Pendrin Mediates Bicarbonate Secretion and Enhances CFTR Function in Airway Surface Epithelia.

Bicarbonate facilitates mucin unpacking and bacterial killing however its transport mechanisms in the airways are not well understood. cAMP stimulates anion efflux through the CFTR (ABCC7) anion channel and this is defective in CF. The anion exchanger pendrin (SLC26A4) also mediates HCO3- efflux and is upregulated by proinflammatory cytokines. Here we examined pendrin and CFTR expression and their contributions to HCO3- secretion by human nasal and bronchial epithelia. In native tissue, both proteins were most abundant at the apical pole of ciliated surface cells with little expression in submucosal glands. In well-differentiated primary nasal and bronchial cell cultures, IL-4 dramatically increased pendrin mRNA levels and apical immunostaining. Exposure to low-Cl- apical solution caused intracellular alkalinization (ΔpHi) that was enhanced 4-fold by IL-4 pretreatment. ΔpHi was unaffected by DIDS or CFTRinh-172 but was reduced by adenoviral shRNA targeting pendrin. Forskolin increased ΔpHi and this stimulation was prevented by CFTRinh-172 implicating CFTR, yet forskolin only increased ΔpHi after pendrin expression had been induced by IL-4. The dependence of ΔpHi on pendrin suggests there is minimal electrical coupling between Cl- and HCO3- fluxes and that CFTR activation increases anion exchange-mediated HCO3- influx. Conversely, inducing pendrin expression increased forskolin-stimulated, CFTRinh-172-sensitive current by ~2-fold in epithelial and non-epithelial cells. We conclude that pendrin mediates most HCO3- secretion across airway surface epithelium during inflammation and enhances electrogenic Cl- secretion via CFTR as described for other SLC26A transporters.