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2001 Fiscal Year Final Research Report Summary

Exploring the administration route of HGF-expressing adenoviral vector (Ad-HGF) and low but local HGF-expression plasmid vector with macroaggregated albumin/polyethyleneiminV(MAA-PEI) for the clinically effective HGF gene transfer therapy.

Research Project

Project/Area Number 12557056
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Respiratory organ internal medicine
Research InstitutionTohoku University

Principal Investigator

NUKIWA Toshihiro  Tohoku University, ROMM, IDAC, Professor, 加齢医学研究所, 教授 (40129036)

Co-Investigator(Kenkyū-buntansha) MIKI Makoto  Tohoku Univ Hosp, Assistant Professor, 医学部・附属病院, 助手 (30312656)
EBINA Masahito  Tohoku Univ Hosp, Assistant Professor, 医学部・附属病院, 助手 (10280885)
HAGIWARA Koichi  Tohoku Univ Hosp, Senior Assistant Professor, 医学部・附属病院, 講師 (00240705)
NAKAMURA Toshikazu  Osaka Univ, Professor, 大学院・医学研究科, 教授 (00049397)
NARUMI Koh  Tohoku Univ Hosp, Assistant Professor, 医学部・附属病院, 助手 (30302219)
Project Period (FY) 2000 – 2001
Keywordshepatocyte growth factor (HGF) / adenoviral vector / plasmid vector / macroaggregated albumin / polyethyleneimine / acute lung injury (ALI) / lung fibrosis / regeneration / lung specific expression
Research Abstract

Hepatocyte growth factor (HGF) is a multi-organ regeneration factor including the anti-apoptotic, angiogenic, proliferative, and morphogenic activity functioning not only in liver but kidney or lung. In the current investigation, in order to apply the HGF gene transfer in the clinical setting for acute lung injury (ALI) and lung fibrosis, we have explored (1) the use of high-expression but antigenic adenoviral vector in the context of administration route, and (2) the use of low-expression but local and non-inflammatory plasmid vector in mouse model. Although high HGF protein was detected by intratracheal Ad-HGF administration, the bleomycin induced ALI and fibrosis persisted with reduced HGF effect. In contrast, in spite of the fact that only fraction of HGF was delivered to the lung by the way of intraperitoneal of intravenous administration of Ad-HGF, the bleomycin induced ALI and fibrosis had been suppressed through repression of both alveolar epithelial cell apoptosis and TGF-b expression. When MAA-PEI was introduced to mix plasmid HGF vector for local HGF expression in the lung, the expression efficiency increased by 10 fold (1 ug plasmid) compared with naked plasmid vector, and the duration of HGF expression prolonged for more than 10 days. Furthemore the concentration of HGF in the lung was only one thousandth of the amount yielded by Ad-HGF, the bleomycin induced ALI and fibrosis was efficiently suppressed. Taken together, while high HGF expression and suppression of lung inflammation was obtained using non-tracheal Ad-HGF administration in the bleomycin induced ALI and fibrosis, local, non-inflammatory and repeatable feature of HGF plasmid/MAA-PEI indicates a possible modality for clinical application in ALI or fibrosis.

  • Research Products

    (13 results)

All Other

All Publications (13 results)

  • [Publications] Saijo Y, Sato G, Usui K, Sato M, Sagawa M, Minami, Nukiwa T: "Expression of nucleolar protein p120 predicts poor prognosis in patients with stage I lung adenocarcinoma"Ann Oncol. 12(8). 1121-1125 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Pradono P, Tazawa R, Maemondo M, Tanaka M, Usui K, Saijo Y, Hagiwara K, Nukiwa T.: "Gene transfer of thromboxane A(2) synthase and prostaglandin I(2) synthase antithetically altered tumor angiogenesis and tumor growth"Cancer Research. 62(1). 63-66 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Maemondo M, Narumi K, Saijo Y, Usui K, Tazawa R, Nakamura T, Nukiwa T: "Targeting Angiogenesis and HGF Function Using an Adenoviral Vector Expressing the HGF Antagonist NK4 for Cancer Therapy"Molecular Therapy. 5(2). 177-185 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ishimoto O, Kawahara C, Enjo K, Obinata M, Nukiwa T, Ikawa S: "Gene transfer of thromboxane A(2) synthase and prostaglandin I(2) synthase antithetically altered tumor angiogenesis and tumor growth"Cancer Research. 62(3). 636-641 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kimura Y, Takahashi K, Totsune K, Darnel AD, Ebina M, Nukiwa T, Sasano H: "Expression of urocortin and corticotropin-releasing factor receptor subtypes in the human heart"J Clin Endocrinol Metab. 87(1). 340-346 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kikuchi T, Hagiwara K, Gomi K, Koayashi T, Takahashi H, Watanabe A, Nukiwa T: "Clarithromycin suppresses lipopolysaccharide (LPS)-mediated interleukin-8 (IL-8) production from human monocytes through AP-1 and NF-kB transcripition factors"Journal of Antimicrobial Chemotherapy. (in press).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 工藤翔二, 中田紘一郎, 貫和敏博: "呼吸器疾患最新の治療"南江堂. 467 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Saijo Y, Sato G, Usui K, Sato M, Sagawa M, Minami, Nukiwa T: "Expression of nucleolar protein pl20 predicts poor prognosis in patients with stage I lung adenocarcinoma"Ann Oncol|.. 12 (8). 1121-5 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Pradono P, Tazawa R, Maemondo M, Tanaka M, Usui K, Saijo Y, Hagiwara K, Nukiwa T.: "Gene transfer of thromboxane A(2) synthase and prostaglandin I(2) synthase antithetically altered tumor angiogenesis and tumor growth"Cancer Res.. 62 (1). 63-6 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Maemondo M, Narumi K, Saijo Y, Usui K, Tahara M, Tazawa R, Hagiwara K, Matsumoto K, Nakamura T, Nukiwa T.: "Targeting angiogenesis and HGF function using an adenoviral vector expressing the HGF antagonist NK4 for cancer therapy"Mol Ther.. 5 (2). 177-85 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ishimoto O, Kawahara C, Enjo K, Obinata M, Nukiwa T, Ikawa S: "Possible oncogenic potential of Delta Np73: a newly identified isoform of human p73"Cancer Res.. 62 (3). 636-41 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kimura Y, Takahashi K, Totune K, Muramatsu Y, Kaneko C, Darnel AD, Suzuki T, Ebina M, Nukiwa T, Sasano H.: "Expression of urocortin and corticotropin-releasing factor receptor subtypes in the human heart"J Clin Endocrinol Nmetab.. 87 (1). 340-6 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kikuchi T, Hagiwara K, Gomi K, Kobayashi T, Takahashi H, Watanabe A, Nukiwa T.: "Clarithromycin suppresses lipopolysaccharide (LPS)-mediated interleukin-8 (IL-8) production from human monocytes through AP-1 and NF-kB transcripition factors"Journal of Antimicrobial Chemotherapy.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2003-09-17  

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