Excessive Plasmin Compromises Hepatic Sinusoidal Vascular Integrity After Acetaminophen Overdose

Area of Science:

• Biochemistry
• Vascular Biology
• Hepatology

Background:

• Plasmin, a serine protease, degrades extracellular matrix (ECM), contributing to vascular fragility.
• Excessive plasmin activity is linked to hemorrhage in embryonic development.
• Acetaminophen (APAP) overdose can compromise liver vascular integrity.

Purpose of the Study:

• To investigate the role of plasmin in liver injury following acetaminophen overdose in adult mice.
• To determine if reducing plasmin activity can prevent APAP-induced hepatic sinusoidal damage.

Main Methods:

• Utilized a murine model of acetaminophen (APAP) overdose.
• Measured hepatic plasmin activity and ECM component fibronectin degradation.
• Assessed sinusoidal bleeding and vascular integrity.
• Administered tranexamic acid (plasmin inhibitor) or used genetic reduction of plasminogen.

Main Results:

• Hepatic plasmin activity significantly increased 6 hours post-APAP overdose.
• Increased plasmin activity preceded fibronectin degradation and sinusoidal bleeding.
• Inhibition of plasmin with tranexamic acid or genetic reduction of plasminogen reduced fibronectin degradation and bleeding.

Conclusions:

• Elevated plasmin activity is a key factor in liver injury after APAP overdose.
• Reducing plasmin activity stabilizes hepatic sinusoidal vascular integrity.
• Targeting plasmin offers a potential therapeutic strategy for acetaminophen-induced liver injury.