title: The coagulation system contributes to synergistic liver injury from exposure to monocrotaline and bacterial lipopolysaccharide.
abstract: Coexposure to a noninjurious dose of bacterial lipopolysaccharide (LPS; 7.4 x 106 EU/kg) and a nontoxic dose of the food-borne toxin monocrotaline (MCT; 100 mg/kg) leads to synergistic hepatotoxicity in Sprague-Dawley rats. Inflammatory factors, such as Kupffer cells (KCs), tumor necrosis factor-alpha (TNF)-alpha, and neutrophils (polymorphonuclear leukocytes; PMNs), are critical to the pathogenesis. Inasmuch as activation of the coagulation system and sinusoidal endothelial cell (SEC) injury precede hepatic parenchymal cell (HPC) injury, and since fibrin deposition occurs within liver lesions, the coagulation system might be a critical component of injury. In this study, this hypothesis is tested, and the interdependence of the coagulation system and inflammatory factors is explored. Administration of the anticoagulants heparin or warfarin to MCT/LPS-cotreated animals attenuated HPC and SEC injury. Morphometric analysis revealed that anticoagulant treatment significantly reduced the area of centrilobular and midzonal lesions. Heparin treatment also reduced fibrin deposition in these regions. Furthermore, anticoagulant treatment decreased hepatic PMN accumulation but did not affect plasma TNF-alpha concentration. Neither KC inactivation nor TNF-alpha depletion prevented activation of the coagulation system. PMN depletion, however, prevented coagulation system activation, suggesting that PMNs are needed for this response. These results provide evidence that the coagulation system and its interplay with PMNs are important in the pathogenesis of MCT/LPS-induced liver injury.
authors.affiliation: Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center and Institute for Environmental Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Yee
authors.forename: Jack R
authors.initials: JR
authors.lastname: Harkema
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Ganey
authors.forename: Robert A
authors.initials: RA
authors.lastname: Roth
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology / Q000473:pathology; D004336:Drug Antagonism; D004357:Drug Synergism; D004926:Escherichia coli; D006493:Heparin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D016686:Monocrotaline / Q000633:toxicity*; D009503:Neutropenia / Q000139:chemically induced / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014859:Warfarin / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D008070:Lipopolysaccharides; D014859:Warfarin; D016686:Monocrotaline; D006493:Heparin