Autocrine/paracrine regulation of the tree by the neuroendocrine hormone growth of the biliary serotonin
Autocrine/paracrine regulation of the tree by the neuroendocrine hormone growth of the biliary serotonin
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DOI：
10.1053/j.gastro.2004.10.002
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发表时间：
2005-01-01
期刊：
影响因子：
29.4
通讯作者：
Alpini, G
中科院分区：
文献类型：
--
作者：
Marzioni, M;Glaser, S;Alpini, G
背景与目的：胆道树是慢性胆汁淤积性肝病的治疗靶点，其特征是增殖反应丧失和胆道树上皮细胞胆管细胞凋亡增强。调控胆管细胞增殖的内源性因素尚不清楚。因此，我们研究了神经内分泌激素血清素作为胆管细胞增殖调节剂的作用。方法：观察血清素1A和1B受体在胆管细胞中的存在。然后，我们在体内和体外测试了通过使用选择性激动剂激活这些受体是否会改变胆管细胞的增殖和功能活性。此外，表征了介导胆管细胞5 -羟色胺受体作用的细胞内信号。我们研究了血清素在胆管细胞中的表达和分泌，以及中和分泌的激素对胆道树生长的影响。结果：胆管细胞表达5 -羟色胺1A和1B受体。它们的激活显著抑制胆管结扎大鼠（慢性胆汁淤积模型）胆道树的生长和胆汁活性。这些变化是由增强的d -肌醇1,4,5-三磷酸/Ca2+/蛋白激酶C信号和随后的腺苷3',5'-环单磷酸/蛋白激酶A/Src/细胞外信号调节激酶1/2级联抑制介导的。胆管细胞分泌血清素，在胆汁淤积过程中，血清素的阻断促进了胆管细胞的增殖。结论：我们观察到基于血清素的自分泌循环的存在，该循环限制了慢性胆汁淤积症过程中胆道树的生长。我们的新发现可能为胆管疾病的治疗开辟新的途径。
Background &Aims: The biliary tree is the target of cholangiopathies that are chronic cholestatic liver diseases characterized by loss of proliferative response and enhanced apoptosis of cholangiocytes, the epithelial cells lining the biliary tree. The endogenous factors that regulate cholangiocyte proliferation are poorly understood. Therefore, we studied the role of the neuroendocrine hormone serotonin as a modulator of cholangiocyte proliferation. Methods: The presence of the serotonin 1A and 1B receptors on cholangiocytes was evaluated. We then tested whether the activation of such receptors by the administration of the selective agonists modifies cholangiocyte proliferation and functional activity both in vivo and in vitro. In addition, the intracellular signal mediating the serotonin receptor action in cholangiocytes was characterized. We studied the expression and secretion of serotonin by cholangiocytes and the effects of the neutralization of the secreted hormone on the growth of the biliary tree. Results: Cholangiocytes express the serotonin 1A and 1B receptors. Their activation markedly inhibits the growth and choleretic activity of the biliary tree in the bile duct-ligated rat, a model of chronic cholestasis. Such changes are mediated by enhanced D-myo-inositol 1,4,5-triphosphate/Ca2+/ protein kinase C signaling and the consequent inhibition of the adenosine 3',5'-cyclic monophosphate/ protein kinase A/Src/extracellular signal-regulated kinase 1/2 cascade. Cholangiocytes secrete serotonin, the blockage of which enhances cholangiocyte proliferation in the course of cholestasis. Conclusions: We observed the existence of an autocrine loop based on serotonin that limits the growth of the biliary tree in the course of chronic cholestasis. Our novel findings might open new approaches for the management of cholangiopathies.