Azithromycin Inhibits Constitutive Airway Epithelial Sodium Channel Activation in Vitro and Modulates Downstream Pathogenesis in Vivo

• Fujikawa Haruka

  Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program,” Kumamoto University

• Kawakami Taise

  Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University

• Nakashima Ryunosuke

  Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University

• Nasu Aoi

  Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University

• Kamei Shunsuke

  Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program,” Kumamoto University Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University

• Nohara Hirofumi

  Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program,” Kumamoto University

• Eto Yuka

  Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University

• Ueno-Shuto Keiko

  Laboratory of Pharmacology, Division of Life Science, Faculty of Pharmaceutical Sciences, Sojo University

• Takeo Toru

  Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University

• Nakagata Naomi

  Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University

• Suico Mary Ann

  Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University Global Center for Natural Resources Sciences, Faculty of Life Sciences, Kumamoto University

• Kai Hirofumi

  Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University Global Center for Natural Resources Sciences, Faculty of Life Sciences, Kumamoto University

• Shuto Tsuyoshi

  Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University Global Center for Natural Resources Sciences, Faculty of Life Sciences, Kumamoto University

書誌事項

タイトル別名

• Azithromycin Inhibits Constitutive Airway Epithelial Sodium Channel Activation <i>in Vitro</i> and Modulates Downstream Pathogenesis <i>in Vivo</i>

抄録

Epithelial sodium channel (ENaC) is an amiloride-sensitive sodium ion channel that is expressed in epithelial tissues. ENaC overexpression and/or hyperactivation in airway epithelial cells cause sodium over-absorption and dysregulated ciliary movement for mucus clearance; however, the agents that suppress constitutive airway ENaC activation are yet to be clinically available. Here, we focused on macrolides, which are widely used antibiotics that have many potential immunomodulatory effects. We examined whether macrolides could modulate constitutive ENaC activity and downstream events that typify cystic fibrosis (CF) and chronic obstructive pulmonary diseases (COPD) in in vitro and in vivo models of ENaC overexpression. Treatment of ENaC-overexpressing human bronchial epithelial cells (β/γENaC-16HBE14o- cells) with three macrolides (erythromycin, clarithromycin, azithromycin) confirmed dose-dependent suppression of ENaC function. For in vivo studies, mice harboring airway specific βENaC overexpression (C57BL/6J-βENaC-transgenic mice) were treated orally with azithromycin, a well-established antimicrobial agent that has been widely prescribed. Azithromycin treatment modulated pulmonary mechanics, emphysematous phenotype and pulmonary dysfunction. Notably, a lower dose (3 mg kg⁻¹) of azithromycin significantly increased forced expiratory volume in 0.1 s (FEV0.1), an inverse indicator of bronchoconstriction. Although not statistically significant, improvement of pulmonary obstructive parameters such as emphysema and lung dysfunction (FEV0.1%) was observed. Our results demonstrate that macrolides directly attenuate constitutive ENaC function in vitro and may be promising for the treatment of obstructive lung diseases with defective mucociliary clearance, possibly by targeting ENaC hyperactivation.

収録刊行物

• Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ

  Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ 43 (4), 725-730, 2020-04-01

  公益社団法人 日本薬学会

キーワード

• epithelial sodium channel (ENaC)
• macrolide
• emphysema
• lung dysfunction
• azithromycin

詳細情報

• CRID: 1390283659867932544
• NII論文ID: 130007825345
• NII書誌ID: AA10885497
• DOI: 10.1248/bpb.b19-01091
• ISSN: 13475215
• ISSN: 09186158
• NDL書誌ID: 030335071
• PubMed: 32009028
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I030335071
• Web Site: https://www.jstage.jst.go.jp/article/bpb/43/4/43_b19-01091/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2021023036
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• 抄録ライセンスフラグ: 使用不可