Pendrin Mediates Bicarbonate Secretion and Enhances Cystic Fibrosis Transmembrane Conductance Regulator 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 cystic fibrosis (CF) transmembrane conductance regulator (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 (ΔpH_i) that was enhanced fourfold by IL-4 pretreatment. ΔpH_i was unaffected by 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS) or CFTR inhibitor CFTR_inh-172, but was reduced by adenoviral shRNA targeting pendrin. Forskolin increased ΔpH_i, and this stimulation was prevented by CFTR_inh-172, implicating CFTR, yet forskolin only increased ΔpH_i after pendrin expression had been induced by IL-4. The dependence of ΔpH_i 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, CFTR_inh-172-sensitive current by approximately twofold in epithelial and nonepithelial 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.

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