Transepithelial ion transport is suppressed in hypoxic sinonasal epithelium

Abstract

Objectives/Hypothesis Sinonasal respiratory epithelial mucociliary clearance (MCC) 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 CFTR and TMEM16A, and 3) the pathogenesis of chronic rhinosinusitis (CRS). 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% O2, 5% CO2). Cultures were mounted in Ussing chambers for ion transport measurements. CFTR and TMEM16A expression were measured using quantitative RT-PCR. Results The change in short-circuit current (ΔISC (µA/cm2) 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<0.05. TMEM16A (UTP-stimulated transport) was inhibited by 48 hours of hypoxic exposure in MNSE (15.92+/−2.87 vs. 51.44+/−3.71(control) p<0.05] 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+/−S.D.) demonstrated significant reductions in both CFTR and TMEM16A mRNA expression in MNSE and HSNE due to airway epithelial hypoxia. Conclusions Sinonasal epithelial CFTR and TMEM16A-mediated Cl− transport and mRNA expression were robustly decreased in an oxygen restricted environment. The findings in the present study indicate persistent hypoxia may lead to acquired defects in sinonasal Cl− transport in a fashion likely to confer mucociliary dysfunction in CRS. Level of Evidence 1b

Medical and Surgical Advancements in the Management of Cystic Fibrosis Chronic Rhinosinusitis

“…41–45 Inflammation and inspissated secretions congest sinus ostia, consequently leading to hypoxia and mucosal edema, which further impairs MCC. 46 The chronic cycling of inflammation and remodeling promote neutrophil-predominant polyp formation, which only continues to increase with age.…”

“…Importantly, CFTR modulators are also beginning to make their way into clinical studies and represent potential future therapies for mucociliary clearance defects in patients with non-CF CRS. 44,45,106–116 …”

New Insights into Upper Airway Innate Immunity

“…In fact, there is evidence that these near-anaerobic conditions may significantly contribute to the pathogenesis of CRS. 30,[32][33][34] Regardless of the mechanism by which mucociliary clearance dysfunction arises, the inability to effectively clear the sinonasal cavity of inhaled pathogens and debris via mucociliary clearance is likely to play a role in the development of this chronic condition. For this reason, therapeutic approaches intended to increase ciliary beating or regulate airway surface liquid secretion remain attractive targets for treatment of CRS.…”

Effect of Cellulose Powder on Human Nasal Epithelial Cell Activity and Ciliary Beat Frequency

“…A previous study showed that cellular activities such as DNA replication may depend on oxygen concentration, so hypoxia might result in a decrease in the rate of cell proliferation [20]. In other studies, it was found that mucus hypersecretion can lead directly to the obstruction of the airways, resulting in poor mucociliary clearance and poor tissue oxygenation [21, 22]. These findings have lent support to the fact that high concentrations of CP may considerably impair the airway epithelial function by forming a thickened gel on the epithelial surface.…”