Investigation of mechanisms of airway remodeling responsible for severe bronchial asthma: possible involvement of epithelial mesenchymal transition

• Project/Area Number: 23591471
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: 独立行政法人国立病院機構三重病院(臨床研究部)
• Principal Investigator: FUJISAWA Takao 独立行政法人国立病院機構三重病院(臨床研究部), その他部局等, 教授 (20511140)
• Co-Investigator(Kenkyū-buntansha): HOSOKI Koua 独立行政法人国立病院機構三重病院, 臨床 研究部, その他 (90422831) ; TODA Masaaki 三重大学, 医学(系)研究科(研究院), 講師 (10202201) ; GABAZZA Esteban 三重大学, 医学(系)研究科(研究院), 教授 (00293770)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 気管支喘息 / 好酸球 / 気道リモデリング / 上皮間葉間移行 / Bronchial asthma / eosinophils / airway remodeling / 上皮間葉移行 / TGF-β1 / 喘息 / ＴＧＦ-β１

Research Abstract

Eosinophilic inflammation and remodeling of the airways are characteristic pathology of bronchial asthma. Epithelial to mesenchymal transition(EMT) plays a critical role in airway remodeling. We hypothesized that infiltrating eosinophils directly induce EMT. EMT was assessed in mice that were intratracheal instilled mouse bone marrow derived eosinophils and in human bronchial epithelial cells co-cultured with eosinophils purified from healthy individuals or with eosinophilic leukemia cell lines. EMT was induced in bronchial epithelial cells co-cultured with human eosinophils and associated with increased expression of TGF-beta1 and Smad3 phosphorylation in the bronchial epithelial cells.Intratracheal instillation of eosinophils caused enhanced fibrosis and increased lung concentration of TGF-beta1. Treatment with anti-TGF-beta1 antibody and siRNA blocked the development of EMT in bronchial epithelial cells. Eosinophils may contribute to the pathogenesis of airway remodeling through EMT

Research Products

• [Journal Article] Montelukast suppresses epithelial to mesenchymal transition of bronchial epithelial cells induced by eosinophils (2014)
  • Author(s): Hosoki K, Kainuma K, Toda M, Harada E, Chelakkot-Govindalayathila AL, Roeen Z, Nagao M, D'Alessandro-Gabazza CN, Fujisawa T, Gabazza EC
  • Journal Title: BiochemBiophysResCommun Volume: 449 Pages: 351-356
• [Journal Article] Eosinophils promote epithelial to mesenchymal transition of bronchial epithelial cells (2013)
  • Author(s): Yasukawa A, Hosoki K, Toda M, Miyake Y, Matsushima Y, Matsumoto T, Boveda-Ruiz D, Gil-Bernabe P, Nagao M, Sugimoto M, Hiraguchi Y, Tokuda R, Naito M, Takagi T, D'Alessandro-Gabazza CN, Suga S, Kobayashi T, Fujisawa T, Taguchi O, Gabazza EC
  • Journal Title: PLoS One Volume: 8
• [Journal Article] Eosinophils promote epithelial to mesenchymal transition of bronchial epithelial cells. (2013)
  • Author(s): Yasukawa A, Hosoki K, Toda M, Miyake Y, Matsushima Y, Matsumoto T, Boveda-Ruiz D, Gil-Bernabe P, Nagao M, Sugimoto M, Hiraguchi Y, Tokuda R, Naito M, Takagi T, D'Alessandro-Gabazza CN, Suga S, Kobayashi T, Fujisawa T, Taguchi O, Gabazza EC.
  • Journal Title: PLoS One Volume: 8 Issue: 5 Pages: 1-12
  • DOI: 10.1371/journal.pone.0064281
  • Peer Reviewed
• [Presentation] Eosinophils promote epithelial to mesenchymal transition of bronchial epithelial cells (2012)
  • Author(s): K Hosoki, T Fujisawa, M Toda, EC Gabazza
  • Organizer: American Academy of Allergy, Asthma and Immunology
  • Place of Presentation: Orland, USA
• [Presentation] 好酸球による気道上皮細胞の上皮間葉移行 (2011)
  • Author(s): 細木興亜
  • Organizer: 第61回日本アレルギー学会秋季学術大会
  • Place of Presentation: 東京
• [Presentation] Eosinophils promote epithelial to mesenchymal transition of bronchial epithelial cells (2011)
  • Author(s): A Yasukawa, K Hosoki, T Fujisawa, M Toda, EC Gabazza
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 千葉