title: Role of neutrophils in a mouse model of halothane-induced liver injury.
abstract: Drug-induced liver injury (DILI) is a major safety concern in drug development. Its prediction and prevention have been hindered by limited knowledge of the underlying mechanisms, in part the result of a lack of animal models. We developed a mouse model of halothane-induced liver injury and characterized the mechanisms accounting for tissue damage. Female and male Balb/c, DBA/1, and C57BL/6J mice were injected intraperitoneally with halothane. Serum levels of alanine aminotransferase and histology were evaluated to determine liver injury. Balb/c mice were found to be the most susceptible strain, followed by DBA/1, with no significant hepatotoxicity observed in C57BL/6J mice. Female Balb/c and DBA/1 mice developed more severe liver damage compared with their male counterparts. Bioactivation of halothane occurred similarly in all three strains based on detection of liver proteins adducted by the reactive metabolite. Mechanistic investigations revealed that hepatic message levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta); IL-6, and IL-8 were significantly higher in halothane-treated Balb/c mice compared to DBA/1 and C57BL/6J mice. Moreover, a higher number of neutrophils were recruited into the liver of Balb/c mice upon halothane treatment compared with DBA/1, with no obvious neutrophil infiltration detected in C57BL/6J mice. Neutrophil depletion experiments demonstrated a crucial role for these cells in the development of halothane-induced liver injury. The halothane-initiated hepatotoxicity and innate immune response-mediated escalation of tissue damage are consistent with events that occur in many cases of DILI. In conclusion, our model provides a platform for elucidating strain-based and gender-based susceptibility factors in DILI development.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: You
authors.forename: Linling
authors.initials: L
authors.lastname: Cheng
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Reilly
authors.forename: Dale
authors.initials: D
authors.lastname: Wegmann
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ju
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004195:Disease Models, Animal; D005260:Female; D005463:Fluoroacetates; D006221:Halothane / Q000378:metabolism; D007728:Kupffer Cells / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000276:immunology; D008107:Liver Diseases / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009504:Neutrophils / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D014269:Trifluoroacetic Acid / Q000378:metabolism
chemical_list: D005463:Fluoroacetates; D011506:Proteins; C500395:trifluoroacetyl chloride; D014269:Trifluoroacetic Acid; D006221:Halothane