| First Author | Sullivan BP | Year | 2012 |
| Journal | Am J Pathol | Volume | 180 |
| Issue | 6 | Pages | 2321-9 |
| PubMed ID | 22507835 | Mgi Jnum | J:184692 |
| Mgi Id | MGI:5426086 | Doi | 10.1016/j.ajpath.2012.02.011 |
| Citation | Sullivan BP, et al. (2012) Fibrin(ogen)-Independent Role of Plasminogen Activators in Acetaminophen-Induced Liver Injury. Am J Pathol 180(6):2321-9 |
| abstractText | 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. |
