Endothelial cell injury and coagulation system activation during synergistic hepatotoxicity from monocrotaline and bacterial lipopolysaccharide coexposure.
A small, noninjurious dose of bacterial lipopolysaccharide (LPS; 7.4 x 106 EU/kg) administered 4 h after a small, nontoxic dose of monocrotaline (MCT; 100 mg/kg) produces synergistic hepatotoxicity in rats within 6 to 12 h 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 h). 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.
Department of Pharmacology, National Food Safety and Toxicology Center, Institute for Environmental Toxicology, Michigan State University, East Lansing, USA.
Steven B
SB
Yee
Umesh M
UM
Hanumegowda
Bryan L
BL
Copple
Masabumi
M
Shibuya
Patricia E
PE
Ganey
Robert A
RA
Roth
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D004357:Drug Synergism; D042783:Endothelial Cells / Q000473:pathology*; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008855:Microscopy, Electron, Scanning; D008862:Microsomes, Liver / Q000187:drug effects / Q000648:ultrastructure; D016686:Monocrotaline / Q000633:toxicity*; D011042:Poisons / Q000633:toxicity*; D011758:Pyrroles / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D006454:Hemoglobins; D008070:Lipopolysaccharides; D011042:Poisons; D011758:Pyrroles; D016686:Monocrotaline; D005337:Fibrin; D005340:Fibrinogen