Nature Medicine
5, 226 - 230 (1999)
doi:10.1038/5593
Hepatocyte growth factor gene therapy of liver cirrhosis in ratsTakahiro Ueki1, Yasufumi Kaneda2, Hiroko Tsutsui3, Kenji Nakanishi3, Yoshiki Sawa4, Ryuichi Morishita5, Kunio Matsumoto6, Toshikazu Nakamura6, Hiroshi Takahashi7, Eizo Okamoto1
& Jiro Fujimoto11
First Department of Surgery, Hyogo College of Medicine, 1−1 Mukogawacho, Nishinomiya 663−8501, Japan
2
Institute for Cellular and Molecular Biology, Osaka University Medical School, 2−2 Yamadaoka, Suita 565−0871, Japan
3
Department of Immunology and Medical Zoology, Hyogo College of Medicine, Japan
4
First Department of Surgery, Osaka University Medical School, Japan
5
Department of Geriatric Medicine, Osaka University Medical School, Japan
6
Biomedical Research Center, Osaka University Medical School, Japan
7
Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Jackson 7, Fruit St., Boston, Massachusetts 02114, USA
Correspondence should be addressed to Jiro Fujimoto sfujimo@hyo−med.ac.jpLiver 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 tissue1. 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 hepatocytes2,
3,
4,
5, shows
mitogenic, motogenic and morphogenic activities for a wide variety of cells6,
7,
8,
9. Moreover, HGF plays an essential part in the development
and regeneration of the liver6,
7,
11, and shows anti−apoptotic
activity in hepatocytes11. 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− 1 (TGF−1), 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.
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