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Polarized distribution of HCO₃^- transport in human normal and cystic fibrosis nasal epithelia

Anthony M. Paradiso, Raymond D. Coakley and Richard C. Boucher

The polarized distribution of HCO₃^- transport was investigated in human nasal epithelial cells from normal and cystic fibrosis (CF) tissues. To test for HCO₃^- transport via conductive versus electroneutral Cl^-/HCO₃^- exchange (anion exchange, AE) pathways, nasal cells were loaded with the pH probe 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein and mounted in a bilateral perfusion chamber. In normal, but not CF, epithelia, replacing mucosal Cl^- with gluconate caused intracellular pH (pH_i) to increase, and the initial rates (pH min^-1) of this increase were modestly augmented (~26 %) when normal cells were pretreated with forskolin (10 µM). Recovery from this alkaline shift was dependent on mucosal Cl^-, was insensitive to the AE inhibitor 4,4'-diisothiocyanatodihydrostilbene-2,2'-disulfonic acid (H₂DIDS; 1.5 mM), but was sensitive to the cystic fibrosis transmembrane conductance regulator (CFTR) channel inhibitor diphenylamine-2-carboxylate (DPC; 100 µM). In contrast, removal of serosal Cl^- caused pH_i to alkalinize in both normal and CF epithelia. Recovery from this alkaline challenge was dependent on serosal Cl^- and blocked by H₂DIDS. Additional studies showed that serosally applied Ba²⁺ (5.0 mM) in normal, but not CF, cells induced influx of HCO₃^- across the apical membrane that was reversibly blocked by mucosal DPC. In a final series of studies, normal and CF cells acutely alkaline loaded by replacing bilateral Krebs bicarbonate Ringer (KBR) with Hepes-buffered Ringer solution exhibited basolateral, but not apical, recovery from an alkaline challenge that was dependent on Cl^-, independent of Na⁺ and blocked by H₂DIDS. We conclude that: (1) normal, but not CF, nasal epithelia have a constitutively active DPC-sensitive HCO₃^- influx/efflux pathway across the apical membrane of cells, consistent with the movement of HCO₃^- via CFTR; and (2) both normal and CF nasal epithelia have Na⁺-independent, H₂DIDS-sensitive AE at their basolateral domain.

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