Abstract 276: Excessive Plasmin Activity Compromises Hepatic Sinusoidal Vascular Integrity After Acetaminophen Overdose

The serine protease plasmin degrades extracellular matrix (ECM) components both through direct cleavage and indirectly through activation of matrix metalloproteinases. We previously reported that excessive plasmin activity and subsequent ECM degradation causes hepatic sinusoidal fragility and lethal hemorrhage in developing embryos. We now report that excessive plasmin activity in a murine acetaminophen (APAP) overdose model likewise compromises postnatal hepatic sinusoidal vascular integrity. We found that hepatic plasmin activity is upregulated significantly at 6 hr after APAP overdose. This plasmin upregulation precedes both degradation of the ECM component fibronectin around liver vasculature and bleeding from centrilobular sinusoids. Importantly, administration of the pharmacological plasmin inhibitor tranexamic acid or genetic reduction of plasminogen, the circulating zymogen of plasmin, ameliorates APAP-induced hepatic fibronectin degradation and sinusoidal bleeding. In conclusion, these studies demonstrate that reduction of plasmin stabilizes hepatic sinusoidal vascular integrity after APAP overdose.