title: Roles of the hemostatic system and neutrophils in liver injury from co-exposure to amiodarone and lipopolysaccharide.
abstract: It has been demonstrated that co-treatment of rats with amiodarone (AMD) and bacterial lipopolysaccharide (LPS) produces idiosyncrasy-like liver injury. In this study, the hypothesis that the hemostatic system and neutrophils contribute to AMD/LPS-induced liver injury was explored. Rats were treated with AMD (400 mg/kg, ip) or vehicle and 16 h later with LPS (1.6×10⁶ endotoxin units/kg, iv) or saline (Sal). AMD did not affect the hemostatic system by itself but significantly potentiated LPS-induced coagulation activation and fibrinolysis impairment. Increased hepatic fibrin deposition and subsequent hypoxia were observed only in AMD/LPS-treated animals, starting before the onset of liver injury. Administration of anticoagulant heparin abolished AMD/LPS-induced hepatic fibrin deposition and reduced AMD/LPS-induced liver damage. Polymorphonuclear neutrophils (PMNs) accumulated in liver after treatment with LPS or AMD/LPS, but PMN activation was only observed in AMD/LPS-treated rats. Rabbit anti-rat PMN serum, which reduced accumulation of PMNs in liver, prevented PMN activation and attenuated AMD/LPS-induced liver injury in rats. PMN depletion did not affect hepatic fibrin deposition. Anticoagulation prevented PMN activation without affecting PMN accumulation. In summary, both the hemostatic system alteration and PMN activation contributed to AMD/LPS-induced liver injury in rats, in which fibrin deposition was critical for the activation of PMNs.
authors.affiliation: * Department of Biochemistry and Molecular Biology.
authors.forename: Jingtao
authors.initials: J
authors.lastname: Lu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Roth
authors.forename: Ernst
authors.initials: E
authors.lastname: Malle
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Ganey
mesh_terms: D000638:Amiodarone / Q000633:toxicity*; 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; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects; D006487:Hemostasis / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology; D000860:Hypoxia / Q000097:blood / Q000139:chemically induced; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000925:Anticoagulants; D008070:Lipopolysaccharides; D005337:Fibrin; D006493:Heparin; D000638:Amiodarone
keywords: amiodarone; hemostatic system; hypochlorous acid.; idiosyncratic drug-induced liver injury; neutrophils
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