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1998 Fiscal Year Final Research Report Summary

Evaluation of expression of multiorganotrophic factor HGF using adenovirus vector containing rat HGF gene and its repressive effects on bleomycin induced lung injury and fibrosis in mice

Research Project

Project/Area Number 09470145
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionTohoku University

Principal Investigator

YAEKASHIWA Masahiro  Institute of Development, Aging and Cancer, Tohoku University, Assistant Professor, 加齢医学研究所, 助手 (70261477)

Co-Investigator(Kenkyū-buntansha) NAKAMURA Toshikazu  Division of Biochemistry, Biomedical Research Center, Osaka University Medical S, 医学部, 教授 (00049397)
SATOH Ken  Institute of Development, Aging and Cancer, Tohoku University, Associate Profess, 加齢医学研究所, 助教授 (00215782)
NUKIWA Toshihiro  Institute of Development, Aging and Cancer, Tohoku University, Professor, 加齢医学研究所, 教授 (40129036)
Project Period (FY) 1997 – 1998
KeywordsHGF / Gene therapy / Bleomycin / Transgene / Lung Fibrosis
Research Abstract

Hepatocyte growth factor (HGF) is a pleiotropic factor that plays an essential role in lung repair and regeneration after injury. In this project, we tried to obtain adequate expression of HGF from transgene in vivo for therapy of lung fibrosis that follows lung injury.
Methods
1. The expression of HGF protein was examined when human HGF cDNA was introduced into cultured cells with pCI-neo Mammalian Expression vector.
2. The expression of HGF protein was examined when rat HGF cDNA was introduced into mice with adenoviral vector (Adex1CAHHGF : constructed with rat HGF gene under control of GAG promoter). Therapeutic effects of HGF protein from transgene was evaluated in mouse models of lung fibrosis induced by bleomycin (BLM).
3. The mechanism of therapeutic effects of HGF on lung fibrosis was analyzed in vitro and in vivo.
Results
1. Human HGF cDNA was introduced in culture cell lines (A549 cell, 293 cell) with pCI-neo mammalian expression vector. The expression of HGF protein was confirmed in the supernatant and transduced cells by ELISA.The transduced cells expressed HGF constantly.
2. High expression of HGF protein and mRNA in liver was observed in mice after intraperitoneal administration of Adex1CAHHGF.The concentration of HGF in liver of mice treated with adenoviralvector elevated at day 3 (286.0 ng/g tissue) and returned to normal level at day 7 (119.9 ng/g tissue). The concentration of HGF in lung moved as that in liver. The lung fibrosis by BLM was suppressed with administration of Adex1CAHHGF.Treatment with HGF resulted in resistance to Staurosporin- and BLM-induced apoptotic cell death in vitro.
Administration of HGF showed anti-TGF-beta1 effects in vivo.

  • Research Products

    (11 results)

All Other

All Publications (11 results)

  • [Publications] Yaekashiwa et al.: "Simultaneous or deloyed administration of hepatocyte growth factor 〜" Am J Respir Crit Care Med. 156(6). 1937-1944 (1997)

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  • [Publications] Abe T et al.: "Bacterial pneumonia causes augmented expression of the secretory 〜" Am J Respir Crit Care Med. 156(4). 1235-1240 (1997)

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      「研究成果報告書概要(和文)」より
  • [Publications] Kikuchi T et al.: "Struoture of the murine secretory leukoprotease inhibitor 〜" Am J Respir Cell Mol Biol. 19(6). 875-800 (1998)

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  • [Publications] Tahara M et al.: "Hepatocyte growth factor leads to recovery from 〜" J Clin Invest. 103(3). 313-320 (1999)

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  • [Publications] 貫和敏博,八重柏政宏: "6.肺線維症(間質性肺炎),in.「HGFの分子医学」" 中村敏一,萩原敏夫監修 メディカルビュー社, 221ページ (1998)

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      「研究成果報告書概要(和文)」より
  • [Publications] Yaekashiwa M,Nakayama S,Saijo T,Abe T,Satoh K,Nakamura T,Nukiwa T: "Treatment of lung fibrosis induced by bleomycin using adenovirus vector carrying hepatocyte growth factor (HGF) Gene" ALA/ATS 1997 International Conference, San Francisco. (1997)

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      「研究成果報告書概要(欧文)」より
  • [Publications] Nakayama S,Sakai T,Yaekashiwa M,Shimizu T,Satoh K,Abe T,Nukiwa T: "What do cytokines in sera tell us about inflammatory status in patients with pulmonary fibrosis?" ALA/ATS 1997 Internartoional Conference, San Francisco. (1997)

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  • [Publications] Shimizugawa M,Ebina M,Onuma K,Kanazawa H,Nakayama S,Yaekashiwa M,Takahashi T,Fujimura S,Nukiwa T: "Angiogenetic factors, VEGF and bFGF,as possible pathogenic contribution to interstitial pneumonia" ATS International Conference, Chicago. (1998)

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  • [Publications] Yaekashiwa M,Nakayama S,Ohnuma K,Sakai T,Abe T,Satoh K,Matsumoto K,Nakamura T,Takahashi T,Nukiwa T: "Simultaneous or delayed administration of Hepatocyte Growth Factor Equally Represses the Fibrotic Changes in Murine Lung Injury Induced by Bleomycin" Am J Respir Crit Care Med. 156. 1937-1944 (1997)

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  • [Publications] Shiraishi K,Sasaki H,Yaekashiwa M,Motomiya M,Nukiwa T: "Total respiratory system compliance after thoracoplasty" Respiratory Medicine. 92. 810-814 (1998)

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  • [Publications] Suzuki T,Saijo Y,Ebina M,Yaekashiwa M,Minegishi M,Tsuchiya S,Konno T,Ono S,Matsumura Y,Fujimura S,Nukiwa T: "Bilateral pneumothoraces with multiple bullae in a patient with bronchiolitis obliterans 10 years after allogeneic bone marrow transplantation" Bone Marrow Transplantation. (in press).

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Published: 1999-12-08  

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