Azithromycin Inhibits Constitutive Airway Epithelial Sodium Channel Activation in Vitro and Modulates Downstream Pathogenesis in Vivo
| Autor: | Tsuyoshi Shuto, Hirofumi Nohara, Toru Takeo, Hirofumi Kai, Yuka Eto, Taise Kawakami, Mary Ann Suico, Shunsuke Kamei, Aoi Nasu, Ryunosuke Nakashima, Haruka Fujikawa, Naomi Nakagata, Keiko Ueno-Shuto |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pharmacology Epithelial sodium channel COPD Lung Mucociliary clearance business.industry Sodium channel Pharmaceutical Science General Medicine respiratory system medicine.disease Cystic fibrosis 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure In vivo 030220 oncology & carcinogenesis medicine Bronchoconstriction medicine.symptom business |
| Zdroj: | Biological and Pharmaceutical Bulletin. 43:725-730 |
| ISSN: | 1347-5215 0918-6158 |
| DOI: | 10.1248/bpb.b19-01091 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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