Abstract
BackgroundInflammation plays a critical role in lung disease development and progression in cystic fibrosis. Azithromycin is used for the treatment of cystic fibrosis lung disease, although its mechanisms of action are poorly understood. We tested the hypothesis that azithromycin modulates lung inflammation in cystic fibrosis mice.MethodsWe monitored cellular and molecular inflammatory markers in lungs of cystic fibrosis mutant mice homozygous for the ΔF508 mutation and their littermate controls, either in baseline conditions or after induction of acute inflammation by intratracheal instillation of lipopolysaccharide from Pseudomonas aeruginosa, which would be independent of interactions of bacteria with epithelial cells. The effect of azithromycin pretreatment (10 mg/kg/day) given by oral administration for 4 weeks was evaluated.ResultsIn naive cystic fibrosis mice, a spontaneous lung inflammation was observed, characterized by macrophage and neutrophil infiltration, and increased intra-luminal content of the pro-inflammatory cytokine macrophage inflammatory protein-2. After induced inflammation, cystic fibrosis mice combined exaggerated cellular infiltration and lower anti-inflammatory interleukin-10 production. In cystic fibrosis mice, azithromycin attenuated cellular infiltration in both baseline and induced inflammatory condition, and inhibited cytokine (tumor necrosis factor-α and macrophage inflammatory protein-2) release in lipopolysaccharide-induced inflammation.ConclusionOur findings further support the concept that inflammatory responses are upregulated in cystic fibrosis. Azithromycin reduces some lung inflammation outcome measures in cystic fibrosis mice. We postulate that some of the benefits of azithromycin treatment in cystic fibrosis patients are due to modulation of lung inflammation.
Highlights
Inflammation plays a critical role in lung disease development and progression in cystic fibrosis
We examined the effect of azithromycin pre-treatment on cellular and molecular parameters in the lungs of Cystic fibrosis (CF) and normal homozygous wild-type mice with or without challenge with lipopolysaccharide from Pseudomonas aeruginosa (LPS), which would be independent of interactions of bacteria with epithelial cells [21,22,23]
Spontaneous lung inflammatory status in CF mice Repeated bacteriological examination of BAL fluid (BALF) samples from CF and normal homozygous wild-type mice showed no known pathogenic infectious agents cultured in polyvalent media, and zero growth detected in selective culture media for yeast and fungus and for Gram negative bacteria
Summary
Inflammation plays a critical role in lung disease development and progression in cystic fibrosis. Cystic fibrosis (CF) is the most common, life-threatening, recessively inherited disease in Caucasian populations. The high morbidity and mortality in CF is due to chronic respiratory infection, culminating in colonization with Pseudomonas aeruginosa, which has been implicated as an important stimulus in the progression of lung disease. This devastating complication, characterized by chronic unopposed neutrophil-dominated inflammation and progressive bronchiectasis, increases rates of lung function decline [9] and is a significant predictor of mortality [10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
