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In vivo gene transfer study for pathogenesis of lung injury. Endothelin and development of obliterative bronchiolitis

Research Project

Project/Area Number 09671378
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Thoracic surgery
Research InstitutionOsaka University

Principal Investigator

TAKEDA Shin-ichi  Osaka University Graduate School of Medicine, Assistant Professor, 医学部, 助手 (30236468)

Co-Investigator(Kenkyū-buntansha) YOON Hyung-eun  Osaka University Graduate School of Medicine Osaka, Assistant Professor, 医学部, 助手 (50283768)
OKUMURA Meinosin  Osaka University Graduate School of Medicine, Assistant Professor, 医学部, 助手 (40252647)
MINAMI Masato  Osaka University Graduate School of Medicine, Assistant Professor, 医学部, 助手 (10240847)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1998: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1997: ¥3,200,000 (Direct Cost: ¥3,200,000)
KeywordsIn vivo gene transfer / Obliterative bronchiolitis / Endothelin-1(ET-1) / Lung transplantation / 生体内遺伝子導入 / Enclothelin(ET) / Bronchiolitis obliterans / Gene Transfer / HVJ / Lung transplantation / Endothelin / Bronchiolitis Obliterans / Gene Trasnfer
Research Abstract

Background. Obliterative bronchiolitis (OB) is a lesion that results when injury to small conducting airways is repaired by a proliferation of fibrous granulation tissue. OB has emerged as a main cause of morbidity and mortality in the setting of lung and heart-lung transplantation. Endothelin-1 (ET-1) initially discovered as a vasoconstrictive peptide, has a mitogenic activity on vascular smooth cells and airway epithelial cells. Overproduction of endothelin has been reported in patients with OB or chronic rejection after lung transplantation. It is still undetermined whether locally overexpressed ET-1 has a potential impact in the pathogenesis of OB. Methods. We locally overexpressed ET-1 using ultraviolet irradiation-inactivated hemagglitinating virus of Japan (HVJ)-liposome-mediated in vivo gene transfer. Plasmid DNA of prepro-ET-1 and high mobility group 1 (HMG1) protein were co-encapsulated in liposomes, and were introduced into airway epithelial cells by HVJ-mediated membrane fu … More sion. Control animals received instillation of HVJ-liposome with an empty expression cassette. To confirm the efficiency of transfection, HVJ liposome with β-galactosidase gene was introduced. The expression of ET-1 and β-galactosidase was assessed by histochemistry. Results. Bronchial epithelium alveolar cells and alveolar macrophage were stained blue (X-Gal) 1 week after in vivo gene transfer of β-gene, indicating β-gal activity. In animals 1 to 2 weeks after in vivo transfection of prepro-ET-1 gene, hyperplastic connective tissue plaque was seen in the alveolar duet and small conducting airway, indicating histologically distinctive bronchiolitis obliterans. Strong ET-1 like immunoactivies were seen in the airway epithelial, hyperplastic connective tissue and alveolar cells. No histopathologic changes were seen in the control animals. Summary and Future Direction. This result first suggests that ET-1 may have an important role in pathogenesis of OB presumably in the "common final pathway". However, the mechanism of mitogenic signaling by ET-1, its regulation of fibroblast proliferation, and its interaction with other cytokines or growth factors remained to be clarified at present. Further studies are needed to ascertain the specific role of ET-1 in the progression of OB. In summary, we conclude that local overexpression of ET-1 has a key role in the pathogenesis of OB. This evidence suggests the potential clinical implication that a pharmacological antagonist or inhibitor may be able to control the progression of this disease in patients with OB. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (9 results)

All Other

All Publications (9 results)

  • [Publications] Shin-ichi_Takeda, Yoshiki Sawa, Masato Minami, Yasufumi Kaneda, Yoshitaka Fujii, Ryota Shirakura, Masashi Yanagisawa, Hikaru Matsuda: "Experimental bronchiolitis obliterans induced by in vivo HVJ liposome-mediated endothelin-1 gene transfer"Ann Thorac Surg. 63. 1562-1567 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shin-ichi_Takeda, Shinichiro Miyoshi, Ken-ichi Omori, Tomoki Utsumi, Shigetoyo Kogaki, Yoshiki Sawa, Masashi Yanagisawa Hikara Matsuda.: "Pulmonary disease models induced by in vivo hemagglutinating virus of Japan liposome-mediated endothelin-1 gene transfer"J Cardiovasc Pharmacol. 31. 336-8 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shinichi Takeda: "Pulnonary disease models induced by in vivo HVJ-liposer・・・・" J cardiovon Pharmacology. 31. S336-S338 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hiroki Kisina: "Microvascular permeability of the non-heart-beating rabbit lung・・・" Amals of Thoracic Surgery. 65. (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shinichiro Miyoshi: "Chest size matching in single and double lung transplantation" Jpn J Thoracic Cardiovascular Surgery. (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shinichi Takeda: "Clinical spectrum of congenital cystic disease of the lung in children" Eur J Cardio-thoracic Surgery. 15. 11-17 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] S.Takeda et al: "Experimental branchiolitis induced..." Amals of Thoratic Surgery. 65. 1562-1567 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] S.Takeda et al: "Endothelin and lung disease models" J Carodiovascular Pharmacology. 31. S336-S338 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] S.Takeda et al: "In vivo assasant of change ain and tissue volume after precomonatoy" J Applied Physiology. 82. 1340-1348 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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