title: Fibrin(ogen)-independent role of plasminogen activators in acetaminophen-induced liver injury.
abstract: 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.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Sullivan
authors.forename: Karen M
authors.initials: KM
authors.lastname: Kassel
authors.forename: Alice
authors.initials: A
authors.lastname: Jone
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Flick
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
mesh_terms: D000082:Acetaminophen; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000990:Antithrombin III; D001777:Blood Coagulation / Q000502:physiology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D004357:Drug Synergism; D005337:Fibrin / Q000502:physiology*; D005340:Fibrinogen / Q000378:metabolism; D005342:Fibrinolysis / Q000502:physiology; D006470:Hemorrhage / Q000139:chemically induced; D008099:Liver / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010447:Peptide Hydrolases / Q000097:blood; D010960:Plasminogen Activators / Q000502:physiology*; D058258:Serpin E2 / Q000172:deficiency; D013917:Thrombin / Q000096:biosynthesis; D010959:Tissue Plasminogen Activator
chemical_list: D058258:Serpin E2; C511869:Serpine2 protein, mouse; C046193:antithrombin III-protease complex; D000082:Acetaminophen; D000990:Antithrombin III; D005337:Fibrin; D005340:Fibrinogen; D000410:Alanine Transaminase; D010447:Peptide Hydrolases; D010960:Plasminogen Activators; D013917:Thrombin; C104096:TNK-tissue plasminogen activator; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9