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

Abstract

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.

Fibrin deposition following bile duct injury limits fibrosis through an αMβ2-dependent mechanism

“…Thus, for comparison we selected CCl 4 -induced liver fibrosis, wherein the chronic administration of toxicant produces liver fibrosis distinct in pattern from ANIT, and without classic bile duct hyperplasia. 31 Similar to a previous study, 32 hepatic fibrin(ogen) deposits were also observed in WT mice challenged with CCl 4 (8 weeks) in a pattern resembling more the borders of the hepatic acinus ( Figure 4A Despite a marked induction of numerous inflammatory chemokines in livers of ANIT-exposed mice (supplemental Figure 2C-H), we did not observe an effect of ANIT exposure or genotype on the number of hepatic macrophages ( Figure 5A). Of importance, we and others have shown lymphocyte accumulation in livers of ANIT-exposed mice.…”

Carboxypeptidase B2 and carboxypeptidase N in the crosstalk between coagulation, thrombosis, inflammation, and innate immunity

“…Intriguingly, concanavalin A challenge, which causes hepatitis, leads to increased mortality in female but not male Cpb2 − / − mice . Chemical challenge with CCl 4 or acetaminophen causes more liver damage in Cpb2 − / − mice than in WT mice . Collectively, these data suggest that CPB2 plays a role in protecting against organ damage, especially in the liver.…”

Fibrinolysis and the control of blood coagulation

“…Deficiencies of uPA may also promote cancer progression in experimental models of inflammatory colon cancer [126]. In murine models, deficiency of TAFI has been linked with increased fibrin deposition and inflammation leading to liver damage [127]. Other polymorphisms in TAFI and PAI-1 have been described that may contribute to thrombotic risk, but the strength of their association is unclear (Table 1B).…”