• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Molecular mechanisms of apoptotic pathway in the pathogenesis of bleomycin-induced scleroderma

Research Project

Project/Area Number 16591090
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Dermatology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

YAMAMOTO Toshiyuki  Tokyo Medical and Dental University, Department of Dermatology, Part-time lecturer, 医学部附属病院, 非常勤講師 (30242192)

Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Keywordsscleroderma / animal model / bleomycin / apoptosis / fibrosis / 皮膚硬化
Research Abstract

To elucidate the role of apoptosis in scleroderma, we examined the induction of apoptosis and expression of Fas, Fas ligand (FasL), as well as caspase-3 in a murine model of bleomycin-induced scleroderma. Effect of systemic in vivo neutralization of FasL on the development of scleroderma was also investigated. Dermal sclerosis was induced by repeated local injections of bleomycin (1mg/mL) in C3H/HeJ mice. Induction of apoptosis was examined by TUNEL assay and DNA gel electrophoresis. TUNEL positivity was prominently detected on keratinocytes and infiltrating mononuclear cells, but not endothelial cells and fibroblasts, in the lesional skin following bleomycin treatment. DNA fragmentation revealed laddering at 3 to 4 week following bleomycin treatment. Immunohistochemistry showed increased expression of Fas in infiltrating mononuclear cells at early phase following bleomycin exposure, whereas constitutive expression in fibroblasts. FasL expression was increased in mononuclear cells as w … More ell as fibroblasts in the sclerotic skin. Results of RT-PCR analysis revealed that expression of FasL mRNA was upregulated and reached a maximum at 3 week, whereas Fas mRNA was continuously detected. mRNA expression as well as activity of caspase-3 was also enhanced at 3 week after bleomycin treatment. Administration of neutralizing anti- FasL antibody together with local bleomycin treatment reduced the development of dermal sclerosis, in association with the reduction of TUNEL-positive mononuclear cells infiltrating in the dermis and aso with the blockade of apoptosis. To further investigate the role of Fas/FasL pathway in the oathogenesis of scleroderma, we examined whether the induction of dermal sclerosis is suppressed in Fas-deficient (lpr) and Fasl-deficient (gld) mice. Results of histological examination showed that the induction of dermal sclerosis was significantly suppressed in both lpr and gld mice by bleomycin treatment. Collagen contents in the skin and TUNEL-positive infiltrating cells were significantly reduced in both lpr and gld mice, as compared with wild-type. These findings suggest that Fas/FasL pathway is an important contributor involved in the pathophysiology of bleomycin-induced scleroderma. Less

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (22 results)

All 2006 2005 2004 Other

All Journal Article (21 results) Book (1 results)

  • [Journal Article] The bleomycin-induced scleroderma model : What have we learned for scleroderma pathogenesis?2006

    • Author(s)
      Yamamoto T.
    • Journal Title

      Arch Dermatol Res 297

      Pages: 333-344

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Cellular and molecular mechanisms of bleomycin-induced murine scleroderma : Current update and future perspective2005

    • Author(s)
      Yamamoto T., Nishioka K.
    • Journal Title

      Exp Dermatol 14

      Pages: 81-95

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Characteristics of animal models of scleroderma2005

    • Author(s)
      Yamamoto T.
    • Journal Title

      Curr Rheumatol Rev 1

      Pages: 101-109

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Increased expression of p53 and p21 (Waf1/Cip1) in the lesional skin of bleomycin-induced scleroderma2005

    • Author(s)
      Yamamoto T., Nishioka K.
    • Journal Title

      Arch Dermatol Res 296

      Pages: 509-513

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cellular and molecular mechanisms of bleomycin-induced murine scleroderma Current update and future perspective.2005

    • Author(s)
      Yamamoto T, Nishioka K.
    • Journal Title

      Exp Dermatol 14

      Pages: 81-95

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Characteristics of animal models for scleroderma.2005

    • Author(s)
      Yamamoto T.
    • Journal Title

      Current Rheumatol Rev 1

      Pages: 101-109

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Icreased expression of p53 and p21(Waf1/Cip1) in the lesional skin of bleomycin-induced scleroderma.2005

    • Author(s)
      Yamamoto T, Nishioka K.
    • Journal Title

      Arch Dermatol Res 296

      Pages: 509-513

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Plasminogen activator inhibitor-1 is elevated, but not essential, in the development of bleomycin-induced murine scleroderma.2005

    • Author(s)
      Matsushita M, Yamamoto T, Nishioka K.
    • Journal Title

      Clin Exp Immunol 139

      Pages: 429-438

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cellular and molecular mechanisms of bleomycin-induced murine scleroderma : Current update and future perspective2005

    • Author(s)
      Yamamoto T, Nishioka K.
    • Journal Title

      Exp Dermatol 14

      Pages: 81-95

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Increased expression of p53 and p21 (Waf1/Cip1) in the lesional skin of bleomycin-induced scleroderma2005

    • Author(s)
      Yamamoto T, Nishioka K.
    • Journal Title

      Arch Dermatol Res 296

      Pages: 509-513

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Plasminogen activator inhibitor-1 is elevated, but not essential, in the development of bleomycin-induced murine scleroderma2005

    • Author(s)
      Matsushita M, Yamamoto T, Nishioka K.
    • Journal Title

      Clin Exp Immunol 139

      Pages: 429-438

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Characteristics of animal models for scleroderma2005

    • Author(s)
      Yamamoto T.
    • Journal Title

      Curr Rheumatol Rev 1

      Pages: 101-109

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cellular and molecular mechanisms of bleomycin-induced murine scleroderma :_Current update and future perspective2005

    • Author(s)
      Yamamoto T, et al.
    • Journal Title

      Exp Dermatol 14

      Pages: 81-95

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Possible role of apoptosis in the pathogenesis of bleomycin-induced scleroderma2004

    • Author(s)
      Yamamoto T., Nishioka K.
    • Journal Title

      J Invest Dermatol 122

      Pages: 44-50

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Possible role of apoptosis in the pathogenesis of bleomycin-induced scleroderma.2004

    • Author(s)
      Yamamoto T, Nishioka K.
    • Journal Title

      J Invest Dermatol 122

      Pages: 44-50

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Upregulation of interleukin-13 and its receptor in a murine model of bleomycin-induced scleroderma.2004

    • Author(s)
      Matsushita M, Yamamoto T, Nishioka K.
    • Journal Title

      Int Arch All Immunol 135

      Pages: 348-356

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Possible role of apoptosis in the pathogenesis of bleomycin-induced scleroderma2004

    • Author(s)
      Yamamoto T, et al.
    • Journal Title

      J Invest Dermatol 122

      Pages: 44-50

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Animal model of sclerotic skin. VI : Evaluation of bleomycin-induced skin sclerosis in nude mice2004

    • Author(s)
      Yamamoto T, et al.
    • Journal Title

      Arch Dermatol Res 295

      Pages: 453-456

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Role of cytokines in scleroderma : Use of animal models

    • Author(s)
      Yamamoto T. et al.
    • Journal Title

      Clin Appl Immunol Rev (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Role of cytokines in the pathogenesis of scleroderma : Use of animal models.

    • Author(s)
      Yamamoto T, Matsushita M, Yokozeki H.
    • Journal Title

      Gun Appl Immunol Rev (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Bleomycin and the skin.

    • Author(s)
      Yamamoto T.
    • Journal Title

      Br J Dermatol (accepted)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] Animal models of human inflammatory skin diseases2004

    • Author(s)
      Yamamoto T.
    • Publisher
      CRC Press
    • Related Report
      2004 Annual Research Report

URL: 

Published: 2004-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi