Paracellular bicarbonate flux across human cystic fibrosis airway epithelia tempers changes in airway surface liquid pH

KEY POINTS: Cl(−) and HCO(3) (−) had similar paracellular permeabilities in human airway epithelia. P(Cl)/P(Na) of airway epithelia was unaltered by pH 7.4 vs. pH 6.0 solutions. Under basal conditions, calculated paracellular HCO(3) (−) flux was secretory. Cytokines that increased airway surface liquid pH decreased or reversed paracellular HCO(3) (−) flux. HCO(3) (−) flux through the paracellular pathway may counterbalance effects of cellular H(+) and HCO(3) (−) secretion. ABSTRACT: Airway epithelia control the pH of airway surface liquid (ASL), thereby optimizing respiratory defences. Active H(+) and HCO(3) (−) secretion by airway epithelial cells produce an ASL that is acidic compared with the interstitial space. The paracellular pathway could provide a route for passive HCO(3) (−) flux that also modifies ASL pH. However, there is limited information about paracellular HCO(3) (−) flux, and it remains uncertain whether an acidic pH produced by loss of cystic fibrosis transmembrane conductance regulator anion channels or proinflammatory cytokines might alter the paracellular pathway function. To investigate paracellular HCO(3) (−) transport, we studied differentiated primary cultures of human cystic fibrosis (CF) and non‐CF airway epithelia. The paracellular pathway was pH‐insensitive at pH 6.0 vs. pH 7.4 and was equally permeable to Cl(−) and HCO(3) (−). Under basal conditions at pH ∼6.6, calculated paracellular HCO(3) (−) flux was weakly secretory. Treating epithelia with IL‐17 plus TNFα alkalinized ASL pH to ∼7.0, increased paracellular HCO(3) (−) permeability, and paracellular HCO(3) (−) flux was negligible. Applying IL‐13 increased ASL pH to ∼7.4 without altering paracellular HCO(3) (−) permeability, and calculated paracellular HCO(3) (−) flux was absorptive. These results suggest that HCO(3) (−) flux through the paracellular pathway counterbalances, in part, changes in the ASL pH produced via cellular mechanisms. As the pH of ASL increases towards that of basolateral liquid, paracellular HCO(3) (−) flux becomes absorptive, tempering the alkaline pH generated by transcellular HCO(3) (−) secretion.