Dataset Information

Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver through ?-Adrenergic Signaling.

ABSTRACT: In addition to being the primary organ involved in redox cycling, the liver is one of the most highly innervated tissues in mammals. The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function, liver regeneration, and hepatic fibrosis. However, less is known regarding the role of the sympathetic nervous system (SNS) in modulating the hepatic response to oxidative stress. Our aim was to investigate the role of the SNS in healthy and oxidatively stressed liver parenchyma. Mice treated with 6-hydroxydopamine hydrobromide were used to realize chemical sympathectomy. Carbon tetrachloride (CCl4) injection was used to induce oxidative liver injury. Sympathectomized animals were protected from CCl4 induced hepatic lipid peroxidation-mediated cytotoxicity and genotoxicity as assessed by 4-hydroxy-2-nonenal levels, morphological features of cell damage, and DNA oxidative damage. Furthermore, sympathectomy modulated hepatic inflammatory response induced by CCl4-mediated lipid peroxidation. CCl4 induced lipid peroxidation and hepatotoxicity were suppressed by administration of an ?-adrenergic antagonist. We conclude that the SNS provides a permissive microenvironment for hepatic oxidative stress indicating the possibility that targeting the hepatic ?-adrenergic signaling could be a viable strategy for improving outcomes in patients with acute hepatic injury.

SUBMITTER: Lin JC

PROVIDER: S-EPMC4699022 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver through α-Adrenergic Signaling.

Lin Jung-Chun JC Peng Yi-Jen YJ Wang Shih-Yu SY Lai Mei-Ju MJ Young Ton-Ho TH Salter Donald M DM Lee Herng-Sheng HS

Oxidative medicine and cellular longevity 20151221

In addition to being the primary organ involved in redox cycling, the liver is one of the most highly innervated tissues in mammals. The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function, liver regeneration, and hepatic fibrosis. However, less is known regarding the role of the sympathetic nervous system (SNS) in modu ...[more]

PMID: 26798417

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Project description:Liver fibrosis, depending on the stage of the disease, could lead to organ dysfunction and cirrhosis, and no effective treatment is actually available. Emergent proof supports a link between oxidative stress, liver fibrogenesis and mitochondrial dysfunction as molecular bases of the pathology. A valid approach to protect against the disease would be to replenish the endogenous antioxidants; thus, we investigated the protective mechanisms of the S-acetyl-glutathione (SAG), a glutathione (GSH) prodrug. Preliminary in vitro analyses were conducted on primary hepatic cells. SAG pre-treatment significantly protected against cytotoxicity induced by CCl4. Additionally, CCl4 induced a marked increase in AST and ALT levels, whereas SAG significantly reduced these levels, reaching values found in the control group. For the in vivo analyses, mice were administered twice a week with eight consecutive intraperitoneal injections of 1 mL/kg CCl4 (diluted at 1:10 in olive oil) to induce oxidative imbalance and liver inflammation. SAG (30 mg/kg) was administered orally for 8 weeks. SAG significantly restored SOD activity, GSH levels and GPx activity, while it strongly reduced GSSG levels, lipid peroxidation and H2O2 and ROS levels in the liver. Additionally, CCl4 induced a decrease in anti-oxidants, including Nrf2, HO-1 and NQO-1, which were restored by treatment with SAG. The increased oxidative stress characteristic on liver disfunction causes the impairment of mitophagy and accumulation of dysfunctional and damaged mitochondria. Our results showed the protective effect of SAG administration in restoring mitophagy, as shown by the increased PINK1 and Parkin expressions in livers exposed to CCl4 intoxication. Thus, the SAG administration showed anti-inflammatory effects decreasing pro-inflammatory cytokines TNF-α, IL-6, MCP-1 and IL-1β in both serum and liver, and suppressing the TLR4/NFkB pathway. SAG attenuated reduced fibrosis, collagen deposition, hepatocellular damage and organ dysfunction. In conclusion, our results suggest that SAG administration protects the liver from CCl4 intoxication by restoring the oxidative balance, ameliorating the impairment of mitophagy and leading to reduced inflammation.

Dataset Information

Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver through ?-Adrenergic Signaling.

Publications

Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver through α-Adrenergic Signaling.

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