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

Greg C. G. Hugenholtz
1   Surgical Research Laboratory, Department of Surgery, University of Groningen, University of Medical Center Groningen, Groningen, The Netherlands
,
Joost C. M. Meijers
2   Departments of Experimental Vascular Medicine and Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
,
Jelle Adelmeijer
1   Surgical Research Laboratory, Department of Surgery, University of Groningen, University of Medical Center Groningen, Groningen, The Netherlands
,
Robert J. Porte
3   Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
,
Ton Lisman
1   Surgical Research Laboratory, Department of Surgery, University of Groningen, University of Medical Center Groningen, Groningen, The Netherlands
3   Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
› Author Affiliations
Further Information

Publication History

Received: 19 December 2012

Accepted after minor revision: 04 February 2013

Publication Date:
22 November 2017 (online)

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.

 
  • References

  • 1 Lisman T, Leebeek FW. Haemostatic alterations in liver disease: a review on pa-thophysiology, clinical consequences, and treatment. Dig Surg 2007; 24: 250-258.
  • 2 Lisman T, Leebeek FW, de Groot PG. Haemostatic abnormalities in patients with liver disease. J Hepatol 2002; 37: 280-287.
  • 3 Anstee QM, Wright M, Goldin R, Thursz MR. Parenchymal extinction: coagulation and hepatic fibrogenesis. Clin Liver Dis 2009; 13: 117-126.
  • 4 Wanless IR, Liu JJ, Butany J. Role of thrombosis in the pathogenesis of congestive hepatic fibrosis (cardiac cirrhosis). Hepatology 1995; 21: 1232-1237.
  • 5 Wanless IR, Wong F, Blendis LM. et al. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 1995; 21: 1238-1247.
  • 6 Wright M, Goldin R, Hellier S. et al. Factor V Leiden polymorphism and the rate of fibrosis development in chronic hepatitis C virus infection. Gut 2003; 52: 1206-1210.
  • 7 Yee TT, Griffioen A, Sabin CA. et al. The natural history of HCV in a cohort of haemophilic patients infected between 1961 and 1985. Gut 2000; 47: 845-851.
  • 8 Anstee QM, Goldin RD, Wright M. et al. Coagulation status modulates murine hepatic fibrogenesis: implications for the development of novel therapies. J Thromb Haemost 2008; 06: 1336-1343.
  • 9 Calvaruso V, Maimone S, Gatt A. et al. Coagulation and fibrosis in chronic liver disease. Gut 2008; 57: 1722-1727.
  • 10 Ganey PE, Luyendyk JP, Newport SW. et al. Role of the coagulation system in acet-aminophen-induced hepatotoxicity in mice. Hepatology 2007; 46: 1177-1186.
  • 11 Villa E, Camma C, Marietta M. et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroente-rology 2012; 143: 1253-1260.
  • 12 von Montfort C, Beier JI, Kaiser JP. et al. PAI-1 plays a protective role in CCl4-induced hepatic fibrosis in mice: role of hepatocyte division. Am J Physiol Gastrointest Liver Physiol 2010; 298: G657-666.
  • 13 Bajt ML, Yan HM, Farhood A. et al. Plasminogen activator inhibitor-1 limits liver injury and facilitates regeneration after acetaminophen overdose. Toxicol Sci 2008; 104: 419-427.
  • 14 Wang W, Boffa MB, Bajzar L. et al. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J Biol Chem 1998; 273: 27176-27181.
  • 15 Nesheim M, Wang W, Boffa M. et al. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis. Thromb Haemost 1997; 78: 386-391.
  • 16 Nagashima M, Yin ZF, Zhao L. et al. Thrombin-activatable fibrinolysis inhibitor (TAFI) deficiency is compatible with murine life. J Clin Invest 2002; 109: 101-110.
  • 17 Swaisgood CM, Schmitt D, Eaton D. et al. In vivo regulation of plasminogen function by plasma carboxypeptidase B. J Clin Invest 2002; 110: 1275-1282.
  • 18 Mao SS, Holahan MA, Bailey C. et al. Demonstration of enhanced endogenous fibrinolysis in thrombin activatable fibrinolysis inhibitor-deficient mice. Blood Coagul Fibrinolysis 2005; 16: 407-415.
  • 19 Vercauteren E, Peeters M, Hoylaerts MF. et al. The hyperfibrinolytic state of mice with combined TAFI and PAI-1 gene deficiency is critically dependent on TAFI deficiency. J Thromb Haemost. 2012 epub ahead of print
  • 20 Lisman T, Leebeek FW, Mosnier LO. et al. Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology 2001; 121: 131-139.
  • 21 Lisman T, Bakhtiari K, Adelmeijer J. et al. Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure. J Thromb Haemost 2012; 10: 1312-1319.
  • 22 Gresele P, Binetti BM, Branca G. et al. TAFI deficiency in liver cirrhosis: relation with plasma fibrinolysis and survival. Thromb Res 2008; 121: 763-768.
  • 23 Colucci M, Binetti BM, Branca MG. et al. Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis. Hepatology 2003; 38: 230-237.
  • 24 Leung LL, Nishimura T, Myles T. Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI). Adv Exp Med Biol 2008; 632: 61-69.
  • 25 te Velde EA, Wagenaar GT, Reijerkerk A. et al. Impaired healing of cutaneous wounds and colonic anastomoses in mice lacking thrombin-activatable fibrinolysis inhibitor. J Thromb Haemost 2003; 01: 2087-2096.
  • 26 Wang H, Zhang Y, Heuckeroth RO. PAI-1 deficiency reduces liver fibrosis after bile duct ligation in mice through activation of tPA. FEBS Lett 2007; 581: 3098-3104.
  • 27 Bergheim I, Guo L, Davis MA. et al. Metformin prevents alcohol-induced liver injury in the mouse: Critical role of plasminogen activator inhibitor-1. Gas-troenterology 2006; 130: 2099-2112.
  • 28 Bruno NE, Yano Y, Takei Y. et al. Immune complex-mediated glomerulonephri-tis is ameliorated by thrombin-activatable fibrinolysis inhibitor deficiency. Thromb Haemost 2008; 100: 90-100.
  • 29 Fujimoto H, Gabazza EC, Taguchi O. et al. Thrombin-activatable fibrinolysis inhibitor deficiency attenuates bleomycin-induced lung fibrosis. Am J Pathol.
  • 30 Renckens R, Roelofs JJ, ter Horst SA. et al. Absence of thrombin-activatable fibrinolysis inhibitor protects against sepsis-induced liver injury in mice. J Immunol 2005; 175: 6764-6771.
  • 31 Asai S, Kimbara N, Tada T. et al. Procarboxypeptidase R deficiency causes increased lethality in concanavalin A-induced hepatitis in female mice. Biol Pharm Bull 2010; 33: 1256-1259.
  • 32 Song JJ, Hwang I, Cho KH. et al. Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis. J Clin Invest 2011; 121: 3517-3527.
  • 33 Nishimura T, Myles T, Piliponsky AM. et al. Thrombin-activatable procarboxy-peptidase B regulates activated complement C5a in vivo. Blood 2007; 109: 1992-1997.
  • 34 Asai S, Sato T, Tada T. et al. Absence of procarboxypeptidase R induces complement-mediated lethal inflammation in lipopolysaccharide-primed mice. J Immunol 2004; 173: 4669-4674.
  • 35 Morser J, Gabazza EC, Myles T. et al. What has been learnt from the thrombin-activatable fibrinolysis inhibitor-deficient mouse?. J Thromb Haemost 2010; 08: 868-876.
  • 36 Sullivan BP, Kassel KM, Jone A. et al. Fibrin(ogen)-independent role of plasminogen activators in acetaminophen-induced liver injury. Am J Pathol 2012; 180: 2321-2329.
  • 37 Jaeschke H, Williams CD, Ramachandran A. et al. Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity. Liver Int 2012; 32: 8-20.
  • 38 Shinohara T, Sakurada C, Suzuki T. et al. Pro-carboxypeptidase R cleaves bradykinin following activation. Int Arch Allergy Immunol 1994; 103: 400-404.
  • 39 Myles T, Nishimura T, Yun TH. et al. Thrombin activatable fibrinolysis inhibitor, a potential regulator of vascular inflammation. J Biol Chem 2003; 278: 51059-51067.
  • 40 Campbell WD, Lazoura E, Okada N. et al. Inactivation of C3a and C5a octapeptides by carboxypeptidase R and carboxypeptidase N. Microbiol Immunol 2002; 46: 131-134.
  • 41 Constandinou C, Henderson N, Iredale JP. Modeling liver fibrosis in rodents. Methods Mol Med 2005; 117: 237-250.
  • 42 Markiewski MM, Mastellos D, Tudoran R. et al. C3a and C3b activation products of the third component of complement (C3) are critical for normal liver recovery after toxic injury. J Immunol 2004; 173: 747-754.
  • 43 Mastellos D, Papadimitriou JC, Franchini S. et al. A novel role of complement: mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration. J Immunol 2001; 166: 2479-2486.
  • 44 Singhal R, Ganey PE, Roth RA. Complement activation in acetaminophen-in-duced liver injury in mice. J Pharmacol Exp Ther 2012; 341: 377-385.
  • 45 Boffa MB, Koschinsky ML. Curiouser and curiouser: recent advances in measurement of thrombin-activatable fibrinolysis inhibitor (TAFI) and in understanding its molecular genetics, gene regulation, and biological roles. Clin Biochem 2007; 40: 431-442.
  • 46 Boffa MB, Nesheim ME, Koschinsky ML. Thrombin activable fibrinolysis inhibitor (TAFI): molecular genetics of an emerging potential risk factor for thrombotic disorders. Curr Drug Targets Cardiovasc Haematol Disord 2001; 01: 59-74.
  • 47 de Bruijne EL, Darwish Murad S, de Maat MP. et al. Genetic variation in thrombin-activatable fibrinolysis inhibitor (TAFI) is associated with the risk of splanchnic vein thrombosis. Thromb Haemost 2007; 97: 181-185.
  • 48 Martini CH, Brandts A, de Bruijne EL. et al. The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis. Br J Haematol 2006; 134: 92-94.
  • 49 van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 2000; 95: 2855-2859.
  • 50 Meltzer ME, Lisman T, de Groot PG. et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 2010; 116: 113-121.
  • 51 Meltzer ME, Doggen CJ, de Groot PG. et al. The impact of the fibrinolytic system on the risk of venous and arterial thrombosis. Semin Thromb Haemost 2009; 35: 468-477.
  • 52 Meltzer ME, Doggen CJ, de Groot PG. et al. Reduced plasma fibrinolytic capacity as a potential risk factor for a first myocardial infarction in young men. Br J Haematol 2009; 145: 121-127.