2001 年度実績報告書

難治性臓器疾患に対するHGF(肝細胞増殖因子)の抗線維化機構の解析と治療への応用

研究課題

研究課題/領域番号	11557010
研究機関	大阪大学
研究代表者	松本邦夫大阪大学, 医学系研究科, 助教授 (90201780)
研究分担者	船越洋大阪大学, 医学系研究科, 助教授 (40273685)
キーワード	HGF / 再生・修復 / 臓器保護 / 抗線維化 / TGF-β1 / 心筋症 / 慢性腎不全 / 肺線維症
研究概要	(1)心筋症モデルを用いたHGFによる心筋線維化の阻止と心機能改善拡張型心筋症のモデルハムスターは生後26週から32週にかけて、心筋の線維化や肥大をもたらすTGF-β1やANPの発現増加と一致して心筋組織の繊維化と心機能の著しい低下を示した。これに対して、病態末期に近い27週目からHGFを3週間にわたり連日投与したところ、TGF-β1ならびにANPの発現抑制と心筋の線維化ならびに心機能の著しい改善が認められた。病態末期からの治療においてこのような治療効果が示された例はなく、HGFは拡張型心筋症に対する有効な治療法となるものと考えられる。 (2)HGFによる慢性腎不全の改善作用とその作用機構慢性腎不全はネフロン実質細胞傷害慢性的に引き起こされる典型的な線維性疾患である。慢性腎不全を自然発症するICGNマウスでは腎不全の進行に伴いTGF-βの発現が著しく増加するが、コラーゲンレペル、尿細管のアポトーシスはTGF-βとよく相関して増加した。一方、HGFの発現はTGF-βと相反的に減少の一途をたどり、尿細管の再生はHGFレベルとよく相関した。ICGNマウスに抗HGF抗体を投与すると、腎臓におけるTGF-βレベルは増加し、これと相関して、コラーゲンの蓄積、尿細管のアポトーシスが増加する一方、尿細管の再生は強く抑制された。したがってHGFはTGF-βと拮抗し慢性腎不全の進行を抑制するように機能していると考えられる。 (3)肺線維症ブレオマイシン投与により誘発させた肺線維症のモデルにおいてTGF-beta1の発現誘導とともにコラーゲン沈着が進行し、組織線維化が増悪された。一方、内因性HGFの発現は初期では高まるが、繊維化が高まるにつれ、著しく抑制されることも明らかとなった。そこでブレオマイシン処理したマウスにHGFの中和抗体を投与すると、実質組織の破壊に一致して線維化が加速されることが明らかとなった。組織線維化において中心的な役割を担うとされる筋線維芽細胞にはHGF受容体であるc-Metが発現しており、HGF刺激によってアポトーシスに陥ることも明らかとなった。

研究成果

(32件)

すべてその他

すべて文献書誌 (32件)

[文献書誌] Matsumoto, K, et al.: "Liver organogenesis promoted by endothelial cells prior to vascular function"Science. 294. 559-563 (2001)
[文献書誌] Tomioka D., et al.: "Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model"Cancer Res.. 61. 7518-7524 (2001)
[文献書誌] Sumi, T., et al.: "Specific activation of LIM-kinase 2 via phosphorylation of the threonine-505 by ROCK, a Rho-dependent protein kinase"J.Biol.Chem.. 276. 670-676 (2001)
[文献書誌] Matsumoto, K, et al.: "Hepatocyte growth factor renotropic role and potential therapeutics for renal diseases"Kid.Intem.. 59. 2023-2038 (2001)
[文献書誌] Sumi, T., et al.: "Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha"J Biol Chem.. 276. 23092-23096 (2001)
[文献書誌] Kuroiwa, T., et al.: "Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function"J Clin lnvest.. 107. 1365-1373 (2001)
[文献書誌] Maehara, N., et al.: "NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells"Br.J.Cancer. 84. 864-873 (2001)
[文献書誌] Mizuno, S., et al.: "Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy"Kidney Intem.. 59. 1034-1314 (2001)
[文献書誌] Nakamura, T., et al.: "Molecular cloning and characterization of Kremen, a novel kringle-containing transmembrane protein"Biochim. Biophys. Acta. 1518. 63-72 (2001)
[文献書誌] Taniyama, Y., et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models : preclinical study for treatment of peripheral arterial disease"Gene Therapy. 8. 181-189 (2001)
[文献書誌] Azuma, H., et al.: "Hepatocyte growth factor prevents development of chronic allograft nephropathy in an experimental rat transplant model"J.Am.Soc.Nephrol.. 12. 12180-1292 (2001)
[文献書誌] Matsumoto, K., et al.: "Inhibition of neointima by angiotensin-converting enzyme inhibitor in porcine coronary artery balloon-injury model"Hypertension. 37. 270-264 (2001)
[文献書誌] Nakagami, H., et al.: "Mitogenic and antiapoptotic actions of hepatocyte growth factor through ERK, STAT3, and AKT in endothelial cells"Hypertension. 37. 581-586 (2001)
[文献書誌] Yamamoto, K., et al.: "Contribution of bcl-2, but not bcl-xl and bax, to antiapoptotic actions of hepatocyte growth factor in hypoxia-conditioned human endothelial cells"Hypertension. 37. 1341-1348 (2001)
[文献書誌] Ueda.H., et al.: "A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats"Cardiovascular Res.. 51. 41-50 (2001)
[文献書誌] Tsuzuki, N., et al.: "HGF reduces the infarct volume after transient focal cerebral ischemia in rats"Neurol Res.. 23. 417-424 (2001)
[文献書誌] Parr, C., et al.: "The HGF/SF-induced phosphorylation of paxillin, matrix adhesion, and invasion of prostate cancer cells were suppressed by NK4, an HGF/SF variant"Biochem Biophys Res Commun. 285. 1330-1337 (2001)
[文献書誌] Beppu, K, et al.: "Hepatocyte growth factor production by peripheral blood mononuclear cells of recurrent cancer patients"Anticancer Res.. 21. 2195-2200 (2001)
[文献書誌] Aoki, M., et al.: "Inhibition of neointimal formation after balloon injury by cilostazol, accompanied by improvement of endothelial dysfunction and induction of hepatocyte growth factor in rat diabetes model"Diabetologia. 44. 1034-1042 (2001)
[文献書誌] Taniyama, Y., et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model : molecular mechanisms of delayed angiogenesis in diabetes"Circulation. 104. 2344-2350 (2001)
[文献書誌] Hayashi, K., et al.: "Gene therapy for preventing neuronal death using hepatocyte growth factor : in vivo gene transfer of HGF to subarachnoid space prevents delayed neuronal death in gerbil hippocampal CA1 neurons"Gene Therpy. 8. 1167-1173 (2001)
[文献書誌] Shibuki, H., et al.: "Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemiareprfusionin injury"Invest.Ophthalmol.Vis.Sci.. 43. 528-536 (2002)
[文献書誌] Maemondo, M., et al.: "Targeting angiogenesis and HGF function using an adenovirul vector expressing the HGF-antagonist NK4 for cancer therapy"Mol.Therapy. 5. 177-185 (2002)
[文献書誌] Sumi, T., et al.: "Mitosis-dependent phosphorylation and activation of LIM-kinase-I"Biochem.Biophys.Res.Cummun.. (印刷中). (2002)
[文献書誌] Sakamaki, Y., et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postneumonectomy compensatory lung growth in mice"Am.J.Respir.Cell Mol.Biol.. (印刷中). (2002)
[文献書誌] Funakoshi, H., et al.: "Identification of Gas6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons"J.Neurosci.Res.. (印刷中). (2002)
[文献書誌] Kishi, A.Y., et al.: "Molecular cloning, expression and partial characterization of Kksy, a novel Xenopus member of Sky receptor tyrosine kinase"Gene. (印刷中). (2002)
[文献書誌] 松本邦夫, 中村敏一: "増殖因子による再生医学の展開-HGFを中心にして-"Biotherapy. 15. 95-104 (2001)
[文献書誌] 松本邦夫, 他: "HGFによる肺の再生と線維化の阻止"呼吸. 20. 935-939 (2001)
[文献書誌] 富岡大策, 他: "NK4/malignostatinによる腫瘍血管新生阻止作用とその制がん効果"最新医学. 56. 1799-1807 (2001)
[文献書誌] 松本邦夫: "肝臓の初期発生を支える血管内皮細胞"実験医学. 20. 468-471 (2002)
[文献書誌] Matsumoto, K., et al.: "分担:HGF-c-Met receptor pathway in tumor invasion-metastasis and potential cancer treatment with NK4 書名:Growth Factors and Their Receptors in Cancer Metastasis"Kluwer Academic Publisher(分担). 35 (2001)

2001 年度 実績報告書

難治性臓器疾患に対するHGF(肝細胞増殖因子)の抗線維化機構の解析と治療への応用

研究代表者

松本 邦夫 大阪大学, 医学系研究科, 助教授 (90201780)

研究成果

[文献書誌] Matsumoto, K, et al.: "Liver organogenesis promoted by endothelial cells prior to vascular function"Science. 294. 559-563 (2001)

[文献書誌] Tomioka D., et al.: "Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model"Cancer Res.. 61. 7518-7524 (2001)

[文献書誌] Sumi, T., et al.: "Specific activation of LIM-kinase 2 via phosphorylation of the threonine-505 by ROCK, a Rho-dependent protein kinase"J.Biol.Chem.. 276. 670-676 (2001)

[文献書誌] Matsumoto, K, et al.: "Hepatocyte growth factor renotropic role and potential therapeutics for renal diseases"Kid.Intem.. 59. 2023-2038 (2001)

[文献書誌] Sumi, T., et al.: "Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha"J Biol Chem.. 276. 23092-23096 (2001)

[文献書誌] Kuroiwa, T., et al.: "Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function"J Clin lnvest.. 107. 1365-1373 (2001)

[文献書誌] Maehara, N., et al.: "NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells"Br.J.Cancer. 84. 864-873 (2001)

[文献書誌] Mizuno, S., et al.: "Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy"Kidney Intem.. 59. 1034-1314 (2001)

[文献書誌] Nakamura, T., et al.: "Molecular cloning and characterization of Kremen, a novel kringle-containing transmembrane protein"Biochim. Biophys. Acta. 1518. 63-72 (2001)

[文献書誌] Taniyama, Y., et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models : preclinical study for treatment of peripheral arterial disease"Gene Therapy. 8. 181-189 (2001)

[文献書誌] Azuma, H., et al.: "Hepatocyte growth factor prevents development of chronic allograft nephropathy in an experimental rat transplant model"J.Am.Soc.Nephrol.. 12. 12180-1292 (2001)

[文献書誌] Matsumoto, K., et al.: "Inhibition of neointima by angiotensin-converting enzyme inhibitor in porcine coronary artery balloon-injury model"Hypertension. 37. 270-264 (2001)

[文献書誌] Nakagami, H., et al.: "Mitogenic and antiapoptotic actions of hepatocyte growth factor through ERK, STAT3, and AKT in endothelial cells"Hypertension. 37. 581-586 (2001)

[文献書誌] Yamamoto, K., et al.: "Contribution of bcl-2, but not bcl-xl and bax, to antiapoptotic actions of hepatocyte growth factor in hypoxia-conditioned human endothelial cells"Hypertension. 37. 1341-1348 (2001)

[文献書誌] Ueda.H., et al.: "A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats"Cardiovascular Res.. 51. 41-50 (2001)

[文献書誌] Tsuzuki, N., et al.: "HGF reduces the infarct volume after transient focal cerebral ischemia in rats"Neurol Res.. 23. 417-424 (2001)

[文献書誌] Parr, C., et al.: "The HGF/SF-induced phosphorylation of paxillin, matrix adhesion, and invasion of prostate cancer cells were suppressed by NK4, an HGF/SF variant"Biochem Biophys Res Commun. 285. 1330-1337 (2001)

[文献書誌] Beppu, K, et al.: "Hepatocyte growth factor production by peripheral blood mononuclear cells of recurrent cancer patients"Anticancer Res.. 21. 2195-2200 (2001)

[文献書誌] Aoki, M., et al.: "Inhibition of neointimal formation after balloon injury by cilostazol, accompanied by improvement of endothelial dysfunction and induction of hepatocyte growth factor in rat diabetes model"Diabetologia. 44. 1034-1042 (2001)

[文献書誌] Taniyama, Y., et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model : molecular mechanisms of delayed angiogenesis in diabetes"Circulation. 104. 2344-2350 (2001)

[文献書誌] Hayashi, K., et al.: "Gene therapy for preventing neuronal death using hepatocyte growth factor : in vivo gene transfer of HGF to subarachnoid space prevents delayed neuronal death in gerbil hippocampal CA1 neurons"Gene Therpy. 8. 1167-1173 (2001)

[文献書誌] Shibuki, H., et al.: "Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemiareprfusionin injury"Invest.Ophthalmol.Vis.Sci.. 43. 528-536 (2002)

[文献書誌] Maemondo, M., et al.: "Targeting angiogenesis and HGF function using an adenovirul vector expressing the HGF-antagonist NK4 for cancer therapy"Mol.Therapy. 5. 177-185 (2002)

[文献書誌] Sumi, T., et al.: "Mitosis-dependent phosphorylation and activation of LIM-kinase-I"Biochem.Biophys.Res.Cummun.. (印刷中). (2002)

[文献書誌] Sakamaki, Y., et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postneumonectomy compensatory lung growth in mice"Am.J.Respir.Cell Mol.Biol.. (印刷中). (2002)

[文献書誌] Funakoshi, H., et al.: "Identification of Gas6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons"J.Neurosci.Res.. (印刷中). (2002)

[文献書誌] Kishi, A.Y., et al.: "Molecular cloning, expression and partial characterization of Kksy, a novel Xenopus member of Sky receptor tyrosine kinase"Gene. (印刷中). (2002)

[文献書誌] 松本邦夫, 中村敏一: "増殖因子による再生医学の展開-HGFを中心にして-"Biotherapy. 15. 95-104 (2001)

[文献書誌] 松本邦夫, 他: "HGFによる肺の再生と線維化の阻止"呼吸. 20. 935-939 (2001)

[文献書誌] 富岡大策, 他: "NK4/malignostatinによる腫瘍血管新生阻止作用とその制がん効果"最新医学. 56. 1799-1807 (2001)

[文献書誌] 松本邦夫: "肝臓の初期発生を支える血管内皮細胞"実験医学. 20. 468-471 (2002)

[文献書誌] Matsumoto, K., et al.: "分担:HGF-c-Met receptor pathway in tumor invasion-metastasis and potential cancer treatment with NK4 書名:Growth Factors and Their Receptors in Cancer Metastasis"Kluwer Academic Publisher(分担). 35 (2001)

2001 年度実績報告書

松本邦夫大阪大学, 医学系研究科, 助教授 (90201780)