catenin pathway-related genes that belong to this translational gene marker set showed, together with clinical diffusing capacity of the lung for carbon monoxide (DLCO) measurements, the potential to stratify IPF patients according to disease severity. Pirfenidone attenuated a subset of the translational gene markers in the bleomycin-induced fibrosis model, in particular those related to Wnt/-catenin-signaling. This novel translational gene marker panel offers improved possibilities to evaluate disease-modifying efficacy of novel therapeutic concepts in the bleomycin-induced rat lung fibrosis model and could be applied as a diagnostic and prognostic tool for IPF patient care. Comparison of bleomycin-treated and control rats after 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks and 8 weeks; 5 animals per group
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Project description:Pulmonary fibrosis results from dysregulated repair of damaged tissue caused by persistent injury of lung epithelium. Multiple cell types in the lung are involved in the process of repair. During lung fibrogenesis, normal endothelial cells (EC) are re-programmed into fibrosis-associated EC. Transcriptional factors that control re-programming are poorly understood. Using single cell RNA-sequencing of EC from donor and idiopathic pulmonary fibrosis (IPF) lungs, and lungs from bleomycin-treated mice, we identified endothelial transcription factors (TF) that were differentially expressed during fibrosis. Focusing on one of endothelial TF, FOXF1, we demonstrated that FOXF1 is decreased in EC within human IPF and mouse bleomycin-injured fibrotic lungs.
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Project description:Pulmonary fibrosis results from dysregulated repair of damaged tissue caused by persistent injury of lung epithelium. Multiple cell types in the lung are involved in the process of repair. During lung fibrogenesis, normal endothelial cells (EC) are re-programmed into fibrosis-associated EC. Transcriptional factors that control re-programming are poorly understood. Using single cell RNA-sequencing of EC from donor and idiopathic pulmonary fibrosis (IPF) lungs, and lungs from bleomycin-treated mice, we identified endothelial transcription factors (TF) that were differentially expressed during fibrosis. Focusing on one of endothelial TF, FOXF1, we demonstrated that FOXF1 is decreased in EC within human IPF and mouse bleomycin-injured fibrotic lungs.
2022-09-16 | GSE213279 | GEO
Project description:Pulmonary fibrosis results from dysregulated repair of damaged tissue caused by persistent injury of lung epithelium. Multiple cell types in the lung are involved in the process of repair. During lung fibrogenesis, normal endothelial cells (EC) are re-programmed into fibrosis-associated EC. Transcriptional factors that control re-programming are poorly understood. Using single cell RNA-sequencing of EC from donor and idiopathic pulmonary fibrosis (IPF) lungs, and lungs from bleomycin-treated mice, we identified endothelial transcription factors (TF) that were differentially expressed during fibrosis. Focusing on one of endothelial TF, FOXF1, we demonstrated that FOXF1 is decreased in EC within human IPF and mouse bleomycin-injured fibrotic lungs.
2022-09-16 | GSE213016 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) and lung cancer share common risk factors, epigenetic and genetic alterations, cellular and molecular aberrations, the activation of similar signaling pathways and poor survival. The aim of this study was to examine the gene expression profiles of stromal cells from patients with IPF and lung adenocarcinoma (ADC) as well as from normal lung.
2021-04-27 | GSE144338 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF)
| PRJNA802122 | ENA
Project description:Intratracheal application of bleomycin is known to induce inflammatory and fibrotic reactions in the lung within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Because some of these features are found in patients with idiopathic pulmonary fibrosis (IPF), the bleomycin-induced lung fibrosis animal model is commonly used. However, exploratory treatments that were successfully used in this animal model and progressed to clinical trials lacked significant efficacy in humans. Here, the bleomycin-induced rat lung fibrosis model was studied using whole genome expression data that was collected at various time points and the relevance to human disease was evaluated through comparison with whole genome expression data from IPF patient-derived lung biopsies. The highest gene expression correlation between both species was observed in animals 7 days after bleomycin instillation. These gene expression signatures helped to identify a set of twelve novel disease-relevant translational gene markers that were able to separate IPF patients from controls. Furthermore, three Wnt/-catenin pathway-related genes that belong to this translational gene marker set showed, together with clinical diffusing capacity of the lung for carbon monoxide (DLCO) measurements, the potential to stratify IPF patients according to disease severity. Pirfenidone attenuated a subset of the translational gene markers in the bleomycin-induced fibrosis model, in particular those related to Wnt/-catenin-signaling. This novel translational gene marker panel offers improved possibilities to evaluate disease-modifying efficacy of novel therapeutic concepts in the bleomycin-induced rat lung fibrosis model and could be applied as a diagnostic and prognostic tool for IPF patient care.
2014-10-28 | GSE48455 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts and continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contibributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, novel flow cytometry strategies to quantify lung fibroblast subsets and transcriptional profiling of lung fibroblasts by bulk and single cell RNA-sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued pro-fibrotic functions of lung fibroblasts. Our studies provide novel insights into the mechanisms that contribute to fibroblast survival, persistence and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis prevents fibrosis resolution.
2020-11-18 | GSE161648 | GEO