Role of endogenous opioids in modulating HSC activity in vitro and liver fibrosis in vivo
Role of endogenous opioids in modulating HSC activity in vitro and liver fibrosis in vivo
复制标题
DOI：
10.1136/gut.2007.120303
复制
发表时间：
2008-03-01
期刊：
影响因子：
24.5
通讯作者：
Svegliati-Baroni, G.
中科院分区：
文献类型：
--
作者：
De Minicis, S.;Candelaresi, C.;Svegliati-Baroni, G.
背景：内源性阿片类物质调节神经和非神经细胞的生长。肝星状细胞（hepatic stellate cells，HSCs）是参与肝纤维化的主要细胞表型，具有神经元细胞的分子标记，对神经递质有反应，目的：探讨内源性阿片类物质在肝纤维化发生中的作用。二甲基亚硝胺（DMN）administration.Results：阿片受体表现出不同的表达模式时，在静态和激活（在体外和体内）HSC的诱导大鼠肝纤维化。阿片受体的激活增加了HSC的增殖和胶原的积累。阿片受体刺激诱导钙依赖性蛋白激酶Ca（PKCa）/细胞外调节激酶（ERK）/磷脂酰肌醇3-激酶（PI 3 K）途径激活，介导内源性阿片类药物对HSC增殖和胶原合成的影响。在DMN处理的大鼠中，阿片类药物拮抗剂纳洛酮降低了α-平滑肌肌动蛋白表达（作为HSC活化的标志物）和胶原沉积，两者都是在处理5周后通过形态测定法测量的。在DMN治疗的大鼠和慢性肝病的人肝活检中，在活跃的纤维化区域的HSC中观察到阿片受体。内源性阿片甲硫氨酸脑啡肽增加其在区3肝细胞的表达接近DMN管理后的坏死区域和在人类活检的慢性肝损伤的细胞靶，并刺激HSC增殖和胶原synthesiz.Conclusions：内源性阿片类药物在慢性肝损伤过程中释放参与肝纤维化的过程中，通过刺激HSC增殖和胶原的产生在旁分泌的方式。
Background: Endogenous opioids modulate the growth of nervous and non-nervous cells. Hepatic stellate cells (HSCs) are the main cell phenotype involved in liver fibrogenesis, display molecular markers of neuronal cells and respond to neurotransmitters.Aim: To evaluate the role of endogenous opioids on liver fibrogenesis.Methods: Activated rat HSCs (passage 1-3) were used to evaluate cell proliferation and intracellular signalling pathway activation. Liver fibrosis was induced in rats by dimethylnitrosamine (DMN) administration.Results: Opioid receptors showed a different pattern of expression when measured in quiescent and activated (in vitro and in vivo) HSCs. The activation of opioid receptors increased HSC proliferation and collagen accumulation. Opioid receptor stimulation induced a calcium-dependent protein kinase Ca (PKCa)/extracellular regulated kinase (ERK)/phosphatidylinositol 3-kinase (PI3K) pathway activation that mediated the effect of endogenous opioids on HSC proliferation and collagen synthesis. In DMN-treated rats, the opioid antagonist naloxone reduced alpha-smooth muscle actin expression (as a marker of HSC activation) and collagen deposition, both measured by morphometry after 5 weeks of treatment. In both DMN-treated rats and human liver biopsies from chronic liver diseases, opioid receptors were observed in HSCs in area of active fibrogenesis. The endogenous opioid met-enkephalin increased its expression in zone 3 hepatocytes close to the area of necrosis after DMN administration and in the cellular target of chronic liver injury in human biopsies, and stimulated HSC proliferation and collagen synthesis.Conclusions: Endogenous opioids released during chronic liver injury participate in the process of liver fibrogenesis by stimulating HSC proliferation and collagen production in a paracrine manner.