Azithromycin And Ciprofloxacin Inhibit Interleukin-8 Secretion Without Disrupting Human Sinonasal Epithelial Integrity In Vitro

Background We recently developed a ciprofloxacin and azithromycin sinus stent (CASS) to target recalcitrant infections in chronic rhinosinusitis (CRS). The objective of this study was to evaluate the anti-inflammatory activity of azithromycin released from the CASS and assess the impact on the integrity and function of primary human sinonasal epithelial cells (HSNECs). Methods Pseudomonas aeruginosalipopolysaccharide (LPS)-stimulated HSNECs were treated with azithromycin and/or ciprofloxacin at concentrations attainable from CASS release. Interleukin-8 (IL-8) secretion was quantified by enzyme-linked immunosorbent assay (ELISA). Epithelial integrity (transepithelial resistance [TEER], paracellular permeability [fluorescein isothiocyanate-labeled dextran], lactate dehydrogenase [LDH] assays) and function (ciliary beat frequency [CBF]) were also evaluated. Results Azithromycin significantly reduced secreted IL-8 fromP. aeruginosaLPS-stimulated HSNECs at all concentrations tested (mean +/- standard deviation; control = 5.77 +/- 0.39 ng/mL, azithromycin [6 mu g/mL] = 4.58 +/- 0.40 ng/mL, azithromycin [60 mu g/mL] = 4.31 +/- 0.06, azithromycin [180 mu g/mL] = 4.27 +/- 0.26 ng/mL,p< 0.05). Co-incubation with azithromycin (6 mu g/mL) and ciprofloxacin (2.4 mu g/mL) in LPS-stimulated HSNECs also displayed a significant reduction in secreted IL-8 when compared toP. aeruginosaLPS alone (co-treatment = 4.61 +/- 0.29 ng/mL,P. aeruginosaLPS = 7.35 +/- 0.89 ng/mL,p< 0.01). The drugs did not negatively impact TEER, paracellular permeability, LDH release, or CBF, indicating retention of cell integrity and function. Conclusion Azithromycin decreasedP. aeruginosaLPS IL-8 production in HSNECs at drug concentrations attainable with sustained release of azithromycin from the CASS. In addition to antibacterial activity, anti-inflammatory properties of the CASS should provide further benefit for patients with recalcitrant CRS.