TAFI deficiency promotes liver damage in murine models of liver failure through defective down-regulation of hepatic inflammation

Greg C. G. Hugenholtz; Joost C. M. Meijers; Jelle Adelmeijer; Robert J. Porte; Ton Lisman

doi:10.1160/TH12-12-0930

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2013; 109(05): 948-955
DOI: 10.1160/TH12-12-0930

Animal Models

Schattauer GmbH

TAFI deficiency promotes liver damage in murine models of liver failure through defective down-regulation of hepatic inflammation

Autoren

Greg C. G. Hugenholtz

¹Surgical Research Laboratory, Department of Surgery, University of Groningen, University of Medical Center Groningen, Groningen, The Netherlands
Joost C. M. Meijers

²Departments of Experimental Vascular Medicine and Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
Jelle Adelmeijer

¹Surgical Research Laboratory, Department of Surgery, University of Groningen, University of Medical Center Groningen, Groningen, The Netherlands
Robert J. Porte

³Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Ton Lisman

¹Surgical Research Laboratory, Department of Surgery, University of Groningen, University of Medical Center Groningen, Groningen, The Netherlands

³Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

Abstract

Summary

Emerging evidence indicates that various haemostatic components can regulate the progression of liver disease. Thrombin-activatable fibrinolysis inhibitor (TAFI) possesses anti-inflammatory properties besides its anti-fibrinolytic function. Here, we investigated the contribution of TAFI to the progression of disease in murine models of chronic and acute liver failure. Chronic carbon tetrachloride (CCL₄) administration induced liver damage and fibrosis both in TAFI knockout (TAFI^−/−) mice and wild-type controls. Smooth muscle actin-α (α-SMA) content of liver tissue was significantly increased after 1 and 3 weeks, and pro-collagen α1 expression was significantly increased after 3 and 6 weeks in TAFI^−/− mice. TAFI^−/− mice showed significantly elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) after 3 weeks of CCL₄. Neutrophil influx was significantly increased in TAFI^−/− mice after 6 weeks of CCL₄. No difference in hepatic fibrin deposition between TAFI^−/− and wild-types was observed. After acetaminophen intoxication, necrosis was significantly increased in TAFI^−/− mice at 24 hours (h) after injection. AST and ALT levels were decreased at 2 and 6 h after acetaminophen injection in TAFI^−/− mice, but were significantly higher in the TAFI^−/− mice at 24 h. Similarly, hepatic fibrin deposition was decreased at 6 h in TAFI^−/− mice, but was comparable to wild-types at 24 h after injection. In conclusion, TAFI deficiency results in accelerated fibrogenesis and increased liver damage in murine models of chronic and acute liver disease, which may be related to increased inflammation.

Keywords

Fibrinolysis - cirrhosis - acute liver failure - thrombin activatable fibrinolysis inhibitor - fibrin

Volltext

Referenzen

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