Dominant-negative soluble PDGF-β receptor inhibits hepatic stellate cell activation and attenuates liver fibrosis
Dominant-negative soluble PDGF-β receptor inhibits hepatic stellate cell activation and attenuates liver fibrosis
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DOI：
10.1038/labinvest.3700094
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发表时间：
2004-06-01
影响因子：
5
通讯作者：
Weiskirchen, R
中科院分区：
文献类型：
--
作者：
Borkham-Kamphorst, E;Herrmann, J;Weiskirchen, R
肝纤维化是肝星状细胞被激活并转分化为肌成纤维细胞表型的结果，具有增殖和合成大量细胞外基质成分的能力。在这一过程中，血小板衍生生长因子（PDGF）是肝星状细胞增殖和迁移最有效的刺激因子，在活跃的肝纤维化过程中过度表达。该细胞因子结合PDGF受体β型，激活Ras，并通过磷酸化Raf-1、MEK和细胞外信号调节激酶ERK1/ERK2，依次传播刺激信号。肝损伤与自分泌PDGF信号的增加和PDGF受体的上调有关。在这项研究中，我们报道了一种显性阴性可溶性PDGF- β受体，由含有PDGF受体β细胞外部分的嵌合IgG组成，可阻断大鼠胆管总结诱导的HSC激活并减弱纤维形成。在培养激活的肝星状细胞中，可溶性受体阻断内源性PDGF受体磷酸化、ERK1/EKR2信号磷酸化，降低HSC的增殖活性。在体内，纯化的可溶性PDGF拮抗剂和表达人工转基因的腺病毒都能显著降低胶原和α -平滑肌肌动蛋白的表达。我们的研究结果表明，PDGF在实验性肝纤维化的进展和开始中起着关键作用，并提示早期抗PDGF干预应该对肝纤维化的治疗产生治疗作用。
Hepatic fibrogenesis is a consequence of hepatic stellate cells that become activated and transdifferentiate into a myofibroblastic phenotype with the ability to proliferate and synthesize large quantities of extracellular matrix components. In this process, platelet-derived growth factor (PDGF) is the most potent stimulus for hepatic stellate cell proliferation and migration, and is overexpressed during active hepatic fibrogenesis. This cytokine binds to the PDGF receptor type beta, activates Ras and sequentially propagates the stimulatory signal sequentially via phosphorylation of Raf-1, MEK and the extracellular-signal regulated kinases ERK1/ERK2. Hepatic injury is associated with both increased autocrine PDGF signaling and upregulation of PDGF receptor. In this study, we report that a dominant-negative soluble PDGF-beta receptor consisting of a chimeric IgG containing the extracellular portion of the PDGF receptor type beta blocks HSC activation and attenuates fibrogenesis induced by ligation of the common bile duct in rats. In culture-activated hepatic stellate cells, the soluble receptor blocks phosphorylation of endogenous PDGF receptor, phosphorylation of the ERK1/EKR2 signal and reduces proliferative activities of HSC. In vivo, both the delivery of the purified soluble PDGF antagonist and the administration of adenoviruses expressing the artificial transgene were able to reduce significantly the expression of collagen and alpha-smooth muscle actin. Our results demonstrate that PDGF plays a critical role in the progression and initiation of experimental liver fibrogenesis, and suggest that early anti-PDGF intervention should have a therapeutical impact on the treatment of liver fibrogenesis.