Elucidation of the pathophysiology of eosinophilic chronic rhinosinusitis focusing on the action of coagulation factors on fibroblasts and eosinophils

• Project/Area Number: 16K11212
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Shimizu Shino 滋賀医科大学, 医学部, 医員 (50505592)
• Co-Investigator(Kenkyū-buntansha): 清水 猛史 滋賀医科大学, 医学部, 教授 (00206202)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 好酸球性副鼻腔炎 / 血液凝固因子 / 鼻茸線維芽細胞 / フィブロネクチン / TGF-beta / eotaxin / RANTES / EGF受容体インヒビター / 線維芽細胞 / トロンビン / 活性化第１０因子 / GM-CSF / fibronectin / PARs / 耳鼻咽喉科学 / 好酸球性鼻副鼻腔炎 / 凝固系因子

Outline of Final Research Achievements

Eosinophilic chronic rhinosinusitis is a refractory disease characterized by recurrent nasal polyps with eosinophil infiltration, sticky rhinorrhea, and olfactory disorder. In this study, we have shown that activated coagulation factors act on the nasal polyp fibroblasts to induce eosinophil infiltration and nasal tissue remodeling. It was found that EGF receptor is involved in the process. In addition, in the rat model, it was shown that systemic or intranasal topical administration of EGF receptor inhibitor suppresses eosinophilic inflammation in upper airways.

Academic Significance and Societal Importance of the Research Achievements

難治性疾患である好酸球性副鼻腔炎は、ステロイド以外に有効な保存的治療薬がない。どうして鼻茸がすぐに再発するのか、どうしてたくさんの好酸球が粘膜に浸潤するのかいまだ解明されていない。本研究の結果から、鼻茸の形成や好酸球浸潤の機序の一部を明らかにすることができた。このような研究を積み重ねることによって、将来的に新しい治療薬が開発される可能性がある。好酸球性副鼻腔炎患者が、繰り返し手術を受けたり長期にステロイドを服用しなくても済むようになるかもしれない。

Research Products

• [Journal Article] The epidermal growth factor receptor inhibitor AG1478 inhibits eosinophilic inflammation in upper airways (2018)
  • Author(s): Shimizu Shino, Takezawa-Yasuoka Kumiko, Ogawa Takao, Tojima Ichiro, Kouzaki Hideaki, Shimizu Takeshi
  • Journal Title: Clinical Immunology Volume: 188 Pages: 1-6
  • DOI: 10.1016/j.clim.2017.11.010
  • Peer Reviewed
• [Journal Article] Thrombin and activated coagulation factor X stimulate the release of cytokines and fibronectin from nasal polyp fibroblasts via protease-activated receptors (2017)
  • Author(s): Shimizu S, Tojima I, Takezawa K, Matsumoto K, Kouzaki H, Shimizu T
  • Journal Title: Am J Rhinol Allergy Volume: 31 Issue: 1 Pages: 13-18
  • DOI: 10.2500/ajra.2017.31.4400
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 上気道炎症における組織リモデリングとその制御 (2018)
  • Author(s): 清水志乃
  • Organizer: 第67回日本アレルギー学会学術大会
  • Invited
• [Presentation] Role of eosinophils in pathophysiology of eosinophilic CRS (2017)
  • Author(s): Takeshi Shimizu
  • Organizer: The 9th annual meeting of the Thai Rhinologic Society
  • Int'l Joint Research / Invited
• [Presentation] Role of infiltrating eosinophils in pathophysiology of CRS (2017)
  • Author(s): Takeshi Shimizu
  • Organizer: Rhinology World Congress Hong Kong
  • Int'l Joint Research / Invited
• [Presentation] 上気道炎症の組織リモデリングにおける凝固系因子と好酸球の役割 (2016)
  • Author(s): 清水志乃
  • Organizer: 日本鼻科学会
  • Place of Presentation: 宇都宮市
  • Year and Date: 2016-10-13
  • Invited