Abstract
Azithromycin (AZM) is a broad-spectrum antibiotic widely used to treat infections. AZM also has been shown to have anti-inflammatory and immunomodulatory functions unrelated to its antibacterial activity that contribute to the effectiveness of this drug in chronic respiratory diseases. The mechanisms behind these beneficial effects are not yet fully elucidated. We have previously shown that AZM enhances barrier integrity of bronchial epithelial cells and directs them towards epidermal differentiation.In this study, we analyzed the effect of AZM pre-treatment of human bronchial and alveolar derived cell lines on mechanical stress in a cyclical pressure air-liquid interface device (CPAD) that models the disruption of the epithelial barrier with increased inflammatory response in lung tissue, which is associated with ventilator-induced lung injury (VILI). Immunostaining and electron microscopy showed that barrier integrity of the epithelium was compromised by cyclically stressing the cells but maintained when cells had been pre-treated with AZM. Lamellar body formation was revealed in AZM pre-treated cells, possibly further supporting the barrier-enhancing effects. RNA sequencing showed that the inflammatory response was attenuated by AZM treatment before cyclical stress. YKL-40, an emerging inflammatory marker, increased both due to cyclical stress and upon AZM treatment. These data confirm the usefulness of the CPAD to model ventilator-induced lung injury and suggest that AZM has barrier protective and immunomodulatory effects, attenuating the inflammatory response during mechanical stress, and might therefore be lung protective during mechanical ventilation. The model could be used to assess further drug candidates that influence barrier integrity and modulate inflammatory response.
Highlights
Azithromycin (AZM) is a broad-spectrum macrolide antibiotic used to treat bacterial infections, mainly of the respiratory system
We have shown that AZM treatment causes bronchial epithelial cells to differentiate towards an epidermal phenotype, along with forming multivesicular and lamellar bodies, and that saturated lipids conjugate to the AZM molecule when it enters the cell (Arason et al, 2019)
VA10 bronchial cells VA10 bronchial cell lines exhibited increased Trans-epithelial electrical resistance (TEER) when treated with AZM (Fig. S1A1) as reported previously by (Arason et al, Fig. 1B: Azithromycin pre-treatment maintains barrier integrity in cyclically stressed hAELVi cell layers Confocal immunofluorescent images of air-liquid interface (ALI)-cultured hAELVi cell layers with/ without AZM treatment (CON/AZM) in static or stress conditions (Static/Stress) for 21 days. i) Actin stained with phalloidin; ii) E-Cadherin and nuclei stained with DAPI
Summary
Azithromycin (AZM) is a broad-spectrum macrolide antibiotic used to treat bacterial infections, mainly of the respiratory system. The antibacterial effects of AZM are mediated through binding to the 50S subunit of the bacterial ribosome (Champney and Burdine, 1998; Champney et al, 1998; Hansen et al, 2002). There is increasing evidence that AZM has other pharmacological effects beyond its antibacterial activity, as it improves the health of patients suffering from chronic airway diseases such as chronic obstructive lung disease (COPD), bronchitis obliterans (BO), diffuse panbronchiolitis (DPB), asthma and cystic fibrosis (CF) (Gibson et al, 2017; Gotfried, 2004; Kawamura et al, 2017; Naderi et al, 2018; Pomares et al, 2018; Principi et al, 2015; Ramos and Criner, 2014) when used continuously. We have shown that AZM treatment causes bronchial epithelial cells to differentiate towards an epidermal phenotype, along with forming multivesicular and lamellar bodies, and that saturated lipids conjugate to the AZM molecule when it enters the cell (Arason et al, 2019).
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