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Excessive Plasmin Compromises Hepatic Sinusoidal Vascular Integrity After Acetaminophen Overdose
Author(s) -
Gao Siqi,
SilasiMansat Robert,
Behar Amanda R.,
Lupu Florea,
Griffin Courtney T.
Publication year - 2018
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30070
Subject(s) - plasmin , aprotinin , fibronectin , extracellular matrix , pharmacology , matrix metalloproteinase , chemistry , tranexamic acid , zymogen , medicine , endocrinology , biochemistry , enzyme , surgery , blood loss
The serine protease plasmin degrades extracellular matrix (ECM) components both directly and indirectly through activation of matrix metalloproteinases. Excessive plasmin activity and subsequent ECM degradation cause hepatic sinusoidal fragility and hemorrhage in developing embryos. We report here that excessive plasmin activity in a murine acetaminophen (APAP) overdose model likewise compromises hepatic sinusoidal vascular integrity in adult animals. We found that hepatic plasmin activity is up‐regulated significantly at 6 hours after APAP overdose. This plasmin up‐regulation 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. Conclusion: These studies demonstrate that reduction of plasmin stabilizes hepatic sinusoidal vascular integrity after APAP overdose. (H epatology 2018; 00:1‐13).