Journal
BIOLOGICAL & PHARMACEUTICAL BULLETIN
Volume 43, Issue 4, Pages 725-730Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/bpb.b19-01091
Keywords
epithelial sodium channel (ENaC); macrolide; emphysema; lung dysfunction; azithromycin
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Funding
- Japan Society for the Promotion Science (JSPS) KAKENHI [JP25460102, JP171-103570]
- JSPS Program on Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation [52510]
- Program for Leading Graduate Schools HIGO (Health life science: Interdisciplinary and Glocal Oriented)
- Program for Leading Graduate Schools HIGO (Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan)
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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 (beta/gamma ENaC-16HBE14o- cells) with three macrolides (erythromycin, clarithromycin, azithromycin) confirmed dose-dependent suppression of ENaC function. For in vivo studies, mice harboring airway specific beta ENaC overexpression (C57BL/6J-/beta NaC-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.
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