[HTML][HTML] Fibrin (ogen)-independent role of plasminogen activators in acetaminophen-induced liver injury

BP Sullivan, KM Kassel, A Jone, MJ Flick… - The American journal of …, 2012 - Elsevier
BP Sullivan, KM Kassel, A Jone, MJ Flick, JP Luyendyk
The American journal of pathology, 2012Elsevier
Hepatic fibrin (ogen) has been noted to occur after acetaminophen (APAP)-induced liver
injury in mice. Deficiency in plasminogen activator inhibitor-1 (PAI-1), an endogenous
inhibitor of fibrinolysis, increases APAP-induced liver injury in mice. However, the roles of
fibrinogen and fibrinolysis in APAP-induced liver injury are not known. We tested the
hypothesis that hepatic fibrin (ogen) deposition reduces severity of APAP-induced liver
injury. APAP-induced (300 mg/kg) liver injury in mice was accompanied by thrombin …
Hepatic fibrin(ogen) has been noted to occur after acetaminophen (APAP)-induced liver injury in mice. Deficiency in plasminogen activator inhibitor-1 (PAI-1), an endogenous inhibitor of fibrinolysis, increases APAP-induced liver injury in mice. However, the roles of fibrinogen and fibrinolysis in APAP-induced liver injury are not known. We tested the hypothesis that hepatic fibrin(ogen) deposition reduces severity of APAP-induced liver injury. APAP-induced (300 mg/kg) liver injury in mice was accompanied by thrombin generation, consumption of plasma fibrinogen, and deposition of hepatic fibrin. Neither fibrinogen depletion with ancrod nor complete fibrinogen deficiency [via knockout of the fibrinogen alpha chain gene (Fbg−∕−)] affected APAP-induced liver injury. PAI-1 deficiency (PAI-1−∕−) increased APAP-induced liver injury and hepatic fibrin deposition 6 hours after APAP administration, which was followed by marked hemorrhage at 24 hours. As in PAI-1−∕− mice, administration of recombinant tissue plasminogen activator (tenecteplase, 5 mg/kg) worsened APAP-induced liver injury and hemorrhage in wild-type mice. In contrast, APAP-induced liver injury was reduced in both plasminogen-deficient mice and in wild-type mice treated with tranexamic acid, an inhibitor of plasminogen activation. Activation of matrix metalloproteinase 9 (MMP-9) paralleled injury, but MMP-9 deficiency did not affect APAP-induced liver injury. The results indicate that fibrin(ogen) does not contribute to development of APAP-induced liver injury and suggest rather that plasminogen activation contributes to APAP-induced liver injury.
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