Effects and regulation of connective tissue growth factor on hepatic stellate cells
Effects and regulation of connective tissue growth factor on hepatic stellate cells
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DOI：
10.1097/01.lab.0000017365.18894.d3
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发表时间：
2002-06-01
影响因子：
5
通讯作者：
Bedossa, P
中科院分区：
文献类型：
--
作者：
Paradis, V;Dargere, D;Bedossa, P
结缔组织生长因子（CTGF）是一种38-kd的蛋白质，参与多种人类纤维化疾病，包括动脉粥样硬化和皮肤及肾纤维化。尽管已经显示人类和实验性肝纤维化通过肝星状细胞（HSC）上调CTGF mRNA而与CTGF表达相关，但CTGF在肝脏中的作用尚未确定。本研究的目的是评估CTGF对大鼠原代HSC的作用及其在体外肝纤维化模型中的调节作用。原代HSC与重组CTGF孵育诱导显著的迁移（2.3倍，50 ng/ml CTGF）和增殖效应（1.8倍，100 ng/ml CTGF）。通过实时RT-PCR程序评估，当细胞在CTGF（2倍，50 ng/ml）存在下孵育时，I型胶原mRNA表达也增加。转化生长因子-β 1（TGF-β 1）强烈刺激CTGF mRNA表达，这是在没有任何中间蛋白质合成的情况下观察到的直接机制。此外，自发激活的HSC铺在塑料和刺激血管内皮生长因子，脂质过氧化产物（HNE，MDA），乙醛，和血小板衍生生长因子（PDGF）-BB显着上调CTGF mRNA表达的HSC。PDGF诱导的CTGF刺激可能部分与TGF-β 1分泌有关，因为在存在中和TGF-β 1抗体的情况下，PDGF-BB刺激后观察到的CTGF mRNA上调被废除。总之，这项研究扩展了CTGF在HSC活化中的作用，并表明CTGF上调可能是HSC活化过程中的一个中心途径。
Connective tissue growth factor (CTGF) is a 38-kd protein involved in several human fibrotic disorders including atherosclerosis and skin and renal fibrosis. Although it has been shown that human and experimental liver fibrosis is associated with CTGF expression through up-regulation of CTGF mRNA by hepatic stellate cells (HSC), the role of CTGF in the liver has not yet been determined. The aim of the present study was to assess the effects of CTGF on rat primary HSC and its regulation in a well-established model of in vitro liver fibrogenesis. Incubation of primary HSC with recombinant CTGF induced a significant migratory (2.3-fold, 50 ng/ml CTGF) and proliferative effect (1.8-fold, 100 ng/ml CTGF). Type I collagen mRNA expression, as assessed by a real-time RT-PCR procedure, was also increased when cells were incubated in the presence of CTGF (2-fold, 50 ng/ml). Transforming growth factor-beta1 (TGF-beta1) strongly stimulated CTGF mRNA expression, a direct mechanism observed in the absence of any intermediate protein synthesis. Furthermore, spontaneous activation of HSC plated on plastic and stimulation by vascular endothelial growth factor, lipid peroxidation products (HNE, MDA), acetaldehyde, and platelet-derived growth factor (PDGF)-BB significantly up-regulated CTGF mRNA expression in HSC. PDGF-induced CTGF stimulation might be related in part to TGF-beta1 secretion because CTGF mRNA up-regulation observed after PDGF-BB stimulation was abrogated in the presence of neutralizing TGF-beta1 antibody. In conclusion, this study extends the role of CTGF in HSC activation and suggests that CTGF up-regulation might be a central pathway during HSC activation.