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.
Highlights
Carbon tetrachloride (CCl4) is a chlorinated hydrocarbon that has widespread use in various industries as a solvent and in medicine as a vermifuge
Immunofluorescences showed that the tyrosine hydroxylase (TH)-positive fibers in the liver without chemical sympathectomy were mainly distributed in the portal tract
Prior chemical sympathectomy with 6-OHDA abolished the CCl4 toxicity, suggesting that it is mediated through adrenergic stimulation of the liver, but the regulatory mechanism of sympathetic innervation remains poorly understood so far [13,14]
Summary
Carbon tetrachloride (CCl4) is a chlorinated hydrocarbon that has widespread use in various industries as a solvent and in medicine as a vermifuge. It is found in low levels in ambient air and water [1,2]. The end result inactivates calcium pump activity with calcium influx. All these alterations eventually lead to liver cell death accompanied by the release into the blood of intrahepatic enzymes [1,3]. The mechanisms of CCl4-induced steatosis remain speculative [10]
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