Thieringer Florian, Maass Thorsten, Czochra Piotr, Klopcic Borut, Conrad Ilka, Friebe Diana, Schirmacher Peter, Lohse Ansgar W, Blessing Manfred, Galle Peter R, Teufel Andreas, Kanzler Stephan
1st Department of Medicine, Johannes-Gutenberg-University, Mainz, Germany.
Gene. 2008 Oct 15;423(1):23-8. doi: 10.1016/j.gene.2008.05.022. Epub 2008 Jun 10.
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-beta1 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-beta1 protein concentration in the liver of transgenic mice, it can be postulated that PDGF-A upregulates expression of TGF-beta1 which is a strong activator of hepatic stellate cells. Thus, these results point towards a fibrosis induction by PDGF-A via the TGF-beta1 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-beta1 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.
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在体内肝纤维化形成中的作用，我们使用CRP基因启动子构建了肝细胞特异性过表达PDGF - A的转基因小鼠。转基因小鼠而非野生型小鼠在肝脏中表现出PDGF - A mRNA的表达。肝脏中PDGF - A的过表达伴随着肝前胶原III mRNA表达以及TGF - β1表达的显著增加。肝脏组织学显示，转基因小鼠而非野生型小鼠的细胞外基质沉积增加。PDGF - A转基因小鼠的肝血窦α - SMA染色呈阳性，表明肝星状细胞被激活。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，可以推测PDGF - A上调了TGF - β1的表达，而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 - β1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通过诱导TGF - β1发挥相关的促纤维化作用。因此，对抗PDGF - A可能是酪氨酸激酶抑制剂在肝纤维化动物模型中显示出保护作用的机制之一。
