腺相关病毒载体介导的肝细胞生长因子生产可减轻小鼠肝纤维化。
Adeno-associated virus vector-mediated production of hepatocyte growth factor attenuates liver fibrosis in mice.
机构信息
First Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo, 663-8501, Japan.
出版信息
Hepatol Int. 2008 Mar;2(1):80-8. doi: 10.1007/s12072-007-9042-1. Epub 2007 Dec 22.
PURPOSE
Adeno-associated virus (AAV) vectors can achieve long-term gene expression and are now feasible for use in human gene therapy. We constructed hepatocyte growth factor (HGF) expressing AAV (AAV5-HGF) and examined its effect in two mouse hepatic fibrosis models.
METHODS
A model of hepatic fibrosis was established by carbon tetrachloride (CCl(4)) administration in Balb/c mice. After the establishment of liver fibrosis, AAV5-HGF was injected once into the portal vein. Mice were killed 3, 6, 9, and 12 weeks after injection. Another model was established by bile duct ligation (BDL). Seven weeks after AAV5-HGF injection, mice underwent BDL, and were then killed 2 weeks after BDL.
RESULTS
Mice that received AAV5-HGF achieved stable HGF expression both in the serum and liver for at least 12 weeks. In both models, significant improvement of the liver fibrosis was found in all mice receiving AAV5-HGF based on Azan-Mallory staining. Suppression of hepatic stellate cells (HSC) was confirmed by immunohistochemistry. Fibrogenic markers were significantly suppressed and collagenase activity increased in the livers of mice receiving AAV5-HGF.
CONCLUSIONS
A single injection of AAV vector containing HGF gene achieved long-term expression of HGF and resulted in resolution of mouse liver fibrosis. HGF gene therapy mediated by AAV is feasible for the treatment of liver fibrosis.
目的
腺相关病毒（AAV）载体可实现长期基因表达，目前已可用于人类基因治疗。我们构建了表达肝细胞生长因子（HGF）的 AAV（AAV5-HGF），并在两种小鼠肝纤维化模型中检验其疗效。
方法
通过四氯化碳（CCl4）处理 Balb/c 小鼠建立肝纤维化模型。肝纤维化建立后，将 AAV5-HGF 单次注入门静脉。在注射后 3、6、9 和 12 周处死小鼠。另一种模型通过胆管结扎（BDL）建立。AAV5-HGF 注射 7 周后，小鼠接受 BDL，并在 BDL 后 2 周处死。
结果
接受 AAV5-HGF 治疗的小鼠在血清和肝脏中至少稳定表达 HGF 12 周。在两种模型中，所有接受 AAV5-HGF 治疗的小鼠的肝纤维化均明显改善，依据阿赞-马洛里染色判断。免疫组化证实肝星状细胞（HSC）被抑制。接受 AAV5-HGF 治疗的小鼠肝组织中纤维生成标记物显著下调，胶原酶活性增加。
结论
单次注射含 HGF 基因的 AAV 载体可实现 HGF 的长期表达，并可使小鼠肝纤维化消退。AAV 介导的 HGF 基因治疗可能适用于肝纤维化的治疗。
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