2003 年度実績報告書

器官修復システムの破綻による組織線維化機構の分子基盤

研究課題

研究課題/領域番号	14207005
研究機関	大阪大学
研究代表者	中村敏一大阪大学, 医学系研究科, 教授 (00049397)
研究分担者	水野信哉大阪大学, 医学系研究科, 助手 (10219644) 船越洋大阪大学, 医学系研究科, 助教授 (40273685) 松本邦夫大阪大学, 医学系研究科, 助教授 (90201780)
キーワード	組織線維化 / HGF / 慢性臓器疾患 / 筋線維芽細胞 / 細胞外マトリックス / TGF-β / 組織再生 / 再生医学
研究概要	慢性的に進行する疾患では、実質細胞の脱落とともにやがては細胞外基質に置換した病態、即ち、組織線維症に陥る。私達は肝硬変や慢性腎症などにおいてHGFが上皮細胞の再生を駆動して間質線維化への移行をブロックすることを明らかにして来たが、間質に対するHGFの直接的な機能については不明であった。そこで本年度は糖尿病性腎症と肺線維症のモデルを用いて筋線維芽細胞におけるHGFの直接的な機能を解析した。 1)糖尿病性腎症に対するHGFによる糸球体硬化症の進展阻止: 糖尿病性腎症の激増により慢性腎不全から血液透析に移行する患者数が世界的に増加の一途を辿っている。今回、ストレプトゾトシン(STZ)を用いてマウスに糖尿病性腎症を誘起し、HGFの生理的機能を検討した。STZ投与後2週目より糸球体におけるHGFの産生促進が観察される一方、6週目以降HGFの産生枯渇に伴って糸球体硬化が進行した。この時期にHGFを補充したところ、HGFは筋線維芽細胞の形質を持つメサンギウム細胞に作用してTGF-β1の産生を抑制することが判明した。これに一致して糸球体肥大は改善し、硬化性病変も軽減した。その結果、糖尿病性の腎不全発症はHGF補充によって阻止できることが判明した。 2)進行した肺線維症に対するHGFによる線維化解除と実質再生促進: 肝臓や腎臓と異なり、細胞増殖能に乏しい肺では慢性傷害・線維化後の再生は困難とされて来た。私達はブレオマイシンを投与した肺線維症のマウスでは間質筋線維芽細胞にHGF受容体であるc-Metが発現することを見出した。この意義を明らかにすべくHGFを投与したところ、MMP-1/-9の発現上昇に一致してコラーゲンが減少する一方、筋線維芽細胞でのアポトーシスが亢進した。さらに間質線維化の縮小に加え、肺実質細胞の再生が高まった。間質線維化解除、実質再生といった生物活性を合わせ持つHGFは進行した肺線維症の病態改善を実現する画期的な治療因子になることが期待される。

研究成果

(38件)

すべてその他

すべて文献書誌 (38件)

[文献書誌] S.Mizuno, T.Nakamura: "Suppression of mesangial TGF-β1 expression by HGF contributes to attenuate glomerulosclenosis and renal dysfunction in murine diabetic nephropathy."Am.J.Physiol.. 286. F134-F143 (2004)
[文献書誌] J.Wen, et al.: "Hepatic gene expression of NK4, an HGF-antagonist/angio-genesis inhibitor suppresses liver metastasis and invasive growth of colon cancer in mice"Cancer Gene Therapy. (In press). (2004)
[文献書誌] J.Wen, et al.: "Hydrocortisone potentiates hepatocyte growth factor expression in vascular endothelial cells"Biomed.Res.. (In press). (2004)
[文献書誌] K.Oshima, et al.: "Intrathecal injection of HVJ-E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats"FASEB J. 18. 212-214 (2004)
[文献書誌] N.Hattori, et al.: "The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism"Am.J Pathol.. (In press). (2004)
[文献書誌] H.Takahashi, et al.: "LlM-kinase as a regulator of actin dynamics in spermatogenesis"Cytogenic and Genome Research. (In press). (2004)
[文献書誌] K.Bessho, et al.: "Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis"Am.J Physiol.. 284. F1171-F1180 (2003)
[文献書誌] S.Yoshida, et al.: "Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation"J.Invest.Dermatol.. 120. 335-343 (2003)
[文献書誌] K.Kitajima, et al.: "A newly identified AMSH-family protein is specifically expressed in haploid stages of testicular germ cells"Biochem.Biophys.Res.Commun.. 309. 135-142 (2003)
[文献書誌] K.Matsumoto, et al.: "Renotropic role and therapeutic potential of HGF in the kidney"Nephrol.Dial.Transplant.. 17. 59-61 (2003)
[文献書誌] T.Inoue, et al.: "Hepatocyte growth factor counteracts tranforming growth factor-β1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6-nephrectomized mice"FASEB J.. 17. 268-270 (2003)
[文献書誌] H.Koike, et al.: "Enhanced angiogenesis and improvement of neuropathy by cotransfection of human hepatocyte growth factor and prostacyclin synthase gene"FASEB J.. 103. 36-48 (2003)
[文献書誌] Tomita, N, et al.: "Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis, ets-1"Circulation. 107. 1411-1417 (2003)
[文献書誌] Y.Matsuno, et al.: "Hepatocyte growth factor gene transfer into liver via the portal vein using electroporation attenuates the rat liver cirrhosis"Gene Therapy. 10. 1559-1566 (2003)
[文献書誌] M.Nakabayashi, et al.: "HGF/NK4 inhibited VEGF-induced angiogenesis in invitro cultured endothelial cells and in vivo rabbit model"Diabetologia. 46. 115-123 (2003)
[文献書誌] T.Manabe, et al.: "Cell-based protein delivery system for pancreatic cancer therapy : NK4 gene-transduced oral mucosal epithelial cell sheet"Clin Cancer Res.. 9. 3158-3166 (2003)
[文献書誌] K.Nishimura, et al.: "Effects of hepatocyte growth factor on urokinase-type Plasminogen activator (uPA) and uPA receptor in Du145 prostate cancer cells"Intern.J.Androl.. 26. 175-179 (2003)
[文献書誌] S.Kato, et al.: "Expression of hepatocyte growth factor and c-Met in the anterior horn cells of the spinal cord in the patients with amyotrophic lateral sclerosis (ALS) : immunohisto chemical studies on sporadic ALS and familial ALS with superoxide dismutase 1 gene mutation"Acta Neuropathol.. 106. 112-120 (2003)
[文献書誌] L.W.Qian, et al.: "Co-cultivation of pancreatic cancer cells with orthotopic tumor-derived fibroblasts : fibroblasts stimulate tumor cell invasion via HGF secretion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production"Cancer Lett.. 190. 105-112 (2003)
[文献書誌] L.W.Quin, et al.: "Radiation stimulates HGF receptor/c-met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and map kinase activity in pancreatic cancer cells"Intern.J.Cancer. 104. 542-549 (2003)
[文献書誌] R.Pai, et al.: "Prostaglandins promote colon cancer cell invasion ; signaling by cross-talk between two distinct growth factor receptors"FASEB-J.. 17. 640-1647 (2003)
[文献書誌] T.A.Martin, et al.: "Growth and angiogenesis of human breast cancer in a nude mouse tumor model is reduced by NK4, the HGF/SF antagonist"Carcirogenesis. 24. 1317-1323 (2003)
[文献書誌] G.Davies, et al.: "The HGF/SF antagonist NK4 reverses fibroblast-and HGF-induced prostate tumot growth and angiogenesis in vivo"Intern.J.Cancer. 106. 348-354 (2003)
[文献書誌] P.Netzer, et al.: "Interaction between hepatocyte growth factor and non-steroidal anti-inflammatory drugs during gastric epithelial wound healing"Digestion. 67. 118-128 (2003)
[文献書誌] 水野信哉, 他: "医学のあゆみ"医師薬出版. 3 (2003)
[文献書誌] 水野信哉, 他: "臨床免疫2003"科学論評社. 9 (2003)
[文献書誌] 水野信哉, 中村敏一: "The Lung Perspective"メディカルレビュー社. 11 (2003)
[文献書誌] 水野信哉, 中村敏一: "Annual Review 腎臓"中外医学社. 11 (2002)
[文献書誌] 橋ガ迫敦子, 他: "血液・免疫・腫瘍"メディカルレビュー社. 8 (2003)
[文献書誌] 中村敏一: "日本医師会雑誌"日本医師会. 5 (2003)
[文献書誌] 田村隆彦, 他: "Biotherapy"癌と化学療法社. 8 (2003)
[文献書誌] 松本邦夫, 中村敏一: "BIO Clinica"北隆館. 7 (2003)
[文献書誌] 町出充, 中村敏一: "現代医療"現代医療社. 9 (2003)
[文献書誌] 福田一弘, 他: "遺伝子医学別"メディカルドゥ. 9 (2003)
[文献書誌] 松本邦夫, 中村敏一: "日本内科学雑誌"日本内科学学会. 5 (2003)
[文献書誌] 船越洋, 中村敏一: "神経治療学"日本神経治療学会. 8 (2003)
[文献書誌] 町出充, 中村敏一: "G.I.Research"先端医学社. 6 (2003)
[文献書誌] 船越洋, 中村敏一: "脳と神経"医学書院. 5 (2003)

2003 年度 実績報告書

器官修復システムの破綻による組織線維化機構の分子基盤

研究代表者

中村 敏一 大阪大学, 医学系研究科, 教授 (00049397)

研究成果

[文献書誌] S.Mizuno, T.Nakamura: "Suppression of mesangial TGF-β1 expression by HGF contributes to attenuate glomerulosclenosis and renal dysfunction in murine diabetic nephropathy."Am.J.Physiol.. 286. F134-F143 (2004)

[文献書誌] J.Wen, et al.: "Hepatic gene expression of NK4, an HGF-antagonist/angio-genesis inhibitor suppresses liver metastasis and invasive growth of colon cancer in mice"Cancer Gene Therapy. (In press). (2004)

[文献書誌] J.Wen, et al.: "Hydrocortisone potentiates hepatocyte growth factor expression in vascular endothelial cells"Biomed.Res.. (In press). (2004)

[文献書誌] K.Oshima, et al.: "Intrathecal injection of HVJ-E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats"FASEB J. 18. 212-214 (2004)

[文献書誌] N.Hattori, et al.: "The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism"Am.J Pathol.. (In press). (2004)

[文献書誌] H.Takahashi, et al.: "LlM-kinase as a regulator of actin dynamics in spermatogenesis"Cytogenic and Genome Research. (In press). (2004)

[文献書誌] K.Bessho, et al.: "Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis"Am.J Physiol.. 284. F1171-F1180 (2003)

[文献書誌] S.Yoshida, et al.: "Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation"J.Invest.Dermatol.. 120. 335-343 (2003)

[文献書誌] K.Kitajima, et al.: "A newly identified AMSH-family protein is specifically expressed in haploid stages of testicular germ cells"Biochem.Biophys.Res.Commun.. 309. 135-142 (2003)

[文献書誌] K.Matsumoto, et al.: "Renotropic role and therapeutic potential of HGF in the kidney"Nephrol.Dial.Transplant.. 17. 59-61 (2003)

[文献書誌] T.Inoue, et al.: "Hepatocyte growth factor counteracts tranforming growth factor-β1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6-nephrectomized mice"FASEB J.. 17. 268-270 (2003)

[文献書誌] H.Koike, et al.: "Enhanced angiogenesis and improvement of neuropathy by cotransfection of human hepatocyte growth factor and prostacyclin synthase gene"FASEB J.. 103. 36-48 (2003)

[文献書誌] Tomita, N, et al.: "Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis, ets-1"Circulation. 107. 1411-1417 (2003)

[文献書誌] Y.Matsuno, et al.: "Hepatocyte growth factor gene transfer into liver via the portal vein using electroporation attenuates the rat liver cirrhosis"Gene Therapy. 10. 1559-1566 (2003)

[文献書誌] M.Nakabayashi, et al.: "HGF/NK4 inhibited VEGF-induced angiogenesis in invitro cultured endothelial cells and in vivo rabbit model"Diabetologia. 46. 115-123 (2003)

[文献書誌] T.Manabe, et al.: "Cell-based protein delivery system for pancreatic cancer therapy : NK4 gene-transduced oral mucosal epithelial cell sheet"Clin Cancer Res.. 9. 3158-3166 (2003)

[文献書誌] K.Nishimura, et al.: "Effects of hepatocyte growth factor on urokinase-type Plasminogen activator (uPA) and uPA receptor in Du145 prostate cancer cells"Intern.J.Androl.. 26. 175-179 (2003)

[文献書誌] L.W.Qian, et al.: "Co-cultivation of pancreatic cancer cells with orthotopic tumor-derived fibroblasts : fibroblasts stimulate tumor cell invasion via HGF secretion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production"Cancer Lett.. 190. 105-112 (2003)

[文献書誌] L.W.Quin, et al.: "Radiation stimulates HGF receptor/c-met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and map kinase activity in pancreatic cancer cells"Intern.J.Cancer. 104. 542-549 (2003)

[文献書誌] R.Pai, et al.: "Prostaglandins promote colon cancer cell invasion ; signaling by cross-talk between two distinct growth factor receptors"FASEB-J.. 17. 640-1647 (2003)

[文献書誌] T.A.Martin, et al.: "Growth and angiogenesis of human breast cancer in a nude mouse tumor model is reduced by NK4, the HGF/SF antagonist"Carcirogenesis. 24. 1317-1323 (2003)

[文献書誌] G.Davies, et al.: "The HGF/SF antagonist NK4 reverses fibroblast-and HGF-induced prostate tumot growth and angiogenesis in vivo"Intern.J.Cancer. 106. 348-354 (2003)

[文献書誌] P.Netzer, et al.: "Interaction between hepatocyte growth factor and non-steroidal anti-inflammatory drugs during gastric epithelial wound healing"Digestion. 67. 118-128 (2003)

[文献書誌] 水野信哉, 他: "医学のあゆみ"医師薬出版. 3 (2003)

[文献書誌] 水野信哉, 他: "臨床免疫2003"科学論評社. 9 (2003)

[文献書誌] 水野信哉, 中村敏一: "The Lung Perspective"メディカルレビュー社. 11 (2003)

[文献書誌] 水野信哉, 中村敏一: "Annual Review 腎臓"中外医学社. 11 (2002)

[文献書誌] 橋ガ迫敦子, 他: "血液・免疫・腫瘍"メディカルレビュー社. 8 (2003)

[文献書誌] 中村敏一: "日本医師会雑誌"日本医師会. 5 (2003)

[文献書誌] 田村隆彦, 他: "Biotherapy"癌と化学療法社. 8 (2003)

[文献書誌] 松本邦夫, 中村敏一: "BIO Clinica"北隆館. 7 (2003)

[文献書誌] 町出充, 中村敏一: "現代医療"現代医療社. 9 (2003)

[文献書誌] 福田一弘, 他: "遺伝子医学別"メディカルドゥ. 9 (2003)

[文献書誌] 松本邦夫, 中村敏一: "日本内科学雑誌"日本内科学学会. 5 (2003)

[文献書誌] 船越洋, 中村敏一: "神経治療学"日本神経治療学会. 8 (2003)

[文献書誌] 町出充, 中村敏一: "G.I.Research"先端医学社. 6 (2003)

[文献書誌] 船越洋, 中村敏一: "脳と神経"医学書院. 5 (2003)

2003 年度実績報告書

中村敏一大阪大学, 医学系研究科, 教授 (00049397)