Fibrinogen Deficiency Increases Liver Injury and Early Growth Response-1 (Egr-1) Expression in a Model of Chronic Xenobiotic-Induced Cholestasis

Abstract

Chronic cholestatic liver injury induced by cholestasis in rodents is associated with hepatic fibrin deposition, and we found evidence of fibrin deposition in livers of patients with cholestasis. Key components of the fibrinolytic pathway modulate cholestatic liver injury by regulating activation of hepatocyte growth factor. However, the exact role of hepatic fibrin deposition in chronic cholestasis is not known. We tested the hypothesis that fibrinogen (Fbg) deficiency worsens liver injury induced by cholestasis. Fbg-deficient mice (Fbg␣ ؊/؊ mice) and heterozygous control mice (Fbg␣ ؉/؊ mice) were fed either the control diet or a diet containing 0.025% ␣-naphthylisothiocyanate (ANIT), which selectively injures bile duct epithelial cells in the liver, for 2 weeks. Hepatic fibrin and collagen deposits were evident in livers of heterozygous control mice fed the ANIT diet. Complete Fbg deficiency was associated with elevated serum bile acids, periportal necrosis, and increased serum alanine aminotransferase activity in mice fed the ANIT diet. Fbg deficiency was associated with enhanced hepatic expression of the transcription factor early growth response-1 (Egr-1) and enhanced induction of genes encoding the Egr-1-regulated proinflammatory chemokines monocyte chemotactic protein-1, KC growth-regulated protein, and macrophage inflammatory protein-2. Interestingly, peribiliary collagen deposition was not evident near necrotic areas in Fbg-deficient mice. The results suggest that in this model of chronic cholestasis, fibrin constrains the release of bile constituents from injured intrahepatic bile ducts, thereby limiting the progression of hepatic inflammation and hepatocellular injury.

The Antifibrinolytic Drug Tranexamic Acid Reduces Liver Injury and Fibrosis in a Mouse Model of Chronic Bile Duct Injury

“…1A). Similar hepatic fibrin deposition has been reported previously in mice fed ANIT diet for 2 weeks (Luyendyk et al, 2011). It is noteworthy that we did not observe a statistically significant increase in hepatic fibrin deposits in TA-treated mice (data not shown).…”

“…Hepatic fibrin deposition is evident in patients with chronic cholestatic liver disease (Luyendyk et al, 2011) and in rodent models of chronic cholestasis (Wang et al, 2007c;Luyendyk et al, 2011). Genetically imposed loss of fibrin(ogen) increases hepatic inflammation and injury in mice fed ANIT diet (Luyendyk et al, 2011).…”

“…BDEC injury in this model is associated with tissue factor-dependent activation of the blood coagulation cascade and increased plasma levels of the coagulation protease thrombin (Sullivan et al, 2010). This increase in thrombin activity is associated with the deposition of insoluble fibrin clots in livers of mice fed ANIT diet (Luyendyk et al, 2011). Notably, increased plasma thrombin levels and hepatic fibrin deposition are also features of chronic cholestatic liver disease in humans (Segal et al, 1997;Luyendyk et al, 2011).…”

“…Although fibrin deposition is an inevitable consequence of tissue injury, its regulation and impact in liver disease are not completely understood (Tripodi and Mannucci, 2007). Previously, we found that fibrin (ogen) deficiency increased hepatocellular necrosis in mice fed ANIT diet (Luyendyk et al, 2011). This suggests a protective role for hepatic fibrin deposition in this model of cholestatic liver injury and that modulating fibrin degradation (i.e., inhibiting fibrinolysis) could prevent the progression of ANIT-induced liver injury and fibrosis.…”

Phenotypic Changes in Hepatic Stellate Cells in Response to Toxic Liver Injury

“…In addition, liver fibrosis is reduced in PAR-1 knockout mice and in mice treated with a PAR-1 antagonist [17,18]. Interestingly, recent studies showed that fibrin is deposited in the livers of patients with fibrosis indicating that even though coagulation factors may be depleted in patients with diminished liver function, sufficient liver function is present to activate the coagulation system locally in the liver, which may stimulate HSC proliferation in a PAR-1-dependent manner [19].…”