Department of Hepatology and Gene Therapy, Center for Applied Medical Research, Pamplona, Spain.
Hepatology. 2010 Mar;51(3):912-21. doi: 10.1002/hep.23412.
We investigated whether gene transfer of insulin-like growth factor I (IGF-I) to the hepatic tissue was able to improve liver histology and function in established liver cirrhosis. Rats with liver cirrhosis induced by carbon tetrachloride (CCl(4)) given orally for 8 weeks were injected through the hepatic artery with saline or with Simian virus 40 vectors encoding IGF-I (SVIGF-I), or luciferase (SVLuc). Animals were sacrificed 8 weeks after vector injection. In cirrhotic rats we observed that, whereas IGF-I was synthesized by hepatocytes, IGF-I receptor was predominantly expressed by nonparenchymal cells, mainly in fibrous septa surrounding hepatic nodules. Rats treated with SVIGF-I showed increased hepatic levels of IGF-I, improved liver function tests, and reduced fibrosis in association with diminished alpha-smooth muscle actin expression, up-regulation of matrix metalloproteases (MMPs) and decreased expression of the tissue inhibitors of MMPs TIM-1 and TIM-2. SVIGF-I therapy induced down-regulation of the profibrogenic molecules transforming growth factor beta (TGFbeta), amphiregulin, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), and vascular endothelium growth factor (VEGF) and induction of the antifibrogenic and cytoprotective hepatocyte growth factor (HGF). Furthermore, SVIGF-I-treated animals showed decreased expression of Wilms tumor-1 (WT-1; a nuclear factor involved in hepatocyte dedifferentiation) and up-regulation of hepatocyte nuclear factor 4 alpha (HNF4alpha) (which stimulates hepatocellular differentiation). The therapeutic potential of SVIGF-I was also tested in rats with thioacetamide-induced liver cirrhosis. Also in this model, SVIGF-I improved liver function and reduced liver fibrosis in association with up-regulation of HGF and MMPs and down-regulation of tissue inhibitor of metalloproteinase 1 (TIMP-1).
IGF-I gene transfer to cirrhotic livers induces MMPs and hepatoprotective factors leading to reversion of fibrosis and improvement of liver function. IGF-I gene therapy may be a useful alternative therapy for patients with advanced cirrhosis without timely access to liver transplantation.
我们研究了胰岛素样生长因子 I（IGF-I）基因转移到肝组织是否能够改善已建立的肝硬化的肝脏组织学和功能。用四氯化碳（CCl 4）经口给予 8 周诱导肝硬化的大鼠，通过肝动脉注射生理盐水或编码 IGF-I（SVIGF-I）或荧光素酶（SVLuc）的猴病毒 40 载体。在载体注射 8 周后处死动物。在肝硬化大鼠中，我们观察到 IGF-I 由肝细胞合成，而 IGF-I 受体主要由非实质细胞表达，主要在围绕肝结节的纤维隔中。用 SVIGF-I 治疗的大鼠表现出肝内 IGF-I 水平升高、肝功能试验改善和纤维化减少，同时 alpha-平滑肌肌动蛋白表达减少、基质金属蛋白酶（MMPs）上调和组织抑制剂 MMPs（TIM-1 和 TIM-2）表达减少。SVIGF-I 治疗诱导致纤维化分子转化生长因子β（TGFβ）、 Amphiregulin、血小板衍生生长因子（PDGF）、结缔组织生长因子（CTGF）和血管内皮生长因子（VEGF）下调和抗纤维化及细胞保护因子肝细胞生长因子（HGF）诱导。此外，SVIGF-I 治疗的动物表现出 Wilms 肿瘤-1（WT-1；参与肝细胞去分化的核因子）表达减少和肝细胞核因子 4 alpha（HNF4alpha）上调（刺激肝细胞分化）。SVIGF-I 在硫代乙酰胺诱导的肝硬化大鼠中也测试了其治疗潜力。在该模型中，SVIGF-I 改善了肝功能并减少了肝纤维化，同时上调了 HGF 和 MMPs 并下调了金属蛋白酶组织抑制剂 1（TIMP-1）。
IGF-I 基因转移到肝硬化肝脏中诱导 MMPs 和肝保护因子，导致纤维化逆转和肝功能改善。IGF-I 基因治疗可能是一种有用的替代疗法，适用于没有及时接受肝移植的晚期肝硬化患者。
