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.

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

“…The role of PAI-1 in models of liver injury and disease has been extensively studied. For example, PAI-1 deficiency increases liver injury in models of acetaminophen and carbon tetrachloride hepatotoxicity (von Montfort et al, 2010;Sullivan et al, 2012b). In agreement with our finding that inhibition of fibrinolysis with TA reduces ANIT-mediated liver injury and fibrosis, we found that PAI-1 deficiency increased ANIT diet-induced liver injury and fibrosis.…”

“…As a hemostatic agent, TA is reported to have a favorable safety profile for existing indications Muse et al, 2011) and has been demonstrated as an inexpensive and effective treatment for traumatic bleeding, as suggested recently by the multicenter Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage-2 trial (Roberts et al, 2011). In agreement with our findings in plasminogen-null mice, administration of TA also attenuated acetaminophen hepatotoxicity in mice, albeit to a lesser extent (Sullivan et al, 2012b). However, the impact of TA treatment on chronic liver injury has not been broadly investigated in humans or animal models.…”

“…In contrast, acetaminophen hepatotoxicity was reduced in plasminogen-null mice (Sullivan et al, 2012b), suggesting that the role of plasmin is injury/model-dependent. Plasminogen activator inhibitor-1 (PAI-1) is a primary physiological inhibitor of fibrinolysis, via inhibition of the urokinase and tissue plasminogen activators uPA and tPA, respectively (Iwaki et al, 2012).…”

“…For Experiment 1, TA (1200 mg/kg i.p., twice a day; United States Pharmacopeia Grade) (Spectrum Chemical Company, New Brunswick, NJ) or its vehicle (sterile endotoxin-free water) was administered for the study duration. This dose was selected as approximating the range of TA doses used in previous mouse studies (Hattori et al, 2000;Sullivan et al, 2012b) and was well tolerated by the mice. The dose required in mice is higher than the recommended human dose (4 g per day), because of the rapid elimination of TA in the kidney by glomerular filtration (Eriksson et al, 1974).…”

CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity

“…Pharmacological inhibition or genetic depletion of the plasmin zymogen plasminogen significantly reduces APAP-induced liver damage in mice (38). Conversely, hepatic fibrosis, necrosis, and hemorrhage are enhanced in APAP-treated mice with a global PAI-1 deficiency (38).…”