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PATHOPHYSIOLOGICAL ANALYSIS OF BRONCHIOLITIS OBLITERANCE USING CD40-DEFICIENT MICE AND GFP-TRANSGENIC MICE

Research Project

Project/Area Number 15590804
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

HASEGAWA Yoshinori  NAGOYA UNIVERSITY, UNIVERSITY HOSPITAL, ASSISTANT PROFESSOR, 医学部附属病院, 講師 (20270986)

Co-Investigator(Kenkyū-buntansha) KAWABE Tsutomu  NAGOYA UNIVERSITY, SCHOOL OF MEDICINE, RESEARCH ASSOCIATE, 医学部, 助手 (20378219)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsBronchiolitis Obliterance / CD40-Gene deficient mice / Sauropus Androgynus / TNF-α / CXCL9 / CXCL10 / CD40 / 遺伝子欠損マウス / 肺胞マクロファージ
Research Abstract

Cases of constrictive bronchiolitis obliterans(BO) have been reported involving patients with bone marrow transplants and heart/lung transplants as well as those with rheumatoid arthritis with or without penicillamine treatment. Although constrictive BO was a relatively rare disease, it has recently become the focus of renewed interest because the number of allograft recipients such as bone marrow and heart/lung transplants has been increasing. To investigate the pathogenesis of BO, we focused on the establishment of mouse experimental mode for BO and the role of CD40 molecule and the bone marrow-derived progenitor cells. Further, we investigate the Sauropus Androgynus-induced BO. When wild-type(WT) mice and CD40KO mice were injected intratracheally with LPS, LPS-induced lung injury was significantly reduced in CD40KO mice. Further, LPS-induced inducible nitric oxide synthase(iNOS) expression and nitric oxide(NO) production was also inhibited in the lungs of CD40KO mice. In addition, t … More he release of inflammatory mediators, that is, TNF-α,IL-1b, macrophage inflammatory protein 2(MIP-2), reactive oxygen, nitrogen intermediates and MMP-9 into the bronchoalveolar lavage fluid, was significantly reduced in CD40KO mice. We studied the function of alveolar macrophages(AMf) in each of mice ex vivo. Although iNOS in WT AMf was induced in response to LPS, no iNOS expression could be detected in CD40KO AMf. In addition, we examined the role of bone marrow-derived progenitor cells in bleomycin-induced pulmonary inflammation using GFP bone marrow chimera mice. Induction of pulmonary inflammation resulted in the increase of GFP+ cells accumulated into the active fibrotic lesions. GFP+ cells also expressed type I collagen. Further, we stimulated the monocyte derived cell lines of U937 with Sauropus Androgynus, which is a leaf shrub for the cause of BO. We found the production of TNF-α, but not CXCL9 or CXCL10. These results indicated that TNF-α might be one of important factor for the pathogenesis of BO. Our data suggest that the functional blockade of CD40 or bone marrow-derived progenitor cells would yield one of the targets for the clinical treatment for lung injury including BO. Less

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (12 results)

All 2005 2004 2003 Other

All Journal Article (10 results) Publications (2 results)

  • [Journal Article] Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity.2005

    • Author(s)
      Kitagawa C, Hasegawa, Y, et al.
    • Journal Title

      Pharmacogenetics and Genomics 15

      Pages: 35-41

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Genetic Polymorphism in the Phenobarbital-responsive Enhancer Module of the UDP-Glucuronosyltransferase 1A1 Gene and Irinotecan Toxicity.2005

    • Author(s)
      Kitagawa C, Ando M, Ando Y, Sekido Y, Wakai K, Imaizumi K, Shimokata K, Hasegawa Y.
    • Journal Title

      Pharmacogenet Genomics 15

      Pages: 35-41

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] CD40 plays a crucial role in lipopolysaccharide-induced acute lung injury.2004

    • Author(s)
      Hashimoto N, Hasegawa, Y, et al.
    • Journal Title

      American Journal of Respiratory Cell and Molecular Biology 30

      Pages: 808-815

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Rapid Detection of UGT1A1 Gene Polymorphisms by Newly Developed Invader Assay.2004

    • Author(s)
      Hasegawa, Y, et al.
    • Journal Title

      Clinical Chemistry 50

      Pages: 1479-1480

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Krupple-like factor 6 is frequently down-regulated and induces apoptosis in non-small cell lung cancer cells.2004

    • Author(s)
      Ito G, Hasegawa, Y, et al.
    • Journal Title

      Cancer Research 64

      Pages: 3838-3848

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] CD40 plays a crucial role in lipopolysaccharide-induced acute lung injury.2004

    • Author(s)
      Hashimoto N, Kawabe T, Imaizumi K, Hara T, Okamoto M, Kojima K, Shimokata K, Hasegawa Y.
    • Journal Title

      Am J Respir Cell Mol Biol 30

      Pages: 808-815

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Rapid Detection of UGT1A1 Gene Polymorphisms by Newly Developed Invader Assay.2004

    • Author(s)
      Hasegawa Y, Sarashina T, Ando M, Kitagawa C, Mori A, Yoneyama M, Ando Y, Shimokata K.
    • Journal Title

      Clinical Chemistry 50

      Pages: 1479-1480

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Krupple-like factor 6 is frequently down-regulated and induces apoptosis in non-small cell lung cancer cells.2004

    • Author(s)
      Ito G, Uchiyama M, Kondo M, Mori S, Usami N, Maeda O, Kawabe T, Hasegawa Y, Shimokata K, Sekido Y.
    • Journal Title

      Cancer Res 64

      Pages: 3838-3843

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] GADD34 induces p53 phosphorylation and p21/WAF1 transcription.2003

    • Author(s)
      Yagi A, Hasegawa, Y, et al.
    • Journal Title

      Journal of Cellular Biochemistry 90

      Pages: 1242-1249

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] GADD34 induces p53 phosphorylation and p21/WAF1 transcription.2003

    • Author(s)
      Yagi A, Hasegawa Y, Xiao H, Haneda M, Kojima E, Nishikimi A, Hasegawa T, Shimokata K, Isobe K.
    • Journal Title

      J Cell Biochem 90

      Pages: 1242-1291

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] UNO, Y.et al.: "Characterization of six base pair deletion in the putative HNF-1 binding site of human PXR promoter"J.Hum.Genet.. 48. 594-597 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] HASHIMOTO, N. et al.: "CD40 Plays a critical role in LPS-induced acute lung injury"Am.J.Respir.Cell.Mol.Biol.. (in press).

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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