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The Non-Antibacterial Effects of Azithromycin and Other Macrolides on the Bronchial Epithelial Barrier and Cellular
Arni Asbjarnarson1, Jon Petur Joelsson1, Fridrik R Gardarsson2
1School of Health Sciences, University of Iceland, 101 Reykjavík, Iceland.
Abstract:
The respiratory epithelium maintains the barrier against inhaled harmful agents. When barrier failure occurs, as in several respiratory diseases, acute or chronic inflammation leading to destructive effects and exacerbations can occur. Macrolides are used to treat a spectrum of infections but are also known for off-label use. Some macrolides, particularly azithromycin (AZM), reduce exacerbations in chronic obstructive pulmonary disease (COPD), whereby its efficacy is thought to be due to its effects on inflammation and oxidative stress. In vitro data indicate that AZM reduces epithelial barrier failure, evidenced by increased transepithelial electrical resistance (TEER). Here, we compared the effects of macrolides on differentiation and barrier integrity in VA10 cells, a bronchial epithelial cell line for 14 and 21 days. Erythromycin, clarithromycin, roxithromycin, AZM, solithromycin, and tobramycin (an aminoglycoside) were analyzed using RNA sequencing, barrier integrity assays, and immunostaining to evaluate effects on the epithelium. All macrolides affected the gene expression of pathways involved in epithelial-to-mesenchymal transition, metabolism, and immunomodulation. Treatment with AZM, clarithromycin, and erythromycin raised TEER and induced phospholipid retention. AZM treatment was distinct in terms of enhancement of the epithelial barrier, retention of phospholipids, vesicle build-up, and its effect on gene sets related to keratinocyte differentiation and establishment of skin barrier.
Insights
Macrolide antibiotics like azithromycin enhance respiratory epithelial barrier function. This may explain their use in reducing exacerbations in chronic obstructive pulmonary disease (COPD).
Area of Science:
- Respiratory medicine
- Cell biology
- Pharmacology
Background:
- The respiratory epithelium is crucial for defense against inhaled pathogens.
- Epithelial barrier dysfunction is implicated in respiratory diseases like COPD.
- Macrolides, including azithromycin (AZM), are used off-label to reduce COPD exacerbations, potentially via anti-inflammatory effects.
Purpose of the Study:
- To compare the effects of various macrolides on bronchial epithelial cell differentiation and barrier integrity.
- To investigate the mechanisms underlying azithromycin's potential to enhance epithelial barrier function.
Main Methods:
- VA10 bronchial epithelial cells were treated with erythromycin, clarithromycin, roxithromycin, AZM, solithromycin, and tobramycin for 14 and 21 days.
- Analyses included RNA sequencing, transepithelial electrical resistance (TEER) assays, and immunostaining.
- Effects on epithelial differentiation, barrier integrity, and cellular processes were evaluated.
Main Results:
- All tested macrolides altered gene expression in pathways related to epithelial-to-mesenchymal transition, metabolism, and immunomodulation.
- Azithromycin, clarithromycin, and erythromycin increased TEER and promoted phospholipid retention.
- Azithromycin uniquely enhanced the epithelial barrier, retained phospholipids, increased vesicle accumulation, and influenced keratinocyte differentiation gene sets.
Conclusions:
- Macrolides modulate gene expression in bronchial epithelial cells.
- AZM, clarithromycin, and erythromycin improve epithelial barrier integrity and phospholipid retention.
- Azithromycin demonstrates distinct effects on epithelial barrier enhancement and differentiation pathways, suggesting a specific mechanism for its benefits in respiratory conditions.
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