Kuei-Chuan Lee1,2, Wei-Fan Hsu3,4, Yun-Cheng Hsieh1,2, Che-Chang Chan1,2, Ying-Ying Yang2,5, Yi-Hsiang Huang1,2,3, Ming-Chih Hou1,2, Han-Chieh Lin6,7. 1. Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. 2. Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. 3. Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. 4. Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan. 5. Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. 6. Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. hclin@vghtpe.gov.tw. 7. Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. hclin@vghtpe.gov.tw.
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.
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: Wolfgang G Eisert; Norbert Hauel; Joachim Stangier; Wolfgang Wienen; Andreas Clemens; Joanne van Ryn Journal: Arterioscler Thromb Vasc Biol Date: 2010-07-29 Impact factor: 8.311
Authors: Andrea De Gottardi; Jonel Trebicka; Christoph Klinger; Aurélie Plessier; Susana Seijo; Benedetta Terziroli; Lorenzo Magenta; David Semela; Elisabetta Buscarini; Philippe Langlet; Jan Görtzen; Angela Puente; Beat Müllhaupt; Carmen Navascuès; Filipe Nery; Pierre Deltenre; Fanny Turon; Cornelius Engelmann; Rupen Arya; Karel Caca; Markus Peck-Radosavljevic; Frank W G Leebeek; Dominique Valla; Juan Carlos Garcia-Pagan Journal: Liver Int Date: 2016-11-19 Impact factor: 5.828
Authors: Anna K Kopec; Nikita Joshi; Keara L Towery; Karen M Kassel; Bradley P Sullivan; Matthew J Flick; James P Luyendyk Journal: J Pharmacol Exp Ther Date: 2014-08-19 Impact factor: 4.030
Authors: Junlan Zhang; Bao Luo; Liping Tang; Yongming Wang; Cecil R Stockard; Inga Kadish; Thomas Van Groen; William E Grizzle; Selvarangan Ponnazhagan; Michael B Fallon Journal: Gastroenterology Date: 2008-12-03 Impact factor: 22.682
Authors: L G Poole; A Pant; K S Baker; A K Kopec; H M Cline-Fedewa; S E Iismaa; M J Flick; J P Luyendyk Journal: J Thromb Haemost Date: 2018-12-10 Impact factor: 5.824
Authors: José Ignacio Fortea; Ángela Puente; Antonio Cuadrado; Patricia Huelin; Raúl Pellón; Francisco José González Sánchez; Marta Mayorga; María Luisa Cagigal; Inés García Carrera; Marina Cobreros; Javier Crespo; Emilio Fábrega Journal: Int J Mol Sci Date: 2020-12-10 Impact factor: 5.923
Authors: Lauren G Poole; Asmita Pant; Holly M Cline-Fedewa; Kurt J Williams; Bryan L Copple; Joseph S Palumbo; James P Luyendyk Journal: Res Pract Thromb Haemost Date: 2020-06-25