Abstract
BackgroundChronic rhinosinusitis engenders enormous morbidity in the general population, and is often refractory to medical intervention. Compounds that augment mucociliary clearance in airway epithelia represent a novel treatment strategy for diseases of mucus stasis. A dominant fluid and electrolyte secretory pathway in the nasal airways is governed by the cystic fibrosis transmembrane conductance regulator (CFTR). The objectives of the present study were to test resveratrol, a strong potentiator of CFTR channel open probability, in preparation for a clinical trial of mucociliary activators in human sinus disease. MethodsPrimary sinonasal epithelial cells, immortalized bronchoepithelial cells (wild type and F508del CFTR), and HEK293 cells expressing exogenous human CFTR were investigated by Ussing chamber as well as patch clamp technique under non-phosphorylating conditions. Effects on airway surface liquid depth were measured using confocal laser scanning microscopy. Impact on CFTR gene expression was measured by quantitative reverse transcriptase polymerase chain reaction.ResultsResveratrol is a robust CFTR channel potentiator in numerous mammalian species. The compound also activated temperature corrected F508del CFTR and enhanced CFTR-dependent chloride secretion in human sinus epithelium ex vivo to an extent comparable to the recently approved CFTR potentiator, ivacaftor. Using inside out patches from apical membranes of murine cells, resveratrol stimulated an ~8 picosiemens chloride channel consistent with CFTR. This observation was confirmed in HEK293 cells expressing exogenous CFTR. Treatment of sinonasal epithelium resulted in a significant increase in airway surface liquid depth (in µm: 8.08+/-1.68 vs. 6.11+/-0.47,control,p<0.05). There was no increase CFTR mRNA. ConclusionResveratrol is a potent chloride secretagogue from the mucosal surface of sinonasal epithelium, and hydrates airway surface liquid by increasing CFTR channel open probability. The foundation for a clinical trial utilizing resveratrol as a therapeutic intervention to increase mucociliary transport and airway surface liquid hydration in sinus disease is strongly supported by these findings.
Highlights
Chronic rhinosinusitis (CRS) affects 16% of the US population with an estimated aggregated cost of 8.6 billion dollars annually in healthcare expenditures[1,2,3]
Impaired Mucociliary clearance (MCC) leads to chronic rhinosinusitis (CRS) and is insidious among the cystic fibrosis (CF) population
Primary sinonasal epithelial cells from humans, mice, and pigs, as well as CFBE immortalized cell lines expressing either wild type or F508del CFTR were cultured at an air-liquid interface according to previously established protocols[5,13,14,15,16,17,18] and used to evaluate whether resveratrol dependent CFTR activation is conserved across species
Summary
Chronic rhinosinusitis (CRS) affects 16% of the US population with an estimated aggregated cost of 8.6 billion dollars annually in healthcare expenditures[1,2,3]. The cystic fibrosis transmembrane conductance regulator (CFTR) mediates the transport of a significant amount of Cl- and HCO3- in both the upper and lower respiratory epithelium. The objectives of the present study were to test resveratrol, a strong potentiator of CFTR channel open probability, in preparation for a clinical trial of mucociliary activators in human sinus disease. Using inside out patches from apical membranes of murine cells, resveratrol stimulated an ~8 picosiemens chloride channel consistent with CFTR This observation was confirmed in HEK293 cells expressing exogenous CFTR. Conclusion: Resveratrol is a potent chloride secretagogue from the mucosal surface of sinonasal epithelium, and hydrates airway surface liquid by increasing CFTR channel open probability. The foundation for a clinical trial utilizing resveratrol as a therapeutic intervention to increase mucociliary transport and airway surface liquid hydration in sinus disease is strongly supported by these findings
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