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Reorganization of alveolar capillaries in pulmonary fibrosis by gene trasfection of Hepatocyte Growth Factor

Research Project

Project/Area Number 14570534
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionTOHOKU UNIVERSITY

Principal Investigator

EBINA Masahito  Tohoku University, Hospital, Lecturer, 医学部附属病院, 講師 (10280885)

Co-Investigator(Kenkyū-buntansha) KIKUCHI Toshiaki  Tohoku University, Hospital, Research Associate, 医学部附属病院, 助手 (10280926)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordspulmonary fibrosis / alveolar capillaries / bleomycin / gene therapy / hepatocyte growth factor / 血管内皮細胞 / 肺組織修復 / ブレオマイシン肺 / プラスミド / 組織再生
Research Abstract

Hepatocyte growth factor (HGF), a pluripotent mediator with anti-fibrotic effects, is a candidate gene therapy for idiopathic pulmonary fibrosis for which current therapy is minimally effective. We examined human 11(hHGF) gene transfer by a unique gene delivery system using macroaggregated albumin-polyethylenimine conplex (MM-PEI). which induces lung specific gene expression without causing inflammation. lntravenous administration of MAA-PEI with 1 μg pCAG.hHGF (MAA-PEI+pCAG.hHGF) to C57BL/6 mice induced a level of hHGF expression in the lung equal to 10 μg of pCAG.hHGF alone, prolonged its expression only in the lung, and reduced the hHGF express ion in other organs. In situ RT-PCR revealed hHGF production in endothelial cells, alveolar macrophages, and alveolar epithelial cells, but not in airway epithelial cells. Inflammatory cytokines (TNF-α and IL-6) and collagen synthesis in the lungs after bleomycin injury were statistically decreased by MAA-PEI+pCAG.hHGF injection. Since regeneration of alveolar epithelial cells and capillary endothelial cells by bone marrow-derived stem cells after bleomycin-induced injury was unaffected by HGF, the primary anti-inflammatory and anti-fibrotic mechanism of HGF after lung injury is likely to be the inhibition of apoptosis, as suggested by in vitro experiments. These results indicate that this novel HGF gene transfer system may have promising clinical applications.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Ebina M, et al.: "Heterogeneous Increase of CD34-positive Alveolar Capillaries in Idiopathic Pulmonary Fibrosis."Am J Respir Crit Care Med. (印刷中). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimizugawa M, et al.: "Intratracheal gene transfer of decorin reduces subpleural fibroproliferation induced by bleomycin."Am J Physiol. 284. L526-L532 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ebina M, Shimizukawa M, et al.: "Heterogeneous Increase in CD34-positive Alveolar Capillaries in Idiopathic Pulmonary Fibrosis"Am J Respir Crit Care Med. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimizukawa M, Ebina M, et al.: "Intratracheal gene transfer of decorin reduces subpleural fibroproliferation induced by bleomycin"Am J Physiol. 284. L526-L532 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ebina M, et al.: "Heterogeneous Increase of CD34-positive Alveolar Capillaries in Idiopathic Pulmonary_Fibrosis"Am J Respir Crit Care Med. (印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimizugawa M, Ebina M, et al.: "Intratracheal gene transfer of decorin reduces subpleural fibroproliferation induced by bleomycm"Am J Physiol. 284. L526-L532 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Koinuma D, et al.: "Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7"EMBO J. 22. 6458-20 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kimura Y, et al.: "Expression of androgen receptor and 5alpha-reductase types 1 and 2 in early gestation fetal lung : a possible correlation with branching morphogenesis"Clin Sci (Lond). 105. 709-713 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakamura A, et al.: "Increased susceptibility to LPS-induced endotoxin shock in secretory leukoprotease inhibitor (SLPI)-deficient mice"J.Exp.Med.. 197. 669-674 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Inoue A, et al.: "Severe acute interstitial pneumonia possibly related to Gefitinib"Lancet. 361. 137-139 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 海老名雅仁, 貫和敏博: "呼吸器疾患(第2版):特発性間質性肺炎の慢性型(特発性肺線維症)の診断と治療"中外医学社(工藤翔二 永井厚志 編集). 279 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakamura A: "Increased Susceptibility to LPS-induced endotoxin shock in secretory leukoprotease inhibitor (SLPI)-deficient mice"Journal of Experimental Medicine. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Inoue A: "Severe acute interstitial pneumonia possibly related to gefinitib"Lancet. 361. 137-139 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kimura Y: "Retinoid receptors in the developing human lung"Clinical Science. 103. 613-621 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ebina M: "Towards an effective gene therapy for idiopathic pulmonary fibrosis"Chest. 121. 32-33 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Koinuma D: "Successful treatment of a case with rapidly progressive (BOOP)using cyclosprorin A and corticosteroid"Internal Medicine. 41. 26-29 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shimizukawa M: "Intratracheal gene transfer of decorin reduces subpleural proliferation induced by bleomycine"American Journal of Physiology. 284. 1526-1532 (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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