Redundant effects of Pirfenidone against fibroblast activation and severe fibrotic lung disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA818159 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18395808.fastq.gz | Fastqsanger.gz | |||
| SRR18395809.fastq.gz | Fastqsanger.gz | |||
| SRR18395810.fastq.gz | Fastqsanger.gz | |||
| SRR18395811.fastq.gz | Fastqsanger.gz | |||
| SRR18395812.fastq.gz | Fastqsanger.gz |
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Project description:Idiopathic Pulmonary Fibrosis (IPF) is a progressive chronic lung disease characterized by excess deposition of extracellular matrix (ECM) proteins in the lung. TGFα is a is a ligand for the epidermal growth factor receptor, and found elevated in several fibrotic lung diseases including IPF. Notably, lung-specific overexpression of TGFα alone in adult mice can cause progressive and extensive adventitial and subpleural fibrosis similar to IPF. Pirfenidone, an FDA approved drug has been shown to improve the decline in lung function in IPF patients. However, the mechanism of action of pirfenidone largely unknown. In the current study, we investigated the effects of pirfenidone using a mouse model of TGFα-induced pulmonary fibrosis and fibroblasts isolated from IPF lungs. Total lung transcriptome analysis suggest a significant overlap in dysregulated gene transcripts between TGFα model and IPF. In vivo studies demonstrate a significant improvement in lung function with pirfenidone therapy compared to vehicle-treated TGFα mice on Dox for six wks. However, pirfenidone treatment did not affect fibroproliferation, myofibroblast transformation, and ECM deposition during TGFα-induced pulmonary fibrosis. In summary, pirfenidone treatment improved lung function but had a limited or no effect on the expression of collagen, ECM genes, fibroproliferation and migration of lung-resident fibroblasts.
2022-06-01 | GSE199034 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease with a poor prognosis. Fibroblasts and myofibroblasts are the key cells in the fibrotic process. Pirfenidone was approved as an anti-fibrotic drug for IPF treatment as it is able to slow disease progression. The mechanisms by which the drug acts on fibroblasts are not clear. Therefore, this study aims to examine the effects of pirfenidone on the human lung fibroblast (HLF) transcriptome in vitro.
2023-05-12 | GSE226249 | GEO
Project description:Background: Malignant mesothelioma is an aggressive cancer with poor prognosis. It is characterized by prominent extracellular matrix, mesenchymal tumor cell phenotypes and chemoresistance. In this study, the ability of pirfenidone to alter mesothelioma cell proliferation and migration as well as mesothelioma tumor microenvironment was evaluated. Pirfenidone is an anti-fibrotic drug used in the treatment of idiopathic pulmonary fibrosis and has also anti-proliferative activities. Aims: Transcriptional profiling using RNA sequencing of human mesothelioma xenograft tumors treated with PBS or pirfenidone. Aim was to compare extracellular matrix and fibrosis related genes. Results: Treatment of mice harboring mesothelioma xenografts with pirfenidone alone did not reduce tumor proliferation in vivo. However, pirfenidone modified the tumor microenvironment by reducing the expression of extracellular matrix associated genes. In addition, GREM1 expression was downregulated by pirfenidone in vivo. Conclusion: By reducing two major upregulated pathways in mesothelioma and by targeting tumor cells and the microenvironment pirfenidone may present a novel anti-fibrotic and anti-cancer adjuvant therapy for mesothelioma.
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Project description:The anti-fibrotic drug pirfenidone inhibits liver fibrosis by targeting glrx
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Project description:Skin fibrotic disease representsa major global healthcare burden, characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix.Fibroblasts are found to be heterogeneous in multiple fibrotic diseases,but the fibroblast heterogeneity of skin fibrotic diseases remains unknown.In this study, we performed single-cell RNA-seq in keloid, a paradigm of skin fibrotic diseases, andnormal scardermis tissues.Our results indicate that keloid and normal scar fibroblasts could be divided into 4 subpopulations: secretory-papillary, secretory-reticular, mesenchymal and pro-inflammatory.The percentage of mesenchymal fibroblast subpopulationincreased significantly in keloid compared to normal scar. Interestingly, we also found increasing mesenchymal fibroblast subpopulation in scleroderma, another skin fibrotic disease.Function studies showed that the mesenchymal fibroblasts promoted collagen synthesis of the other fibroblasts in keloid partiallythrough secreting POSTN. These findings will help us understandskin fibroticpathogenesis in depth,and provided potential target cells for fibrotic diseases therapies.
2021-05-23 | GSE163973 | GEO
Project description:Skin fibrotic disease representsa major global healthcare burden, characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix.Fibroblasts are found to be heterogeneous in multiple fibrotic diseases,but the fibroblast heterogeneity of skin fibrotic diseases remains unknown.In this study, we performed single-cell RNA-seq in keloid, a paradigm of skin fibrotic diseases, andnormal scardermis tissues.Our results indicate thatkeloid and normal scar fibroblasts could be divided into 4 subpopulations: secretory-papillary, secretory-reticular, mesenchymal and pro-inflammatory.The percentage of mesenchymal fibroblast subpopulationincreased significantly in keloid compared to normal scar. Interestingly, we also found increasing mesenchymal fibroblast subpopulation in scleroderma, another skin fibrotic disease.Function studies showed that the mesenchymal fibroblasts promoted collagen synthesis of the other fibroblasts in keloid partiallythrough secreting POSTN. These findings will help us understandskin fibroticpathogenesis in depth,and provided potential target cells for fibrotic diseases therapies.
2021-06-01 | GSE175866 | GEO
Project description:BackgroundPirfenidone, an antifibrotic agent used for the treatment of idiopathic pulmonary fibrosis (IPF), functions by inhibiting myofibroblast differentiation, which is involved in transforming growth factor (TGF)-β1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-β1-induced human fibrotic lung fibroblasts and lung fibrosis has not been elucidated.MethodsThe effects of pirfenidone were evaluated in lung fibroblasts isolated from fibrotic human lung tissues after TGF-β1 exposure. The ability of two new pharmacological targets of pirfenidone, collagen triple helix repeat containing protein 1(CTHRC1) and four-and-a-half LIM domain protein 2 (FHL2), to mediate contraction of collagen gels and migration toward fibronectin were assessed in vitro.ResultsCompared to control lung fibroblasts, pirfenidone significantly restored TGF-β1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-β1- and CTHRC1-induced fibroblast activity, upregulation of bone morphogenic protein-4(BMP-4)/Gremlin1, and downregulation of α-smooth muscle actin, fibronectin, and FHL2, similar to that observed post-CTHRC1 inhibition. In contrast, FHL2 inhibition suppressed migration and fibronectin expression, but did not downregulate CTHRC1.ConclusionsOverall, pirfenidone suppressed fibrotic fibroblast-mediated fibrotic processes via inverse regulation of CTHRC1-induced lung fibroblast activity. Thus, CTHRC1 can be used for predicting pirfenidone response and developing new therapeutic targets for lung fibrosis.
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Project description:Functional Pdgfra fibroblast heterogeneity in normal and fibrotic mouse lung
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Project description:Dynamic fibroblast state transitions underlie the heart’s fibrotic response, raising the possibility that tactical control of these transitions could alter maladaptive fibrotic outcomes. Transcriptome maturation by Muscleblind-like 1 (MBNL1) has emerged as a driver of differentiated cell states. Indeed, MBNL1 expression is elevated in conjunction with profibrotic transcripts in lineage traced myofibroblasts and modeling this gain in function by fibroblast-specific overexpression of an MBNL1 transgene induced a myofibroblast transcriptional identity in healthy hearts and promoted maladaptive myocyte remodeling and scar maturation following injury. Both fibroblast-specific and myofibroblast-specific loss of MBNL1 limited scar production and maturation, which was ascribed to negligible myofibroblast activity. MBNL1 deletion drove expansion of all quiescent cardiac fibroblast states and promoted mesenchymal stem cell characteristics while forced MBNL1 expression restricted state diversity by transitioning most fibroblasts to the most mature myofibroblast identity. These data suggest MBNL1 is a post-transcriptional switch controlling quiescent to myofibroblast transitions during cardiac wound healing.
2022-01-20 | GSE193308 | GEO
Project description:Investigating the effect of Pirfenidone on NSCLC cells Although immune checkpoint and targeted therapies offer remarkable benefits for lung cancer treatment, some patients do not qualify for these regimens or do not exhibit consistent benefit. Provided that lung cancer appears to be driven by transforming growth factor beta signaling, we investigated the single drug potency of Pirfenidone, an approved drug for the treatment of lung fibrosis which is known to inhibit TGFB1 mRNA. Human A549 and H1975 lung adenocarcinoma cell lines were stimulated for 6h and 25h with 0.75 mg/ml or 1.5 mg/ml Pirfenidone or the respective volume of PBS as vehicle control. Total RNA was extracted and subjected to transcriptome analysis by microarrays.
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