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

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 1 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.