title: Oxidized low-density lipoprotein and tissue factor are involved in monocrotaline/lipopolysaccharide-induced hepatotoxicity.
abstract: These studies were aimed at characterizing an animal model of inflammation-induced hepatotoxicity that would mimic features of idiosyncratic liver toxicity observed in humans. An attempt was made to identify oxidative damage and the involvement of coagulation system in liver after monocrotaline (MCT) administration under the modest inflammatory condition induced by lipopolysaccharide (LPS) exposure. Mice were given MCT (200 mg/kg) or an equivalent volume of sterile saline (Veh.) po followed 4 h later by ip injection of LPS (6 mg/kg) or vehicle. Mice co-treated with MCT and LPS showed increased plasma alanine aminotransferase (ALT), decrease in platelet number, and a reduction in hematocrit. Accumulation of oxidized low-density lipoprotein (ox-LDL) was remarkably higher in the liver sections of mice co-treated with MCT and LPS compared to those given MCT or LPS alone. A similar trend was observed in the expression of CXCL16 receptor in the same liver sections. Elevated expression of tissue factor (TF) and fibrinogen was also observed in the liver sections of MCT/LPS co-treated mice. The in vitro results showed that incubation of HepG2 cells with CXCL16 antibody strongly diminished uptake of ox-LDL. Expression of ox-LDL, CXCL16, and TF represents an early event in the onset of hepatotoxicity induced by MCT/LPS; thus, it may contribute to our understanding of idiosyncratic liver injury and points to potential targets for protection or intervention.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Hammad
authors.forename: Mohamed Sadek
authors.initials: MS
authors.lastname: Abdel-Bakky
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.forename: M K
authors.initials: MK
authors.lastname: Ashfaq
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D018929:Cell Culture Techniques; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000235:genetics; D019743:Chemokines, CXC / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D003627:Data Interpretation, Statistical; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D056945:Hep G2 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016686:Monocrotaline / Q000633:toxicity*; D010084:Oxidation-Reduction; D051116:Receptors, Scavenger / Q000235:genetics; D013925:Thromboplastin / Q000378:metabolism*
chemical_list: C423727:CXCL16 protein, human; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; C498926:Cxcl16 protein, mouse; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D051116:Receptors, Scavenger; C099252:oxidized low density lipoprotein; D016686:Monocrotaline; D003094:Collagen; D013925:Thromboplastin; D000410:Alanine Transaminase