| Project/Area Number |
17590782
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
DOHI Makoto The University of Tokyo, Faculty of Medicine,, Assistant professor (60222155)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Ryoichi the University of Tokyo, Faculty of Medicine, Research Associate (60272556)
YAMAMOTO Kazuhiko the University of Tokyo, Faculty of Medicine, Professor (80191394)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥300,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | bronchial asthma / interleukin 10 / airway remodeling / hydroxyproline / mouse model / リモデリング / ハイドロキシプロン / 肺線維化 / TGF-β / ブレオマイシン / 肺胞マクロファージ / 樹状細胞 / 遺伝子治療 |
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| Research Abstract |
In this project, we investigated whether interleukin (IL)-10 suppresses experimental allergic airway inflammation by suppressing dendritic cell functions. Balb/c mice were immunized and aerosol challenged with ovalbumin (OVA). We delivered the IL-10 gene to the mice before systemic sensitization or during aerosol challenge. Both presensitization delivery and delivery during inflammation suppressed airway eosinophilia and airway hyperreactivity. IL-10 gene delivery suppressed overall functions of CD11c+antigen presenting cells in the lung such as antigen-presenting capacity, cytokine production, and transportation of OVA antigen to lymph node. Next we examined whether IL-10 suppresses fibrosing process in the lung. Bleomycin was administered to C57/B16 mice and lung fibrosis was induced. IL-10 was introduced to the system on day 1 after bleomycin treatment by intravenous injection of IL-10 producing plasmid. IL-10 delivery did not affect bleomycin-induced lung inflammation, but it signi
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ficantly attenuated lung fibrosis. IL-10 reduced production and activation of transforming growth factor beta (TGF-β). It also down-regulated the expression of αvβ6 integrin that plays an important role in the activation of TGF-β. As alveolar macrophages were major cell source of TGF-β production in the lung, we next analyzed the effect of IL-10 on TGF-β production of alveolar macrophages. Results of ex vivo and in vitro studies demonstrated that IL-10 suppressed the production of TGF-β from alveolar macrophages. Finally we found that even when delivered during the fibrosig phase, IL-10 gene delivery significantly suppressed pathological findings, hydroxyproline content, and production of TGF-β in the lung. Taken together, the results obtained from the project strongly suggest that IL-10 delivery could be a new therapeutic approach to severe asthma with remodeling of the airway. To further investigate the effect of IL-10 on airway remodeling, appropriate experimental model that can correctly evaluate the indicators of remodeling should be developed in future. Less
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