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ToxSci Advance Access published online on May 2, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg106
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received February 11, 2003; accepted March 31, 2003
© 2003 Society of Toxicology

Systems Toxicology

Endothelial Cell Injury and Coagulation System Activation During Synergistic Hepatotoxicity from Monocrotaline and Bacterial Lipopolysaccharide Coexposure

Steven B. Yee 1, Umesh M. Hanumegowda 1, Bryan L. Copple 1, Masabumi Shibuya 2, Patricia E. Ganey 1, Robert A. Roth 1*

1 Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center and Institute for Environmental Toxicology, Michigan State University, East Lansing, MI 48824
2 Division of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo 108-8639, Japan

* To whom correspondence should be addressed. E-mail: rothr{at}msu.edu.


  Abstract

A small, noninjurious dose of bacterial lipopolysaccharide (LPS; 7.4x106 EU/kg) administered 4 hours after a small, nontoxic dose of monocrotaline (MCT; 100 mg/kg) produces synergistic hepatotoxicity in rats within 6 to 12 hours after MCT exposure. The resulting centrilobular (CL) and midzonal (MZ) liver lesions are characterized by hepatic parenchymal cell (HPC) necrosis. Pronounced hemorrhage, disruption of sinusoidal architecture and loss of central vein intima suggest that an additional component to injury may be the liver vasculature. In the present investigation, the hypothesis that sinusoidal endothelial cell (SEC) injury and coagulation system activation occur in this model was tested. Plasma hyaluronic acid (HA) concentration, a biomarker for SEC injury, was significantly increased in cotreated animals before the onset of HPC injury and remained elevated through the time of maximal HPC injury (i.e., 18 hours). SEC injury was confirmed by immunohistochemistry and electron microscopy. Pyrrolic metabolites were produced from MCT by SECs in vitro, which suggests that MCT may injure SECs directly through the formation of its toxic metabolite, monocrotaline pyrrole. Inasmuch as SEC activation and injury can promote hemostasis, activation of the coagulation system was evaluated. Coagulation system activation, as marked by a decrease in plasma fibrinogen, occurred before the onset of HPC injury. Furthermore, extensive fibrin deposition was observed immunohistochemically within CL and MZ regions after MCT/LPS cotreatment. Taken together, these results suggest that SEC injury and coagulation system activation are components of the synergistic liver injury resulting from MCT and LPS coexposure.

Key Words: liver, inflammation, lipopolysaccharide, monocrotaline, sinusoidal endothelial cells, coagulation, hemorrhage, hyaluronic acid .


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