Transepithelial ion transport is suppressed in hypoxic sinonasal epithelium

Objectives/Hypothesis: Sinonasal respiratory epithelial mucociliary clearance is dependent on the transepithelial transport of ions such as Cl − . The objectives of the present study were to investigate the role of oxygen restriction in 1) Cl − transport across primary sinonasal epithelial monolayers, 2) expression of the apical Cl − channels cystic fibrosis transmembrane conductance regulator (CFTR) and transmembrane protein 16A (TMEM16A), and 3) the pathogenesis of chronic rhinosinusitis. Study Design: In vitro investigation. Methods: Murine nasal septal epithelial (MNSE), wild type, and human sinonasal epithelial (HSNE) cultures were incubated under hypoxic conditions (1% O 2 , 5% CO 2 ). Cultures were mounted in Ussing chambers for ion transport measurements. CFTR and TMEM16A expression were measured using quantitative reverse‐transcription polymerase chain reaction (RT‐PCR). Results: The change in short‐circuit current (ΔI SC in microamperes per square centimeter) attributable to CFTR (forskolin‐stimulated) was significantly decreased due to a 12‐hour hypoxia exposure in both MNSE (13.55 ± 0.46 vs. 19.23 ± 0.18) and HSNE (19.55 ± 0.56 vs. 25.49 ± 1.48 [control]; P < .05). TMEM16A (uridine triphosphate–stimulated transport) was inhibited by 48 hours of hypoxic exposure in MNSE (15.92 ± 2.87 vs. 51.44 ± 3.71 [control]; P < .05) and by 12 hours of hypoxic exposure in HSNE (16.75 ± 0.68 vs. 24.15 ± 1.35 [control]). Quantitative RT‐PCR (reported as relative mRNA levels ± standard deviation) demonstrated significant reductions in both CFTR and TMEM16A mRNA expression in MNSE and HSNE owing to airway epithelial hypoxia. Conclusions: Sinonasal epithelial CFTR and TMEM16A‐mediated Cl − transport and mRNA expression were robustly decreased in an oxygen‐restricted environment. These findings indicate that persistent hypoxia may lead to acquired defects in sinonasal Cl − transport in a fashion likely to confer mucociliary dysfunction in chronic rhinosinusitis.