Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, GuangZhou, Peoples Republic of China.
Am J Physiol Cell Physiol. 2011 Aug;301(2):C469-77. doi: 10.1152/ajpcell.00452.2010. Epub 2011 May 4.
Fibroblast growth factor 2 (FGF-2) and its main receptor FGFR1 have been shown to promote hepatic stellate cell (HSC) activation and proliferation. However, scant information is available on the anti-fibrogenic activity of FGFR1 inhibitors. The aim of this study was to assess the impact of a selective FGFR1 tyrosine kinase inhibitor NP603 on HSC proliferation and hepatic fibrosis. We demonstrated that rat primary HSCs secreted significant amounts of FGF-2, and its tyrosine phosphorylation of FGFR1 was attenuated by NP603. NP603 inhibited HSC activaton by measuring the expression of α-smooth muscle actin (α-SMA) and the production of type I collagen using ELISA. Furthermore, NP603 (25 μM) in vitro strongly suppressed HSC growth induced by FGF-2 (10 ng/ml) and FCS. This effect correlated with the suppression of extracellular-regulated kinase (ERK) activity and its downstream targets cyclin D1 and p21. In addition, PO NP603 (20 mg·kg(-1)·day(-1)) administration significantly decreased hepatic collagen deposition and α-SMA expression in CCl(4)-treated rats. Collectively, these studies suggest that selective blocking of the FGFR1-mediated pathway could be a promising therapeutic approach for the treatment of hepatic fibrosis.
成纤维细胞生长因子 2（FGF-2）及其主要受体 FGFR1 已被证明可促进肝星状细胞（HSC）的激活和增殖。然而，关于 FGFR1 抑制剂的抗纤维化活性的信息很少。本研究旨在评估选择性 FGFR1 酪氨酸激酶抑制剂 NP603 对 HSC 增殖和肝纤维化的影响。我们证明大鼠原代 HSCs 分泌大量 FGF-2，其 FGFR1 的酪氨酸磷酸化被 NP603 减弱。NP603 通过测量 α-平滑肌肌动蛋白（α-SMA）的表达和使用 ELISA 测量 I 型胶原的产生来抑制 HSC 激活。此外，NP603（25 μM）在体外强烈抑制由 FGF-2（10 ng/ml）和 FCS 诱导的 HSC 生长。这种作用与细胞外调节激酶（ERK）活性及其下游靶标细胞周期蛋白 D1 和 p21 的抑制相关。此外，PO NP603（20 mg·kg（-1）·day（-1））给药可显著降低 CCl（4）处理大鼠的肝胶原沉积和 α-SMA 表达。总之，这些研究表明，选择性阻断 FGFR1 介导的途径可能是治疗肝纤维化的一种有前途的治疗方法。
