Quercetin Increases Cystic Fibrosis Transmembrane Conductance Regulator–Mediated Chloride Transport and Ciliary Beat Frequency: Therapeutic Implications for Chronic Rhinosinusitis

Abstract

Increasing epithelial chloride (Cl(-)) secretion in the upper airways represents a putative method for promoting mucociliary clearance through augmentation of airway surface liquid depth. Several naturally occurring flavonoid compounds, including quercetin, have shown the capacity to increase transepithelial Cl(-) transport. Quercetin exhibits well-known antioxidant and anti-inflammatory activity and is now recognized as a potent activator of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel activity in a fashion largely independent of cyclic adenosine monophosphate signaling. The present study investigates whether this compound activates Cl(-) secretion and ciliary beat frequency (CBF) in well-characterized culture models of sinonasal epithelium. Cystic fibrosis and non-cystic fibrosis primary human sinonasal epithelial (HSNE) and murine nasal septal epithelial (MNSE) cultures were studied for transepithelial ion transport in Ussing chambers under voltage clamp conditions and CBF was performed using pharmacologic manipulation. Change in short circuit current (DeltaI(SC), expressed as microamperes per squared centimeter) in response to quercetin were significantly greater than controls in both MNSE (23.23 ± 5.44 versus 2.47 ± 1.62; p < 0.0001) and HSNE (-8.72 ± 1.88 versus -1.88 ± 0.66; p < 0.01) cultures. CBF was significantly increased in quercetin-treated cells (expressed as fold change over baseline) in wild type (1.65 ± 0.13 versus 1.23 ± 0.05 [control]; p < 0.01), but not CFTR(-/-) (1.65 ± 0.29 versus 1.48 ± 0.38; p = 0.23). Quercetin significantly increased transepithelial Cl(-) transport and CBF in MNSE and HSNE cultures. Future studies investigating quercetin as a means to promote mucociliary transport in individuals with rhinosinusitis are warranted.