Targeting the lung epithelial barrier to inhibit neutrophilic inflammation

OBJECTIVE:
Respiratory epithelium acts as a first line of defence against external stimuli of biological and material origin. Macrolide antibiotics display disease-modifying effects in addition to their primary antimicrobial activities. Evidence supporting a dual role of macrolides in reducing inflammation and promoting barrier repair led us to develop non-antibiotic compounds with similar qualities while avoiding antimicrobial resistance. We now introduce a new class of compounds, “barriolides”, based on an azithromycin (Azm) backbone, a well-tolerated and highly prescribed macrolide antibiotic commonly used in the treatment of exacerbations in patients with chronic airway diseases. Barriolides are targeted to enhance the airway epithelial barrier and inhibit inflammation.

METHODS:
Using a cigarette-smoke inflammation mouse model, the lead compound dose-dependently reduced neutrophil infiltration and concentrations of key inflammatory cytokines, TNFα and IL-6, after 2 weeks’ pre-treatment. In another mouse model involving SO2 gas exposure, pre-treatment with the set of barriolide compounds reduced permeability of exogenously (tail vein) injected human serum albumin into the bronchoalveolar fluid.

RESULTS:
Across both in vivo models, our compounds display significant anti-inflammatory properties, comparable to those of Azm.

CONCLUSIONS:
These data give support to the potential for barriolides to modify diseases involving neutrophilic infiltration and epithelial barrier dysfunction.