2005 Fiscal Year Final Research Report Summary
Regulation of airway inflammation and remodeling by chemokines in bronchial asthma
| Project/Area Number |
15591044
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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 |
膠原病・アレルギー・感染症内科学
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| Research Institution | Teikyo University |
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Principal Investigator |
ADACHI Tetsuya Teikyo University School of Medicine, Dept.of Internal Medicine, Assistant Professor, 医学部, 講師 (30321996)
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| Co-Investigator(Kenkyū-buntansha) |
OHTA Ken , 医学部, 教授 (30160500)
CHIHARA Junichi Akita University School of Medicine, Dept.of Clinical and Laboratory Medicine, Professor, 医学部, 教授 (80197615)
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| Project Period (FY) |
2003 – 2005
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| Keywords | bronchial asthma / remodeling / bronchial epithelial cell / eosinophil / cytokine / chemokine / signal transduction |
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| Research Abstract |
Eotaxin possesses a chemotactic activity for eosinophils, which is a central mechanism in the pathogenesis of asthma. Epidermal growth factor (EGF), a key molecule in airway remodeling, is transactivated via several G protein-coupled receptors (GPCRs) in cancer cells. We have previously found that bronchial epithelial cells express CCR3 whose stimulation activates MAP kinases. In 2003, we found that the MAP kinase activation is mediated via EGF receptor (EGFR). The EGFR activation was essential for IL-8 production.
In 2004, we applied the model of receptor tyrosine kinase (RTK) transactivation in eosinophils. It has recently been shown that eosinophils, effecter cells in asthma, play an important role in airway remodeling. Eosinophils from some donors express platelet-derived growth factor receptor (PDGFR) in mRNA and protein levels. After pretreatment of eosinophils with the PDGFR inhibitor AG1295, the eotaxin-induced MAP kinase activation and chemotaxis were significantly abrogated.
In 2005, we examined the in vivo effect of an EGFR inhibitor AG1478 on airway inflammation and remodeling in a murine model of asthma. The ovalbumin-induced eosinophil influx in bronchoalveolar lavage fluid was reduced by pretreatment of AG 1478. In the histological findings, AG1478 significantly inhibited eosinophil infiltration, airway wall thickness, and mucus production from epithelial cells. These results suggest that EGFR has a critical role in airway inflammation and remodeling.
In the 3 years' term, we investigated the regulation of allergic inflammation and remodeling modified by chemokines. Especially the RTK transactivation is a new concept in the regulation of allergy, leading to its application in new therapeutic strategy.
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Research Products
(3 results)
