Wound healing and local neuroendocrine regulation in the injured liver.
ABSTRACT 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.
Chapter: Hepatic Fibrosis[Show abstract] [Hide abstract]
ABSTRACT: Hepatic fibrosis is a reversible wound-healing response characterized by the accumulation of extracellular matrix (ECM) or “scar;” it follows chronic, but not self-limited, liver disease. The ECM components in fibrotic liver are similar, regardless of the underlying cause. Activation or transdifferentiation of hepatic stellate cells into contractile myofibroblasts is the central event in hepatic fibrosis. Resident activated stellate cells and other myofibroblasts derived from intra- and extrahepatic sources orchestrate the accumulation of cytokines, production and degradation of the normal ECM, vascular and organ contraction, and modulation of inflammation. Both hepatic fibrosis and even cirrhosis may be reversible, however the exact stage at which cirrhosis becomes irreversible is not known. Cirrhosis represents a continuum of progressive ECM accumulation and risk of decompensation, yet patients may be asymptomatic for many years. The methods for noninvasive staging of hepatic fibrosis have improved significantly and can replace liver biopsy in many patients. Emerging antifibrotic therapies target key cytokines, receptors, and soluble molecules associated with stellate cell activation and inflammation. Clinical trials of antifibrotic therapies are well underway, and continued progress is anticipated that will ultimately yield new approaches for patients with fibrotic liver disease.Schiff's Diseases of the Liver, Eleventh Edition, 10/2011: pages 295 - 315; , ISBN: 9781119950509
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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 · 1.37 Impact Factor
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ABSTRACT: Liver is a central nexus integrating metabolic and immunologic homeostasis in the human body, and the direct or indirect target of most molecular therapeutics. A wide spectrum of therapeutic and technological needs drive efforts to capture liver physiology and pathophysiology in vitro, ranging from prediction of metabolism and toxicity of small molecule drugs, to understanding off-target effects of proteins, nucleic acid therapies, and targeted therapeutics, to serving as disease models for drug development. Here we provide perspective on the evolving landscape of bioreactor-based models to meet old and new challenges in drug discovery and development, emphasizing design challenges in maintaining long-term liver-specific function and how emerging technologies in biomaterials and microdevices are providing new experimental models.Advanced drug delivery reviews 03/2014; DOI:10.1016/j.addr.2014.02.011 · 11.96 Impact Factor