Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
J Gastroenterol Hepatol. 2014 May;29(5):1073-82. doi: 10.1111/jgh.12480.
Vascular endothelial (VEGF) and fibroblast growth factor (FGF)-induced hepatic stellate (HSCs) and liver endothelial cells (LECs) activation accelerates hepatic fibrogenesis and angiogenesis, and hemodynamic dysarrangements in cirrhosis. VEGF targeting agents had been reported as potential drugs for cirrhosis. However, the evaluation of effects of dual VEGF/FGF targeting agent in cirrhosis is still limited.
Using hemodynamic parameters, blood chemistry, primary isolated HSCs and LECs, histology, and digital imaging, we assess the effects of 2-week brivanib alaninate, a dual VEGFR/FGFR inhibitor, treatment in the pathophysiology of bile duct-ligated-cirrhotic rats.
Fibrogenic and angiogenic markers in the serum and liver of bile duct-ligated-cirrhotic rats, including hydroxyproline, transforming growth factor-β1, angiopoietin-1, VEGF, FGF-2, endocan and phosphorylated-VEGFR2/VEGFR2, and phosphorylated-FGFR/FGFR together with hepatic CD31/angiopoietin-1 expressions (immunohistochemistry staining), angiogenesis (micro-computed tomography scan), microcirculatory dysfunction (in vivo miscroscopy and in situ liver perfusion study), portal hypertension, and hyperdynamic circulations (colored microsphere methods) were markedly suppressed and ameliorated by brivanib alaninate treatment. In in vitro study, acute brivanib alaninate incubation inhibited the transforming growth factor-β1-induced HSCs contraction/migration and VEGF-induced LECs angiogenesis. Concomitantly, the overexpression of various fibrogenic and angiogenic markers in HSCs and LECs, and in their culture media, was increased in parallel and these changes were suppressed by acute brivanib alaninate incubation.
This study demonstrated that brivanib alaninate targeting multiple mechanisms and working in the different pathogenic steps of the complications of cirrhotic rats with portal hypertension.
血管内皮生长因子（VEGF）和成纤维细胞生长因子（FGF）诱导的肝星状细胞（HSCs）和肝内皮细胞（LECs）激活加速了肝纤维化和血管生成，以及肝硬化中的血液动力学紊乱。VEGF 靶向药物已被报道为肝硬化的潜在药物。然而，对双 VEGF/FGF 靶向药物在肝硬化中的作用评估仍然有限。
我们使用血液动力学参数、血液化学、原代 HSCs 和 LECs、组织学和数字成像，评估双 VEGFR/FGFR 抑制剂布立尼布在胆管结扎肝硬化大鼠病理生理学中的作用。
胆管结扎肝硬化大鼠血清和肝脏中的纤维化和血管生成标志物，包括羟脯氨酸、转化生长因子-β1、血管生成素-1、VEGF、FGF-2、内皮细胞蛋白聚糖和磷酸化-VEGFR2/VEGFR2、以及磷酸化-FGFR/FGFR 以及肝 CD31/血管生成素-1 表达（免疫组织化学染色）、血管生成（微计算机断层扫描）、微循环功能障碍（体内显微镜和原位肝灌注研究）、门静脉高压和高动力循环（彩色微球法），均被布立尼布治疗显著抑制和改善。在体外研究中，急性布立尼布孵育抑制了转化生长因子-β1 诱导的 HSCs 收缩/迁移和 VEGF 诱导的 LECs 血管生成。同时，HSCs 和 LECs 及其培养物中各种纤维化和血管生成标志物的过度表达也平行增加，这些变化被急性布立尼布孵育抑制。
这项研究表明，布立尼布靶向多种机制，并作用于伴有门静脉高压的肝硬化大鼠并发症的不同发病步骤。
