Arni Asbjarnarson, Fridrik Runar Gardarsson, Jon Petur Joelsson, Bryndis Valdimarsdottir, Ari Jon Arason, Snaevar Sigurdsson, Michael Parnham, Jennifer Kricker and Thorarinn Gudjonsson
Introduction. Macrolides are frequently prescribed antibiotics, used to treat a spectrum of respiratory and skin infections. They are also known for their off-label use, some macrolides being effective against inflammation and oxidative stress, affecting several signaling pathways. Recently, their enhancing effects on the respiratory epithelial barrier have become more evident.
Materials and Methods. In this study the non-antimicrobial effects of the traditional 14-membered macrolide antibiotics; erythromycin, clarithromycin and roxithromycin, the 15-membered nitrogen containing macrolide, azithromycin, the ketolide solithromycin and the aminoglycoside tobramycin were analyzed in vitro. A bronchial epithelial cell line, VA10, was treated with macrolides for 14 and 21 days in air-liquid interface (ALI) conditions. Along with RNA sequencing, transepithelial electrical resistance (TEER), permeability, protein expression and histological effects were observed to evaluate the epithelial barrier and cellular differentiation
Results. Treatment with azithromycin differs from the other macrolides by a more pronounced increase in TEER, thickness of cell layer, decreased permeability, increased accumulation of phospholipids, enhancement of epidermal and keratinocyte differentiation as well as having a distinct effect on gene expression. Erythromycin and clarithromycin showed both moderate increase in TEER and decreased permeability.
Conclusion. Collectively, we have shown that macrolides have profound effects on gene expression and phenotype in human bronchial cells. Azithromycin has distinctly greater epithelial barrier-inductive properties, although all macrolides tested affect gene expression in VA10 cells with profound effects on pathways involved in epithelial-mesenchymal transition, cellular metabolism and immunomodulation. This study may aid in understanding the non-antibacterial effects of macrolides in airway epithelial related diseases.
