Abstract
BACKGROUND: Neutrophilic chronic rhinosinusitis (CRS) is characterized by persistent inflammation and often responds poorly to corticosteroid therapy. In this disease, neutrophil extracellular traps (NETs) are increasingly recognized as key mediators of mucosal damage and polypogenesis. The removal of NETs by deoxyribonuclease 1 could be a potential therapeutic approach to overcome steroid resistance in neutrophilic CRS. In this study, we established a mouse model of neutrophilic CRS and evaluated the effect of a genetically engineered deoxyribonuclease 1 'AR-CR8 Dnase1' on NETs and polyp formation in the mice. METHODS: Human neutrophils were isolated and treated with LPS to induce NET formation. An animal model for neutrophilic CRS and polyps was developed by intranasal administration of LPS and Staphylococcal toxin. H&E staining and immunofluorescence were performed to identify polyps, NETs, and immune cells in nasal cavities. RESULTS: AR-CR8 Dnase1 effectively degraded NET-like structures in LPS-stimulated human neutrophils. In the mouse CRS model, the intranasal administration of AR-CR8 Dnase1 noticeably reduced the burden of nasal polyps. The intranasal treatment of Dnase1 was effective as much as an injection of dexamethasone in reducing polyp number and NET accumulation in this model. CONCLUSIONS: These results suggest that an engineered deoxyribonuclease 1 like AR-CR8 Dnase1 be an emerging bio-drug to inhibit inflammatory reaction and polyp formation in patients with neutrophilic CRS. AR-CR8 Dnase1 may be an alternative therapeutic for patients with CRS who are not suitable for steroid therapy, and further studies comparing dosing, durability, and safety are needed before considering clinical use. TRIAL REGISTRATION: Not applicable.