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Lenvatinib prevents liver fibrosis by inhibiting hepatic stellate cell activation and sinusoidal capillarization in experimental liver fibrosis.
- Source :
-
Journal of cellular and molecular medicine [J Cell Mol Med] 2021 Apr; Vol. 25 (8), pp. 4001-4013. Date of Electronic Publication: 2021 Feb 20. - Publication Year :
- 2021
-
Abstract
- Molecular targeted agents are pharmacologically used to treat liver fibrosis and have gained increased attention. The present study examined the preventive effect of lenvatinib on experimental liver fibrosis and sinusoidal capillarization as well as the in vitro phenotypes of hepatic stellate cells. LX-2, a human stellate cell line, was used for in vitro studies. In vivo liver fibrosis was induced in F344 rats using carbon tetrachloride by intraperitoneal injection for 8 weeks, and oral administration of lenvatinib was started two weeks after initial injection of carbon tetrachloride. Lenvatinib restrained proliferation and promoted apoptosis of LX-2 with suppressed phosphorylation of extracellular signal-regulated kinase 1/2 and AKT. It also down-regulated COL1A1, ACTA2 and TGFB1 expressions by inhibiting the transforming growth factor-β1/Smad2/3 pathway. Treatment with lenvatinib also suppressed platelet-derived growth factor-BB-stimulated proliferation, chemotaxis and vascular endothelial growth factor-A production, as well as basic fibroblast growth factor-induced LX-2 proliferation. In vivo study showed that lenvatinib attenuated liver fibrosis development with reduction in activated hepatic stellate cells and mRNA expression of profibrogenic markers. Intrahepatic neovascularization was ameliorated with reduced hepatic expressions of Vegf1, Vegf2 and Vegfa in lenvatinib-treated rats. Collectively, these results suggest the potential use of lenvatinib as a novel therapeutic strategy for liver fibrosis.<br /> (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Subjects :
- Animals
Capillaries metabolism
Capillaries pathology
Carbon Tetrachloride toxicity
Cells, Cultured
Hepatic Stellate Cells metabolism
Hepatic Stellate Cells pathology
Liver blood supply
Liver Cirrhosis chemically induced
Liver Cirrhosis pathology
Male
Neovascularization, Pathologic chemically induced
Neovascularization, Pathologic pathology
Rats
Rats, Inbred F344
Capillaries drug effects
Hepatic Stellate Cells drug effects
Liver drug effects
Liver Cirrhosis prevention & control
Neovascularization, Pathologic prevention & control
Phenylurea Compounds pharmacology
Protein Kinase Inhibitors pharmacology
Quinolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1582-4934
- Volume :
- 25
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of cellular and molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 33609067
- Full Text :
- https://doi.org/10.1111/jcmm.16363