Ruddell Richard G, Oakley Fiona, Hussain Ziafat, Yeung Irene, Bryan-Lluka Lesley J, Ramm Grant A, Mann Derek A
Liver Research Group, Divison of Infection, Inflammation and Repair, University of Southampton School of Medicine, and Southampton General Hospital, UK.
Am J Pathol. 2006 Sep;169(3):861-76. doi: 10.2353/ajpath.2006.050767.
Hepatic stellate cells (HSCs) are key cellular components of hepatic wound healing and fibrosis. There is emerging evidence that the fibrogenic function of HSCs may be influenced by neurochemical and neurotrophic factors. This study addresses the potential for the serotonin (5-HT) system to influence HSC biology. Rat and human HSCs express the 5-HT1B, 5-HT1F 5-HT2A 5-HT2B, and 5-HT7 receptors, with expression of 5-HT1B 5-HT2A and 5-HT2B being induced on HSC activation. Induction of 5-HT2A and 5-HT2B was 106+/-39- and 52+/-8.5-fold that of quiescent cells, respectively. 5-HT2B was strongly associated with fibrotic tissue in diseased rat liver. Treatment of HSCs with 5-HT2 antagonists suppressed proliferation and elevated their rate of apoptosis; by contrast 5-HT was protective against nerve growth factor-induced apoptosis. 5-HT synergized with platelet-derived growth factor to stimulate increased HSC proliferation. HSCs were shown to express a functional serotonin transporter and to participate in both active uptake and release of 5-HT. We conclude that HSCs express key regulatory components of the 5-HT system enabling them to store and release 5-HT and to respond to the neurotransmitter in a profibrogenic manner. Antagonists that selectively target the 5-HT class of receptors may be exploited as antifibrotic drugs.
肝星状细胞（HSCs）是肝脏伤口愈合和纤维化的关键细胞成分。越来越多的证据表明，肝星状细胞的纤维化功能可能受神经化学和神经营养因子的影响。本研究探讨了血清素（5-羟色胺，5-HT）系统影响肝星状细胞生物学特性的可能性。大鼠和人类肝星状细胞表达5-HT1B、5-HT1F、5-HT2A、5-HT2B和5-HT7受体，其中5-HT1B、5-HT2A和5-HT2B的表达在肝星状细胞激活时被诱导。5-HT2A和5-HT2B的诱导水平分别是静止细胞的106±39倍和52±8.5倍。5-HT2B与患病大鼠肝脏的纤维化组织密切相关。用5-HT2拮抗剂处理肝星状细胞可抑制其增殖并提高其凋亡率；相反，5-HT可保护细胞免受神经生长因子诱导的凋亡。5-HT与血小板衍生生长因子协同作用，刺激肝星状细胞增殖增加。研究表明，肝星状细胞表达功能性血清素转运体，并参与5-HT的主动摄取和释放。我们得出结论，肝星状细胞表达5-HT系统的关键调节成分，使其能够储存和释放5-HT，并以促纤维化方式对神经递质作出反应。选择性靶向5-HT类受体的拮抗剂可作为抗纤维化药物加以利用。
