東京大学医科学研究所再生医学分野Division of Regenerative Medicine, Institute of Medical Science, The University of Tokyo― 76 ―The liver tissue is innervated by sympathetic nerves. Intrahepatic sympathetic nerves are involved in the regulation of metabolic reactions and hepatocyte-based regeneration after surgical resection. We previously demonstrated that intrahepatic bile ducts consisting of cholangiocytes and periportal fibroblasts (PMCs) guide formation and regeneration of intrahepatic nerve network by secreting nerve growth factor (NGF) 4). However, the role of intrahepatic nerves in chronic liver injury remains unknown. Here we demonstrate that isoproterenol (ISO), a β-adrenergic receptor agonist, promotes ductular expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) in vivo. In vitro analyses indicate that ISO directly increases cAMP level in cholangiocytes and promotes their proliferation in 3D culture. ISO also directly increases cAMP level in PMCs and induces expression of growth factors including fibroblast growth factor 7 (Fgf7). In addition to DDC-model, we also examined the effect of ISO on thioacetamide (TAA) induced liver injury model; in this model, ductular expansion leads to liver fibrosis. Mice treated with TAA and ISO showed increased ductular expansion and augmented fibrosis. In contrast, propranolol (PPL), a β-adrenergic receptor antagonist, reduced fibrosis. Taken together, the results indicate that intrahepatic sympathetic nerves regulate remodeling of bile ducts followed by liver fibrosis by the activation of β-adrenergic receptors on cholangiocytes and PMCs. Abstractはじめに肝臓の自律神経は他臓器との間にネットワークを形成し，摂食や代謝を調節していることが示されている．例として，交感神経刺激によるグリコーゲン分解および糖新生の促進や血管の収縮誘導，副交感神経刺激によるグリコーゲン合成の促進などが報告されている．また，マウスやラットを用いた研究では，迷走神経の切断による部分肝切除後の肝再生の遅延1,2）や，神経毒（6-hydroxydopamine）Role…of…epithelial-nerve…interaction…in…chronic…liver…injury慢性肝疾患の進行過程における上皮ー神経の組織間ネットワークの機能解明谷水 直樹Naoki Tanimizu
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