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Published on: February 10, 2015
Endostar, a novel human recombinant endostatin, attenuates liver fibrosis in CCl4-induced mice
Jing Chen1, Dian-Gang Liu2, Guang Yang3
1Department of Gastroenterology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
Abstract:
Decreasing hepatic fibrosis remains one of the major therapeutic challenges in hepatology. The present study aims to evaluate the effect of Endostar on both CCl4-induced liver fibrosis in mice and a hepatic stellate cell (HSC) line. Two main models were studied: (i) a liver fibrosis model was induced in BALB/c mice using CCl4 by intraperitoneal injection for six weeks. Six animal groups were studied: group 1: normal animals; group 2: CCl4-induced liver fibrosis; group 3: CCl4 + Endostar 20 mg/kg/d, six weeks; group 4: CCl4 + Endostar 10 mg/kg/d, six weeks; group 5: CCl4 + Endostar 20 mg/kg/d, four weeks; group 6: CCl4 + Endostar 10 mg/kg/d, four weeks corresponded to different Endostar doses and duration of administration. Liver fibrosis was evaluated by histopathological staining and liver hydroxyproline content. Expressions of collagen type I, α-smooth muscle actin (α-SMA), TGF-β1 and VEGFR were measured by real-time polymerase chain reaction (PCR). (ii) A liver cell model. HSC-T6 cells were cultured with or without Endostar for 12 h or 24 h. Expressions of collagen type I, α-SMA, and TGF-β1 were measured by real-time PCR. Collagen I and transforming growth factor β1 (TGF-β1) contents in cell supernatant were measured by enzyme-linked immunosorbent assay. As compared to the group without Endostar, liver fibrosis scores and hydroxyproline content were decreased in both Endostar groups (P < 0.05). Moreover, Endostar inhibited the hepatic expression of α-SMA, TGF-β1, Collagen-1, VEGFR1, and VEGFR2 mRNA (P < 0.05). In the HSC-T6 cell line model, Endostar profoundly inhibited the expression of α-SMA, Collagen-1, and TGF-β1 mRNA. Expressions of Collagen-1 and TGF-β1 protein were decreased in the Endostar group as compared to the normal controls in the supernatant of HSC-T6 cells (P < 0.05). Endostar decreased both liver fibrosis in CCl4-induced mice and collagen synthesis in HSCs in vitro. Therefore, this recombinant human endostatin is a promising compound for counteracting liver fibrosis.
Insights
Endostar effectively reduced liver fibrosis in mice and collagen synthesis in liver cells. This recombinant human endostatin shows promise for treating liver fibrosis.
Area of Science:
- Hepatology
- Fibrosis research
- Pharmacology
Background:
- Hepatic fibrosis poses a significant therapeutic challenge in hepatology.
- Current treatments for liver fibrosis are limited.
- Understanding the mechanisms of fibrosis is crucial for developing new therapies.
Purpose of the Study:
- To evaluate the anti-fibrotic effects of Endostar.
- To investigate Endostar's impact on carbon tetrachloride (CCl4)-induced liver fibrosis in mice.
- To assess Endostar's effect on hepatic stellate cell (HSC) lines in vitro.
Main Methods:
- A mouse model of CCl4-induced liver fibrosis was established.
- Mice were treated with varying doses and durations of Endostar.
- Hepatic fibrosis was assessed via histopathology and hydroxyproline content.
- Gene and protein expression of fibrosis markers (α-SMA, TGF-β1, Collagen-1, VEGFRs) were analyzed using RT-PCR and ELISA.
- HSC-T6 cells were treated with Endostar to evaluate its direct effects on collagen synthesis.
Main Results:
- Endostar treatment significantly decreased liver fibrosis scores and hydroxyproline content in mice.
- Endostar inhibited the hepatic expression of α-SMA, TGF-β1, Collagen-1, VEGFR1, and VEGFR2 mRNA.
- In vitro, Endostar significantly reduced α-SMA, Collagen-1, and TGF-β1 mRNA and protein expression in HSCs.
- These findings demonstrate Endostar's potent anti-fibrotic activity both in vivo and in vitro.
Conclusions:
- Endostar demonstrates significant efficacy in reducing liver fibrosis in a mouse model.
- Endostar inhibits key molecular pathways involved in hepatic fibrosis, including collagen synthesis.
- Recombinant human endostatin is a promising therapeutic candidate for counteracting liver fibrosis.
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