Does hepatic vagus nerve modulate the progression of biliary fibrosis in rats? Khalil Hajiasgharzadeh a , Seyed Mohammad Tavangar b , Mohammad Javan a , Ahmad R. Dehpour c, ⁎, Ali R. Mani a, ⁎ a Department of Physiology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran b Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran c Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran abstract article info Article history: Received 16 April 2014 Received in revised form 23 June 2014 Accepted 12 July 2014 Available online xxxx Keywords: Cirrhosis Vagus nerve Fibrosis Inflammation α7 nicotinic acetylcholine receptor 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 progres- sion 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. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Liver is the largest solid organ in the body and plays a central role in the regulation of homeostasis. Chronic liver injury leads to expression and secretion of chemokines such as monocyte chemoattractant peptide-1 (MCP-1) that are responsible for infiltration of inflammatory cells in the liver (Marra et al., 1998). Inflammatory mediators can trigger trans-differentiation of hepatic stellate cells as well as bone marrow-derived cells to myofibroblasts (Ebrahimkhani et al., 2008). Myofibroblast formation is associated with remodeling of extracellular matrix and fibrosis via expression of mediators such as tissue inhibitor of metalloproteinase-1 (TIMP-1) (Ebrahimkhani et al., 2008). Therefore, extensive liver fibrosis (cirrhosis) is the most common feature of chronic hepatic inflammation. Although, liver fibrosis is a major cause of liver failure worldwide, the available treatments remain ineffective. A logical way to reduce hepatic inflammation is to potentiate the physiological anti-inflammatory mechanism(s) that modulate inflam- mation in the liver. The “cholinergic anti-inflammatory pathway” has recently been described by Tracey and colleagues and refers to the role that autonomic nervous system plays in regulation of host defense and in physiologic responses to pathogens (Tracey, 2007). Their studies have shown that the vagus nerve activation can reduce inflammation via activation of alpha7-nicotinic acetylcholine receptors (α7nAChR) that are located on inflammatory cells (Wang et al., 2003). There are reports to show that there is a cross-talk between liver and central nervous system during neural inflammation (Campbell et al., 2008). However the role of such cross-talk during the course of hepatic inflam- mation is not well understood. Liver is innervated by both sympathetic and parasympathetic nerves that contain afferent and efferent aminergic, cholinergic, peptidergic, and nitrergic components (McCuskey, 2004). There is evidence to show that hepatic innervation plays a role in the regulation of hepatic metabolism and hemodynamics (Lautt, 1983; Bioulac-Sage et al., Autonomic Neuroscience: Basic and Clinical xxx (2014) xxx–xxx Abbreviations: α7nAChR, α7 nicotinic acetylcholine receptor; α-SMA, α smooth mus- cle actin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BDL, bile duct ligated; DAB, diaminobenzidine; ISPP, intrasplenic pulp pressure; MLA, methyllycaconitine; MCP-1, monocyte chemoattractant peptide-1; SHV, selective hepatic vagotomy; TIMP-1, tissue inhibitor of metalloproteinase-1. ⁎ Corresponding authors. Tel.: +98 2188853577. E-mail address: mani@modares.ac.ir (A.R. Mani). AUTNEU-01675; No of Pages 9 http://dx.doi.org/10.1016/j.autneu.2014.07.005 1566-0702/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu Please cite this article as: Hajiasgharzadeh, K., et al., Does hepatic vagus nerve modulate the progression of biliary fibrosis in rats?, Auton. Neurosci. (2014), http://dx.doi.org/10.1016/j.autneu.2014.07.005