| Project/Area Number |
10470352
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Otorhinolaryngology
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| Research Institution | Chiba University |
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Principal Investigator |
KONNO Akiyoshi Chiba University, School of Medicine, Department of Otorhinolaryngology, Professor, 医学部, 教授 (70009497)
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| Co-Investigator(Kenkyū-buntansha) |
NAGATA Hiroshi Chiba University, School of Medicine, Department of Otorhinolaryngology, Lecturer, 医学部・付属病院, 講師 (20237530)
NUMATA Tsutomu Chiba University, School of Medicine, Department of Otorhinolaryngology, Lecturer, 医学部, 講師 (60189355)
TERADA Nobuhisa Chiba University, School of Medicine, Department of Otorhinolaryngology, Lecturer, 医学部, 講師 (70197797)
仲野 公一 千葉大学, 医学部, 助手 (50261920)
本杉 英昭 千葉大学, 医学部, 助手 (30292676)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 1999: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1998: ¥9,200,000 (Direct Cost: ¥9,200,000)
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| Keywords | allergic rhinitis / eosinophils / cytokine / chemokine / constructive cells in nasal mucosa / eotaxin / ケモカイン / E-カドヘリン / 鼻粘膜構築細胞 / アレルギー性炎症 / エオタキシン / RANTES / IL-5 / 上皮傷害 |
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| Research Abstract |
Eosinophil play a central role in the development of allergic diseases, including asthma, allergic rhinitis and atopic dermatitis. Eosinophil migration in vivo is regulated by many cytokines and chemokines. There is increasing evidence that eotaxin is a key mediator in the development of tissue eosinophila. We demonstrated that eotaxin upregulated the expression of intercellular dahesion molecule-1(ICAM-1) and vascular cells (HMMEC), but not human umbilical vein endothelial cells(HUVEC). The eotaxin-induced eosinophil adhesion to HMMEC was also increased. On HUVEC, however, eotaxin did not induce increases of eosinophil adhesion. Anti-ICAM-1 and anti-VCAM-1 mAbs significantly decreased eotaxin-induced eosinophil adhesion. These results suggest that eotaxin regulates eosinophil accumulation to the nasal mucosa through its effect on the adhesion molecules on microvascular endothelial cells.
We also indicated that IL-13, as well as IL-4, may be important in eotaxin mediated eosinophilic in
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flammation and that fibroblasts are the major cell source for eotaxin in nasal mucosa. Signal transduction through CCR3 depends on protein tyrosin kinase and extracellular calcium was also studied. In endothelial cells, the signaling pathway will be different form eosinophil and fibroblast. Eosinophils cultured with endothilial cells show different behavior from single culture by stimulus with eotaxin and eotaxin-2. This indicates there exists a certain established system seems to cause the signal transfer between eosinophils and endothelial cells.
In all patients with nasal allergy, eotaxin levels in nasal lavage fluids reached to the maximum value 30 min after antigen challenge and returned to the pre-challenge values 2hr after nasal antigen challenge. In the control group, however, no significant differences were noted in the eotaxin level between before antigen challenge and after antigen challenge. The levels of eotaxin in lavage samples correlated significantly with lavage levels of eosinophil counts and EPX. No relationship was observe between PAF and eosinophil counts or EPX, nor was there a relationship between IL-16 and eosinophil counts or EPX. These results strongly suggest that eotaxin is one of the most improtant factor in eosinophilic inflammation in nasal mucosa.
Unlike other eosinophil chemoattractants, eotaxin is eosinophil specific, because its specific receptor, CCR-3, is expressed on eosinophils but not on neutrophils. In this study we showed that IL-4 induces CCR-3 in dose dependent matter. It is well recognized that E-cadherin is a potent cell adhesion molecule indispensable in the maintenance of the structural and functional rigidity of the epithelium. We demonstrated that transepithelial migration of inflammatory cells can directly induce the decrease in epithelial E-cadherin expression. Furthemore, the most prominent change was induced by transmigration of activated eosinophils, which might be caused by some mechanisms independent of the eosinophil contents. The decrease in E-cadherin expression may trigger the damage of epithelial barrier, which contributes to the pathogenesis of allergic diseases. Less
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