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Reversion of in vivo fibrogenesis by novel chromone scaffolds
Reversion of in vivo fibrogenesis by novel chromone scaffolds
- Source :
- EBioMedicine
- Publication Year :
- 2019
- Publisher :
- Elsevier, 2019.
-
Abstract
- Background Myofibroblasts are known to play a key role in the development of idiopathic pulmonary fibrosis (IPF). Two drugs, pirfenidone and nintedanib, are the only approved therapeutic options for IPF, but their applications are limited due to their side effects. Thus, curative IPF drugs represent a huge unmet medical need. Methods A mouse hepatic stellate cell (HSC) line was established that could robustly differentiate into myofibroblasts upon treatment with TGF-β. Eupatilin was assessed in diseased human lung fibroblasts from IPF patients (DHLFs) as well as in human lung epithelial cells (HLECs). The drug's performance was extensively tested in a bleomycin-induced lung fibrosis model (BLM). Global gene expression studies and proteome analysis were performed. Findings Eupatilin attenuated disease severity of BLM in both preventative and therapeutic studies. The drug inhibited the in vitro transdifferantiation of DHLFs to myofibroblasts upon stimulation with TGF-β. No such induction of the in vitro transdifferantiation was observed in TGF-β treated HLECs. Specific carbons of eupatilin were essential for its anti-fibrotic activity. Eupatilin was capable of dismantling latent TGF-β complex, specifically by eliminating expression of the latent TGF-β binding protein 1 (LTBP1), in ECM upon actin depolymerization. Unlike eupatilin, pirfenidone was unable to block fibrosis of DHLFs or HSCs stimulated with TGF-β. Eupatilin attenuated phosphorylation of Smad3 by TGF-β. Eupatilin induced myofibroblasts to dedifferentiate into intermediate HCS-like cells. Interpretation Eupatilin may act directly on pathogenic myofibroblasts, disarming them, whereas the anti-fibrotic effect of pirfenidone may be indirect. Eupatilin could increase the efficacy of IPF treatment to curative levels.
- Subjects :
- 0301 basic medicine
Research paper
Eupatilin
CD, chromone scaffold derivative
Stem cells
Idiopathic pulmonary fibrosis
chemistry.chemical_compound
Mice
0302 clinical medicine
Fibrosis
Chromone scaffold
Transforming Growth Factor beta
Phosphorylation
Myofibroblasts
DHLF, diseased human lung fibroblast
Epithelial–mesenchymal transition
Cell Differentiation
General Medicine
Pirfenidone
Extracellular Matrix
030220 oncology & carcinogenesis
Nintedanib
Dedifferentiation
Myofibroblast
medicine.drug
NASH, non-alcoholic steatohepatitis
BLM, bleomycin-induced lung fibrosis model
General Biochemistry, Genetics and Molecular Biology
Cell Line
03 medical and health sciences
Bleomycin
In vivo
medicine
Hepatic Stellate Cells
IPF, idiopathic pulmonary fibrosis
Animals
Humans
Smad3 Protein
Flavonoids
business.industry
Fibroblasts
medicine.disease
CS, chromone scaffold
Disease Models, Animal
030104 developmental biology
chemistry
Gene Expression Regulation
Latent TGF-beta Binding Proteins
Cell Transdifferentiation
Cancer research
business
Subjects
Details
- Language :
- English
- ISSN :
- 23523964
- Volume :
- 39
- Database :
- OpenAIRE
- Journal :
- EBioMedicine
- Accession number :
- edsair.doi.dedup.....9d51eade2f05c6a25366163c9dcd9de8