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

Abstract

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 overabsorption 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-βENaCtransgenic 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.

Differential Effect of Three Macrolide Antibiotics on Cardiac Pathology and Electrophysiology in a Myocardial Infarction Rat Model: Influence on Sodium Nav1.5 Channel Expression

“…Importantly, we used a much longer duration in our experiment, and it was expected to notice much more QT prolongation on the ECG and reduced conductance on Nav1.5. Differently, Fujikawa et al demonstrated that macrolide antibiotics suppress the airway epithelial sodium channels in vitro [ 28 ]…”

SARS-CoV-2 (COVID-19) and cystic fibrosis

“…CF patients have a higher prevalence of RSV and a higher viral load in bronchoalveolar lavage fluid (BALF) than non-CF patients (37). Moreover,~15-25% of CF patients with a respiratory viral infection also culture positive for a known CF bacterial pathogen (23,50,78). Coinfection with RSV and P. aeruginosa is associated with declines in pulmonary function and increased morbidity and mortality (28,53).…”

Testing the effects of combining azithromycin with inhaled tobramycin forP. aeruginosain cystic fibrosis: a randomised, controlled clinical trial

“…29 34 One potential explanation is that beneficial effects of azithromycin in the airway unrelated to Pseudomonas outweighed the effects of increased P. aeruginosa burden, resulting in a disconnect between changes in lung function and airway infection. [35][36][37][38][39] Another potential explanation is that our study population, by design, was not naïve to inhaled tobramycin, and neither group (ie, azithromycin or placebo treated) had a significant increase in FEV 1 during inhaled tobramycin use. A diminishing effect on FEV 1 over subsequent cycles of inhaled tobramycin was reported in even the earliest clinical trials.…”

“…This did not occur in our trial, similar to what has been seen in studies of inhaled levofloxacin in CF and multiple inhaled antibiotics in non-CF bronchiectasis 30 35 . One potential explanation is that beneficial effects of azithromycin in the airway unrelated to pseudomonas outweighed the effects of increased Pa burden, resulting in a disconnect between changes in lung function and airway infection 36 – 40 . Another potential explanation is that our study population, by design, was not naïve to inhaled tobramycin, and neither group (i.e., azithromycin or placebo-treated) had a significant increase in FEV 1 during inhaled tobramycin use.…”