Azithromycin inhibits constitutive airway epithelial sodium channel activation in vitro and modulates downstream pathogenesis in vivo.

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-Tg 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 second (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.
PMID: 32009028 [PubMed - as supplied by publisher]

Source: Biological and Pharmaceutical Bulletin - January 30, 2020 Category: Drugs & Pharmacology Authors: Fujikawa H, Kawakami T, Nakashima R, Nasu A, Kamei S, Nohara H, Eto Y, Ueno-Shuto K, Takeo T, Nakagata N, Suico MA, Kai H, Shuto T Tags: Biol Pharm Bull Source Type: research