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The suppressive effect of activated protein C on chronic inflammatory lung disease caused by bone marrow-derived fibroblasts

Research Project

Project/Area Number 17590788
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

GABAZZA Esteban  Mie University, Department of Medicine, Professor and Chairman, 大学院医学系研究科, 教授 (00293770)

Co-Investigator(Kenkyū-buntansha) TAGUCHI Osamu  Mie University hospital, Lecturer, 医学部附属病院, 講師 (90197244)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsActivated protein C / Bone marrow / Growth factors / Lung fibrosis / Fibroblasts / Extracellular matrix / Pulmonary hypertension / Chemokines / 線維芽細胞 / プロテインCインヒビター / 骨髄細胞 / 細胞内伝達機構 / 炎症性サイトカイン / 活性化プロテインCレセプター / 実験動物モデル
Research Abstract

Chronic inflammatory lung diseases including pulmonary hypertension, interstitial lung diseases and pulmonary fibrosis have currently no therapy and patients with these disorders have poor prognosis. The excessive production and secretion of extracellular matrix components such as collagen, fibronectin, entactin and tenascins by fibroblasts play a fundamental role in the pathogenesis of intractable chronic inflammatory lung diseases. Recently, it has been shown that fibroblasts that accumulate in the fibrotic pulmonary tissues derived from bone marrow. However, the mechanism by which fibroblasts are activated and subsequently recruited into the lungs remains unknown. In the present study, we focused on the anti-inflammatory activity of activated protein C and evaluated whether activated protein C is able to affect the motility and recruitment of fibroblasts in the lungs and their ability to secrete components of the extracellular matrix. The results of this investigation showed that activated protein C is able to inhibit in vitro the secretion of growth factors (platelet-derived growth factor), and chemokines including macrophage inflammatory protein-la, monocyte chemoattractant protein-1 and stromal-derived growth factor-1 from fibroblasts, epithelial and endothelial cells. In vivo experiments showed that activated protein C blocks the recruitment of fibroblasts and the secretion of inflammatory cytokines from lung structural cells. Overall, this study shows that activated protein C is capable of suppressing the activation of fibroblasts, suggesting that this mechanism is responsible for the inhibitory activity of activated protein C on chronic inflammatory pulmonary diseases.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (23 results)

All 2006 2005

All Journal Article (19 results) Book (2 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] Protective role of protein C inhibitor in monocrotaline-induced pulmonary hypertension2006

    • Author(s)
      Yoichi Nishii
    • Journal Title

      Journal of Thrombosis and Haemostasis 4・11

      Pages: 2331-2339

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Decreased protein C activation in patients with fulminant hepatic failure2006

    • Author(s)
      Michihiko Yamaguchi
    • Journal Title

      Scandinavian Journal of Gastroenterology 41・3

      Pages: 331-337

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Lipopolysaccharide-induced decreased protein S expression in liver cells is mediated by MEK/ERK signaling and NFkappaB activation : involvement of membrane-bound CD14 and toll-like receptor-42006

    • Author(s)
      Tatsuya Hayashi
    • Journal Title

      Journal of Thrombosis and Haemostasis 4・8

      Pages: 1763-1773

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Thrombin-activatable fibrinolysis inhibitor deficiency attenuates bleomycin-induced lung fibrosis2006

    • Author(s)
      Hajime Fujimoto
    • Journal Title

      American Journal of Pathology 168・4

      Pages: 1086-1096

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Intratracheal gene transfer of tissue factor pathway inhibitor attenuates pulmonary fibrosis2006

    • Author(s)
      Naoki Kijiyama
    • Journal Title

      Biochemical and Biophysical Research Communications 339・4

      Pages: 1113-1119

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Protective role of protein C inhibitor in monocrotaline-induced pulmonary hypertension2006

    • Author(s)
      Nishii Y
    • Journal Title

      J Thromb Haemostas 4(11)

      Pages: 2331-2339

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Decreased protein C activation in patients with fulminant hepatic failure2006

    • Author(s)
      Yamaguchi M
    • Journal Title

      Scand J Gastroenterol 41(3)

      Pages: 331-337

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Lipopolysaccharide-induced decreased protein S expression in liver cells is mediated by MEK/ERK signaling and NFkappaB activation : involvement of membrane-bound CD14 and toll-like receptor-42006

    • Author(s)
      Hayashi T
    • Journal Title

      J Thromb Haemostas 4(8)

      Pages: 1763-1773

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Thrombin-activatable fibrinolysis inhibitor deficiency attenuates bleomycin-induced lung fibrosis2006

    • Author(s)
      Fujimoto H
    • Journal Title

      Am J Pathol 168(4)

      Pages: 1086-1096

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Intratracheal gene transfer of tissue factor pathway inhibitor attenuates pulmonary fibrosis2006

    • Author(s)
      Kijiyama N
    • Journal Title

      Biochem Biophys Res Commun 339(4)

      Pages: 1113-1119

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Deficiency of tenascin C attenuates allergen-induced bronchial asthma in the mouse2006

    • Author(s)
      Hiroki Nakahara
    • Journal Title

      European Journal of Immunology 36・12

      Pages: 3334-3345

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Histamine type 1 receptor deficiency reduces airway inflammation in murine asthma model2006

    • Author(s)
      Kenichi Miyamoto
    • Journal Title

      International Archives of Allergy and Immunology 140・3

      Pages: 215-222

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Differential regulation of protein S expression in hepatocytes and sinusoidal endothelial cells in rats with cirrhosis2006

    • Author(s)
      K Fuji
    • Journal Title

      Journal of Thrombosis and Haemostasis 4・12

      Pages: 2607-2615

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Thrombin-activatable fibrinolysis inhibitor deficiency attenuates bleomycin-induced lung fibrosis.2006

    • Author(s)
      Hajime Fujimoto
    • Journal Title

      American Journal of Pathology 168:4(印刷中)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Intratracheal gene transfer of tissue factor pathway inhibitor attenuates pulmonary fibrosis.2006

    • Author(s)
      Naoki Kijiyama
    • Journal Title

      Biochemical and Biophysical Research Communications 339:4

      Pages: 1113-1119

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Anti-inflammatory effect of activated protein C in gastric epithelial cells2005

    • Author(s)
      Misaki Nakamura
    • Journal Title

      Journal of Thrombosis and Haemostasis 3・12

      Pages: 2721-2729

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Anti-inflammatory effect of activated protein C in gastric epithelial cells2005

    • Author(s)
      Nakamura M
    • Journal Title

      J Thromb Haemostas 3(12)

      Pages: 2721-2729

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Anti-inflammatory effect of activated protein C in gastric epithelial cells.2005

    • Author(s)
      Misaki Nakamura
    • Journal Title

      Journal of Thrombosis and Haemostasis 3:12

      Pages: 2721-2729

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Vacuolating cytotoxin A is associated with increased thrombin generation in gastric mucosa.2005

    • Author(s)
      Yuko Suzuki
    • Journal Title

      Helicobaster 10:4

      Pages: 323-331

    • Related Report
      2005 Annual Research Report
  • [Book] Encyclopedia of Respiratory Medicine2006

    • Author(s)
      Esteban C Gabazza
    • Total Pages
      2576
    • Publisher
      Elsevier
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Book] Encyclopedia of Respiratory Medicine2006

    • Author(s)
      Esteban Gabazza
    • Publisher
      Elsevier社(印刷中)
    • Related Report
      2005 Annual Research Report
  • [Patent(Industrial Property Rights)] SCHERING AKTIENGESELLSCHAFT2005

    • Inventor(s)
      Esteban C Gabazza, その他
    • Industrial Property Rights Holder
      SCHERING AKTIENGES ELLSCHAFT
    • Filing Date
      2005
    • Acquisition Date
      2005-10-03
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Patent(Industrial Property Rights)] SCHERING AKTIENGESELLSCHAFT2005

    • Inventor(s)
      Esteban C Gabazza, その他
    • Industrial Property Rights Holder
      SCHERING AKTIENGES ELLSCHAFT
    • Filing Date
      2005
    • Acquisition Date
      2005-10-03
    • Related Report
      2006 Annual Research Report

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Published: 2005-04-01   Modified: 2021-04-07  

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