title: Role of the sympathetic nervous system in carbon tetrachloride-induced hepatotoxicity and systemic inflammation.
abstract: Carbon tetrachloride (CCl4) is widely used as an animal model of hepatotoxicity and the mechanisms have been arduously studied, however, the contribution of the sympathetic nervous system (SNS) in CCl4-induced acute hepatotoxicity remains controversial. It is also known that either CCl4 or SNS can affect systemic inflammatory responses. The aim of this study was to establish the effect of chemical sympathectomy with 6-hydroxydopamine (6-OHDA) in a mouse model of CCl4-induced acute hepatotoxicity and systemic inflammatory response. Mice exposed to CCl4 or vehicle were pretreated with 6-OHDA or saline. The serum levels of aminotransferases and alkaline phosphatase in the CCl4-poisoning mice with sympathetic denervation were significantly lower than those without sympathetic denervation. With sympathetic denervation, hepatocellular necrosis and fat infiltration induced by CCl4 were greatly decreased. Sympathetic denervation significantly attenuated CCl4-induced lipid peroxidation in liver and serum. Acute CCl4 intoxication showed increased expression of inflammatory cytokines/chemokines [eotaxin-2/CCL24, Fas ligand, interleukin (IL)-1α, IL-6, IL-12p40p70, monocyte chemoattractant protein-1 (MCP-1/CCL2), and tumor necrosis factor-α (TNF-α)], as well as decreased expression of granulocyte colony-stimulating factor and keratinocyte-derived chemokine. The overexpressed levels of IL-1α, IL-6, IL-12p40p70, MCP-1/CCL2, and TNF-α were attenuated by sympathetic denervation. Pretreatment with dexamethasone significantly reduced CCl4-induced hepatic injury. Collectively, this study demonstrates that the SNS plays an important role in CCl4-induced acute hepatotoxicity and systemic inflammation and the effect may be connected with chemical- or drug-induced hepatotoxicity and circulating immune response.
authors: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors: Jung-Chun
authors: JC
authors: Lin
authors: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C; Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.
authors: Yi-Jen
authors: YJ
authors: Peng
authors: Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C; Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C.
authors: Shih-Yu
authors: SY
authors: Wang
authors: Division of Gastroenterology, Department of Internal Medicine, Cardinal Tien Hospital, Fu Jen Catholic University, Taipei 231, Taiwan, R.O.C.
authors: Ton-Ho
authors: TH
authors: Young
authors: Center for Molecular Medicine, MRC IGMM, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors: Donald M
authors: DM
authors: Salter
authors: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C; Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C; Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C.
authors: Herng-Sheng
authors: HS
authors: Lee
mesh_terms: D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D018932:Chemokine CCL2 / Q000097:blood; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D003907:Dexamethasone / Q000627:therapeutic use; D008099:Liver / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D000637:Transaminases / Q000097:blood
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D003907:Dexamethasone; D000637:Transaminases; D000469:Alkaline Phosphatase