Spontaneous hepatic fibrosis in transgenic mice overexpressing PDGF-A
Spontaneous hepatic fibrosis in transgenic mice overexpressing PDGF-A
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DOI：
10.1016/j.gene.2008.05.022
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发表时间：
2008-10-15
期刊：
影响因子：
3.5
通讯作者：
Kanzler, Stephan
中科院分区：
文献类型：
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作者：
Thieringer, Florian;Maass, Thorsten;Kanzler, Stephan
血小板衍生生长因子（PDGF）在急性和慢性组织损伤后的修复机制中发挥着核心作用。为了进一步评估 PDGF-A 在体内肝纤维化中的作用，我们使用 CRP 基因启动子生成了肝细胞特异性过度表达 PDGF-A 的转基因小鼠。转基因小鼠而非野生型小鼠在肝脏中显示出 PDGF-A mRNA 的表达。肝脏 PDGF-A 过表达伴随着肝脏 III 型前胶原 mRNA 表达以及 TGF-β 1 表达的显着增加。肝脏组织学显示转基因小鼠的细胞外基质沉积增加，而野生型小鼠则没有。 PDGF-A转基因小鼠显示α-SMA呈阳性正弦染色，表明肝星状细胞活化。由于PDGF-A的促纤维化作用伴随着转基因小鼠肝脏中TGF-β1蛋白浓度的增加，因此可以推测PDGF-A上调TGF-β1的表达，TGF-β1是肝星状细胞的强激活剂。因此，这些结果表明 PDGF-A 通过 TGF-β 1 信号通路诱导纤维化。 总之，转基因小鼠肝脏中 PDGF-A 的表达和功能分析表明 PDGF-A 通过 TGF-β 1 诱导发挥相关的促纤维化作用。因此，抵消 PDGF-A 可能是酪氨酸激酶抑制剂的作用之一，该抑制剂在肝纤维化动物模型中显示出保护作用。 (C) 2008 Elsevier B.V. 保留所有权利。
Platelet derived growth factor (PDGF) plays a central role in repair mechanisms after acute and chronic tissue damage. To further evaluate the role of PDGF-A in liver fibrogenesis in vivo, we generated transgenic mice with hepatocyte-specific overexpression of PDGF-A using the CRP-gene promoter. Transgenic but not wildtype mice showed expression of PDGF-A mRNA in the liver. Hepatic PDGF-A overexpression was accompanied by a significant increase in hepatic procollagen III mRNA expression as well as TGF-beta 1 expression. Liver histology showed increased deposition of extracellular matrix in transgenic but not in wildtype mice. PDGF-A-transgenic mice showed positive sinusoidal staining for alpha-SMA indicating an activation of hepatic stellate cells. Since the profibrogenic effect of PDGF-A was accompanied by increased TGF-beta 1 protein concentration in the liver of transgenic mice, it can be postulated that PDGF-A upregulates expression of TGF-beta 1 which is a strong activator of hepatic stellate cells. Thus, these results point towards a fibrosis induction by PDGF-A via the TGF-beta 1 signalling pathway.In conclusion, expression and functional analysis of PDGF-A in the liver of transgenic mice suggest a relevant profibrogenic role of PDGF-A via TGF-beta 1 induction. Counteracting PDGF-A may therefore be one of the effects of tyrosine kinase inhibitors which showed protective effects in animal models of liver fibrosis. (C) 2008 Elsevier B.V. All rights reserved.