fibrin and Chemical-and-Drug-Induced-Liver-Injury--Chronic

Hepatic deposition of cross-linked fibrin(ogen) occurs alongside platelet accumulation as a hallmark of acetaminophen (APAP)-induced liver injury.. We sought to define the precise role of the fibrinogen γ-chain C-terminal integrin α. We observed an altered pattern of fibrin(ogen) deposition in the livers of APAP-challenged Fibγ. The results indicate that fibrinogen-γ

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury, Chronic; Fibrin; Fibrinogen; Integrins; Lysine; Mice

Methotrexate (MTX) is a widely used drug for treatment of many malignant, rheumatic, and autoimmune diseases. However, hepatotoxicity remains one of the most serious side effects of MTX. The extrinsic coagulation pathway is activated after tissue injury through the release of tissue factor (TF) which activates a cascade of clotting factors including prothrombin and fibrinogen. Liver sinusoidal endothelial cells express endothelial nitric oxide synthase (eNOS) as a source for nitric oxide (NO) that serves as vasodilator and antithrombotic factor. In the current study, we tested the possible role of coagulation system activation in MTX-induced hepatotoxicity. Our results showed that single-dose administration of MTX significantly altered rat liver functions with concurrent turbulence in redox status. Immunofluorescence staining showed accumulation of fibrin in the periportal hepatocytes and downregulation of eNOS expression in hepatic endothelial and sinusoidal cells following MTX treatment. Moreover, MTX administration increased the expression of inducible nitric oxide synthase (iNOS) and NOSTRIN (eNOS traffic inducer) in the hepatic sinusoids. On the other hand, pre-treatment with enoxaparin rescued against MTX-induced liver injury with subsequent amelioration of liver redox status. Furthermore, it significantly prevented the effect of MTX on the expression of fibrin, iNOS, eNOS, and NOSTRIN. We concluded that liver tissue aggregation of the coagulation product, fibrin, may play a crucial role in the pathogenesis of MTX-induced liver injury.

Topics: Adaptor Proteins, Signal Transducing; Animals; Anticoagulants; Antirheumatic Agents; Chemical and Drug Induced Liver Injury, Chronic; DNA-Binding Proteins; Enoxaparin; Fibrin; Immunosuppressive Agents; Liver; Male; Methotrexate; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Protective Agents; Rats, Sprague-Dawley