Lin Jung-Chun, Peng Yi-Jen, Wang Shih-Yu, Young Ton-Ho, Salter Donald M, Lee Herng-Sheng
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.
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.
PLoS One. 2015 Mar 23;10(3):e0121365. doi: 10.1371/journal.pone.0121365. eCollection 2015.
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.
四氯化碳（CCl4）被广泛用作肝毒性的动物模型，其作用机制已得到深入研究，然而，交感神经系统（SNS）在CCl4诱导的急性肝毒性中的作用仍存在争议。此外，已知CCl4或SNS均可影响全身炎症反应。本研究的目的是在CCl4诱导的急性肝毒性和全身炎症反应小鼠模型中，确定6-羟基多巴胺（6-OHDA）化学去交感神经的作用。将暴露于CCl4或赋形剂的小鼠用6-OHDA或生理盐水进行预处理。去交感神经的CCl4中毒小鼠血清转氨酶和碱性磷酸酶水平显著低于未去交感神经的小鼠。去交感神经后，CCl4诱导的肝细胞坏死和脂肪浸润明显减少。去交感神经显著减轻了CCl4诱导的肝脏和血清脂质过氧化。急性CCl4中毒表现为炎性细胞因子/趋化因子[嗜酸性粒细胞趋化因子-2/CCL24、Fas配体、白细胞介素（IL）-1α、IL-6、IL-12p40p70、单核细胞趋化蛋白-1（MCP-1/CCL2）和肿瘤坏死因子-α（TNF-α）]表达增加，以及粒细胞集落刺激因子和角质形成细胞衍生趋化因子表达减少。交感神经去支配减弱了IL-1α、IL-6、IL-12p40p70、MCP-1/CCL2和TNF-α的过表达水平。地塞米松预处理显著降低了CCl4诱导的肝损伤。总体而言，本研究表明，SNS在CCl4诱导的急性肝毒性和全身炎症中起重要作用，其作用可能与化学或药物诱导的肝毒性及循环免疫反应有关。
