Wound healing and local neuroendocrine regulation in the injured liver

Cell signalling, Liver Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
Expert Reviews in Molecular Medicine (Impact Factor: 5.15). 02/2008; 10(11):e11. DOI: 10.1017/S146239940800063X
Source: PubMed


The hepatic wound-healing response is a complex process involving many different cell types and factors. It leads to the formation of excessive matrix and a fibrotic scar, which ultimately disrupts proper functioning of the liver and establishes cirrhosis. Activated hepatic myofibroblasts, which are derived from cells such as hepatic stellate cells (HSCs), play a key role in this process. Upon chronic liver injury, there is an upregulation in the local neuroendocrine system and it has recently been demonstrated that activated HSCs express specific receptors and respond to different components of this system. Neuroendocrine factors and their receptors participate in a complex network that modulates liver inflammation and wound healing, and controls the development and progression of liver fibrosis. The first part of this review provides an overview of the molecular mechanisms governing hepatic wound healing. In the second section, we explore important components of the hepatic neuroendocrine system and their recently highlighted roles in HSC biology and hepatic fibrogenesis. We discuss the therapeutic interventions that are being developed for use in antifibrotic therapy.

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    • "In order to assess liver fibrosis we used classical H&E and trichrome staining as well as hepatic hydroxyproline assay. Liver cirrhosis is associated with contraction of myofibroblasts which leads to increased hepatic resistance and portal hypertension (Ebrahimkhani et al., 2008). As an indirect assay to assess portal pressure, we measured intrasplenic pressure in the experimental groups. "
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    ABSTRACT: Recent studies have shown that vagus nerve activation inhibits cytokine production in a variety of non-neural cells though activation of α7 nicotinic acetylcholine receptor (α7nAChR). Since chronic inflammation plays a pivotal role in liver fibrosis, this study was designed to investigate the role of hepatic vagus nerve in the progression of hepatic fibrosis in rats. Cirrhosis was induced by chronic ligation of the bile duct. Hepatic hydroxyproline level, portal pressure, serum transaminase level, hepatic TIMP-1 (tissue inhibitor of metalloproteinase-1) and MCP-1 (monocyte chemoattractant peptide-1) expression were measured in order to assess the progression of liver cirrhosis. α7nAChR expression was assessed using RT-PCR as well as immunostaining. RT-PCR analysis of the liver showed that α7nAChR mRNA is expressed in rat liver. Immunostaining study demonstrated that hepatic α7nAChR is mainly expressed in the hepatocytes of cirrhotic liver with minimum α7nAChR expression in biliary epithelium or myofibroblasts. Bile duct ligation was associated with portal hypertension, increased hepatic hydroxyproline level as well as TIMP-1 and MCP-1 expression in the liver. However neither selective hepatic vagotomy nor methyllycaconitine (an α7nAChR antagonist) could significantly affect development of portal hypertension or hepatic fibrosis in rats. Selective hepatic vagotomy could only attenuate serum aspartate aminotransferase level in bile duct ligated rats but did not have a significant effect on hepatic inflammation as assessed by MCP-1 mRNA expression. Our study provides evidence against a crucial role for the hepatic vagus nerve as an intrinsic protective mechanism in modulation of hepatic fibrosis in a rat model of biliary cirrhosis.
    Autonomic Neuroscience 10/2014; 185. DOI:10.1016/j.autneu.2014.07.005 · 1.56 Impact Factor
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    • "Moreover, chronic persistent inflammation typically precedes fibrosis. Chronic liver injuries activate and transform quiescent hepatic stellate cells (HSCs) into activated myofibroblasts, which is the central pathogenic mechanism of fibrotic disorders [2]. The development of cirrhosis is usually associated with oxidative stress and lipid peroxidation (LPO) [3]. "
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    ABSTRACT: Aim. This study aimed to assess the antioxidant activity of quercetin (Q) in an experimental model of cirrhosis induced by CCl(4) inhalation. Materials and Methods. We used 25 male Wistar rats (250 g) that were divided into 3 groups: control (CO), CCl(4), and CCl(4) + Q. The rats were subjected to CCl(4) inhalation (2x/week) for 16 weeks, and they received phenobarbital in their drinking water at a dose of 0.3 g/dL as a P450 enzyme inducer. Q (50 mg/Kg) was initiated intraperitoneally at 10 weeks of inhalation and lasted until the end of the experiment. Statistical analysis was by ANOVA Student Newman-Keuls (mean ± SEM), and differences were considered statistically significant when P < 0.05. Results. After treatment with quercetin, we observed an improvement in liver complications, decreased fibrosis, as analyzed by picrosirius for the quantification of collagen, and decreased levels of matrix metalloproteinase 2 (MMP-2) compared with the CCl(4) group. It also reduced oxidative stress, as confirmed by the decrease of substances reacting to thiobarbituric acid (TBARS), the increased activity of antioxidant enzymes, and the reduced glutathione ratio and glutathione disulfide (GSH/GSSG). Conclusion. We suggest that the use of quercetin might be promising as an antioxidant therapy in liver fibrosis.
    04/2012; 2012(1):762920. DOI:10.5402/2012/762920
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    • "The liver plays a central role in metabolic processes such as the synthesis of serum proteins (e.g. albumin), storage of glycogen, maintaining homeostasis, and immunological functions [1]. The most notable characteristic of the liver is its regenerative ability and investigations have shown that the liver can regenerate to its full size even after a 67% hepatectomy [2] [3]. "
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    ABSTRACT: The liver is unique for its ability to regenerate after injury, however, critical injuries or disease cause it to lose this quality. Stem cells have been explored as a possibility to restore the function of seriously damaged livers, based on their self-renewability and multiple differentiation capacity. These experiments examine the ability of muscle derived stem cells (MDSCs) to differentiate into hepatocyte-like cells in vitro and acquire functional liver attributes for repairing damaged livers. In vitro experiments were performed using MDSCs from postnatal mice and mouse hepatocyte cell lines. Our data revealed that MDSCs differentiated into hepatocyte-like cells and expressed liver cell markers, albumin, hepatocyte nuclear factor 4 α, and alpha feto-protein, both at the RNA and protein level. Additionally, in vivo studies showed successful engraftment of MDSCs into hepatectomized mouse livers of mice. These results provide evidence suggesting that MDSCs have the capacity to differentiate into liver cell-like cells and may serve as potential candidates to aid in liver regeneration.
    International journal of clinical and experimental pathology 01/2010; 3(7):681-90. · 1.89 Impact Factor
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