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% CO2). 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 (DISC 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 6 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.