Suppression of CFTR-mediated Cl^- secretion of airway epithelium in vitamin C-deficient mice

Hyperoxic ventilation induces detrimental effects on the respiratory system, and ambient oxygen may be harmful unless compensated by physiological anti-oxidants, such as vitamin C. Here we investigate the changes in electrolyte transport of airway epithelium in mice exposed to normobaric hyperoxia and in gulonolacton oxidase knock-out (gulo[-/-]) mice without vitamin C (Vit-C) supplementation. Short-circuit current (I_sc) of tracheal epithelium was measured using Ussing chamber technique. After confirming amiloridesensitive Na+ absorption (ΔI_sc,amil), cAMP-dependent Cl- secretion (ΔI_sc,forsk) was induced by forskolin. To evaluate Ca²⁺-dependent Cl- secretion, ATP was applied to the luminal side (ΔI_sc,ATP). In mice exposed to 98% PO₂ for 36 hr, ΔI_sc,forsk decreased, ΔIsc,amil and ΔIsc,ATP was not affected. In gulo(-/-) mice, both ΔI_sc,forsk and ΔIsc,ATP decreased from three weeks after Vit-C deprivation, while both were unchanged with Vit-C supplementation. At the fourth week, tissue resistance and all electrolyte transport activities were decreased. An immunofluorescence study showed that the expression of cystic fibrosis conductance regulator (CFTR) was decreased in gulo(-/-) mice, whereas the expression of KCNQ1 K⁺ channel was preserved. Taken together, the CFTR-mediated Cl- secretion of airway epithelium is susceptible to oxidative stress, which suggests that supplementation of the antioxidant might be beneficial for the maintenance of airway surface liquid.