Ueki T, Kaneda Y, Tsutsui H, Nakanishi K, Sawa Y, Morishita R, Matsumoto K, Nakamura T, Takahashi H, Okamoto E, Fujimoto J
First Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
Nat Med. 1999 Feb;5(2):226-30. doi: 10.1038/5593.
Liver cirrhosis is the irreversible end result of fibrous scarring and hepatocellular regeneration, characterized by diffuse disorganization of the normal hepatic structure of regenerative nodules and fibrotic tissue. It is associated with prominent morbidity and mortality, and is induced by many factors, including chronic hepatitis virus infections, alcohol drinking and drug abuse. Hepatocyte growth factor (HGF), originally identified and cloned as a potent mitogen for hepatocytes, shows mitogenic, motogenic and morphogenic activities for a wide variety of cells. Moreover, HGF plays an essential part in the development and regeneration of the liver, and shows anti-apoptotic activity in hepatocytes. In a rat model of lethal liver cirrhosis produced by dimethylnitrosamine administrations, repeated transfections of the human HGF gene into skeletal muscles induced a high plasma level of human as well as enodogenous rat HGF, and tyrosine phosphorylation of the c-Met/HGF receptor. Transduction with the HGF gene also suppressed the increase of transforming growth factor-beta1 (TGF-beta1), which plays an essential part in the progression of liver cirrhosis, inhibited fibrogenesis and hepatocyte apoptosis, and produced the complete resolution of fibrosis in the cirrhotic liver, thereby improving the survival rate of rats with this severe illness. Thus, HGF gene therapy may be potentially useful for the treatment of patients with liver cirrhosis, which is otherwise fatal and untreatable by conventional therapy.
肝硬化是纤维化瘢痕形成和肝细胞再生的不可逆终末结果，其特征为再生结节和纤维化组织的正常肝结构弥漫性紊乱。它与显著的发病率和死亡率相关，由多种因素引起，包括慢性肝炎病毒感染、饮酒和药物滥用。肝细胞生长因子（HGF）最初被鉴定并克隆为肝细胞的一种强效促有丝分裂原，对多种细胞显示出促有丝分裂、促运动和形态发生活性。此外，HGF在肝脏的发育和再生中起重要作用，并在肝细胞中显示出抗凋亡活性。在由二甲基亚硝胺给药产生的致死性肝硬化大鼠模型中，将人HGF基因反复转染到骨骼肌中可诱导人及内源性大鼠HGF的血浆水平升高，以及c-Met/HGF受体的酪氨酸磷酸化。用HGF基因转导还抑制了在肝硬化进展中起重要作用的转化生长因子-β1（TGF-β1）的增加，抑制了纤维化形成和肝细胞凋亡，并使肝硬化肝脏中的纤维化完全消退，从而提高了患有这种严重疾病的大鼠的存活率。因此，HGF基因治疗可能对肝硬化患者的治疗具有潜在的用途，而肝硬化用传统疗法是致命且无法治疗的。
