2005 Fiscal Year Final Research Report Summary
Molecular Basis of Anti-fibrosis via Destruction of an Organ Self-repair System
| Project/Area Number |
14207005
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | Osaka University |
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Principal Investigator |
NAKAMURA Toshikazu Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (00049397)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUMOTO Kunio Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (90201780)
FUNAKOSHI Hiroshi Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (40273685)
MIZUNO Shinya Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (10219644)
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| Project Period (FY) |
2002 – 2005
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| Keywords | HGF / Chronic Organ Failure / Anti-fibrosis System / Myofibroblasts / TGF-β / Extra-cellular Matrix / Self-repair System / Regenerative Medicine |
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| Research Abstract |
Myofibroblast formation and overproduction of extra-cellular matrix (ECM) are common events in the pathogenesis of tissue fibrosis under chronic injuries, such as liver cirrhosis, pulmonary fibrosis and cardiomyopathy. In the present study, we found that HGF directly targeted the interstitial myofibroblasts and reduced ECM accumulation using the animal model of pulmonary fibrosis, liver cirrhosis and dilated cardiomyopathy.
1) Regression of pulmonary fibrosis by HGE :
We used bleomycin-injected mice as a model of lung fibrosis and found that HGF elicited apoptotic changes in the myofibroblast cell population in vivo. Furthermore, we obtained in vitro evidence that : (i) HGF degraded ECM proteins (i.e., cell anchorage) around the myofibroblasts, via induction of proteinases such as MMP-9/-1/-2 ; (ii) under such ECM-deficient conditions, the myofibroblasts lose the anchorage then anoikis-like apoptotic cell death occurred. Importantly, an MMP-inhibitor diminished HGF-mediated apoptotic cell death of myofibroblasts, in vitro as well as in vivo, thus indicating that HGF-induced anti-fibrotic effects largely depended on inductions of MMPs by HGF. We published these results in FASEB-Journal 19 : 580 (2005)
2) Reduction of interstitial fibrosis in liver cirrhosis and cardiomyopathy by HGF :
In the rat model of liver cirrhosis, HGF enhanced myofibroblast apoptosis and inhibited proliferation of interstitial myofibroblasts. These effects were associated with the reduction of ECM-accumulated areas. In vitro, HGF counteracted the PDGF-mediated proliferation of the lipocyte-derived myofibroblasts. In the hamster model of cardiomyopathy, HGF reduced TGF-beta production in the interstitial myofibroblasts, followed by the reduction of ECM as well as improvement in the cardiac functions. These outcomes were published in Am-J-Pathol 166 : 1017 (2005) and in Am-J-Physiol 288 : H2131 (2005), respectively.
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[Journal Article] Preclinical study of a "Tailor-made" combination of NK4-expressing gene therapy and gefitinib (ZD 1839, Iressa) for disseminated peritoneal scirrhous gastric cancer2006
Author(s)
Y.Namiki, T.Namiki, H.Yoshida, M.Date, M.Yashiro, K.Matsumoto, T.Nakamura, K.Yanagihara, N.Tada, J.Satoi, K.Fujise
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Journal Title
Int.J.Cancer 118
Pages: 1545-1555
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Hepatocyte Growth Factor Contributes to Fracture Repair by Upregulating the Expression of BMP Receptors.2006
Author(s)
Imai, Y., Terai, H., Nomura-Furuwatari, C., Mizuno, S., Matsumoto, K., Nakamura, T., Takaoka, K.
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Journal Title
J.Bone Miner.Res. 20
Pages: 1723-1730
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Involvement of hepatocyte growth factor in the development of bone metastasis of a mouse mammary cancer cell line, BALB/c-MC.2006
Author(s)
Ono K, Kamiya S, Akatsu T, Nakamura C, Li M, Amizuka N, Matsumoto K, Nakamura T, Kugai N, Wada S
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Journal Title
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[Journal Article] Hepatocyte growth factor attenuates airway hyperresponsiveness, and airway inflammation and remodeling.2005
Author(s)
W.Ito, A.Kanehiro, K.Matsumoto, A.Hirano, K.Ono, H.Maruyama, Y.Tamimoto, M.Kataoka, T.Nakamura, E.W.Gelfand, M.Tanimoto
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Journal Title
Am.J.Respir.Cell Mol.Biol. 32
Pages: 268-280
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Suppression of peritoneal implantation of gastric cancer cells by adenovirus vector-mediated NK4 expression.2005
Author(s)
H.Fujiwara, T.Kubota, H.Amaike, S.Inada, K.Takashima, K.Atsugi, M.Yoshimura, M.Maemondo, K.Narumi, K.Matusmoto, T.Nakamura, A.Hagiwawra, H.Yamagishi
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Journal Title
Cancer Gene Ther. 12
Pages: 206-216
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Suppression of metastasis of human pancreatic cancer to the liver by transportal injection of recombinant adenoviral NK4 in nude mice.2005
Author(s)
Murakami, M., Nagai, E., Mizumoto, K., Saimura, M., Ohuchida, K., Inadome, N., Matsumoto, K., Nakamura, T., Maemondo, M., Nukiwa, T., Tanaka, M.
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Journal Title
Int.J.Cancer 117
Pages: 160-165
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Novel therapeutic strategy for stroke in rats by bone marrow stromal cells and ex vivo HGF gene transfer with HSV-1 vector.2005
Author(s)
M.Z.Zhao, N.Nonoguchi, N.Ikeda, T.Watanabe, Y.Kajimoto, D.Miyazawa, D.Furutama, H.Funakosshi, T.Nakamura, M.Dizawa, M.Shibata, Y.Otsuki, R.S.Coffin, W.Liu, T.Kuroiwa, S.Miyatake
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Journal Title
J.Cereb.Blood Flow Metab. 18
Pages: 1-13
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Adenoviral gene transduction of hepatocyte growth factor elicits inhibitory effects for hepatoma.2005
Author(s)
K.Yuge, T.Takahashi, S.Nagano, Y.Terazaki, Y.Murofushi, H.Ushikoshi, T.Kawai, N.C.Khai, T.Nakamura, H.Fujiwara, K.Kosai
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Journal Title
Int.J.Oncol. 27
Pages: 77-85
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Possible effects of hepatocyte growth factor for the prevention of peritoneal fibrosis.2005
Author(s)
K.Matsuo, Y.Maeda, Y.Naiki, T.Matsuoka, Y.Tamai, S.Yonekawa, M.Sakaguchi, I.Iwamoto, H.Hasegawa, K.Matsumoto, T.Nakamura, A.Kanamaru
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Journal Title
Nephron Exp.Nephrol. 99
Pages: e87-e94
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Hepatocyte growth factor gene transfer to alveolar septa for effective suppression lung fibrosis.2005
Author(s)
M.Watanabe, M.Ebina, F.M.Orson, A.Nakamura, K.Kubota, D.Koinuma, K.Akiyama, M.Maemondo, S.Okouchi, M.Takara, K.Matsumoto, T.Nakamura, T.Nukiwa
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Journal Title
Molecular Therapy 12
Pages: 58-67
Description
「研究成果報告書概要(欧文)」より
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