Dabigatran Reduces Liver Fibrosis in Thioacetamide-Injured Rats.

Abstract

BACKGROUND:

Liver fibrosis can progress to cirrhosis, hepatocellular carcinoma, or liver failure. Unfortunately, the antifibrotic agents are limited. Thrombin activates hepatic stellate cells (HSCs). Therefore, we investigated the effects of a direct thrombin inhibitor, dabigatran, on liver fibrosis.

METHODS:

Adult male Sprague-Dawley rats were injected intraperitoneally with thioacetamide (TAA, 200 mg/kg twice per week) for 8 or 12 weeks to induce liver fibrosis. The injured rats were assigned an oral gavage of dabigatran etexilate (30 mg/kg/day) or vehicle in the last 4 weeks of TAA administration. Rats receiving an injection of normal saline and subsequent oral gavage of dabigatran etexilate or vehicle served as controls.

RESULTS:

In the 8-week TAA-injured rats, dabigatran ameliorated fibrosis, fibrin deposition, and phosphorylated ERK1/2 in liver, without altering the transcript expression of thrombin receptor protease-activated receptor-1. In vitro, dabigatran inhibited thrombin-induced HSC activation. Furthermore, dabigatran reduced intrahepatic angiogenesis and portal hypertension in TAA-injured rats. Similarly, in the 12-week TAA-injured rats, a 4-week treatment with dabigatran reduced liver fibrosis and portal hypertension.

CONCLUSIONS:

By inhibiting thrombin action, dabigatran reduced liver fibrosis and intrahepatic angiogenesis. Dabigatran may be a promising therapeutic agent for treatment of liver fibrosis.

• Authors: Kuei-Chuan Lee, Wei-Fan Hsu, Yun-Cheng Hsieh, Che-Chang Chan, Ying-Ying Yang, Yi-Hsiang Huang, Ming-Chih Hou, Han-Chieh Lin
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 64 Issue 1 Pg. 102-112 (01 2019) ISSN: 1573-2568 [Electronic] United States
• PMID: 30288660 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antithrombins
• Thioacetamide
• Fibrin
• Collagen
• Extracellular Signal-Regulated MAP Kinases
• Dabigatran

Topics

• Animals
• Antithrombins (pharmacology)
• Cell Line
• Chemical and Drug Induced Liver Injury (etiology, metabolism, pathology, prevention & control)
• Collagen (metabolism)
• Cytoprotection
• Dabigatran (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fibrin (metabolism)
• Hepatic Stellate Cells (drug effects, metabolism, pathology)
• Hypertension, Portal (chemically induced, physiopathology, prevention & control)
• Liver (drug effects, metabolism, pathology)
• Liver Cirrhosis, Experimental (chemically induced, metabolism, pathology, prevention & control)
• Male
• Neovascularization, Pathologic
• Phosphorylation
• Portal Pressure (drug effects)
• Rats, Sprague-Dawley
• Thioacetamide