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

KEY POINTS Cl- and HCO3- had similar paracellular permeabilities in human airway epithelia. PCl /PNa of airway epithelia was unaltered by pH 7.4 vs. pH 6.0 solutions. Under basal conditions, calculated paracellular HCO3- flux was secretory. Cytokines that increased airway surface liquid pH decreased or reversed paracellular HCO3- flux. HCO3- flux through the paracellular pathway may counterbalance effects of cellular H+ and HCO3- secretion. ABSTRACT Airway epithelia control the pH of airway surface liquid (ASL), thereby optimizing respiratory defenses. Active H+ and HCO3- secretion by airway epithelial cells produce an ASL that is acidic compared to the interstitial space. The paracellular pathway could provide a route for passive HCO3- flux that also modifies ASL pH. However, there is limited information about paracellular HCO3- flux, and it remains uncertain whether an acidic pH produced by loss of CFTR anion channels or proinflammatory cytokines might alter paracellular pathway function. To investigate paracellular HCO3- 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 HCO3- . Under basal conditions at pH ∼6.6, calculated paracellular HCO3- flux was weakly secretory. Treating epithelia with IL-17 plus TNFα alkalinized ASL pH to ∼7.0, increased paracellular HCO3- permeability, and paracellular HCO3- flux was negligible. Applying IL-13 increased ASL pH to ∼7.4 without altering paracellular HCO3- permeability, and calculated paracellular HCO3- flux was absorptive. These results suggest that HCO3- flux through the paracellular pathway counterbalances, in part, changes in ASL pH produced via cellular mechanisms. As the pH of ASL increases towards that of basolateral liquid, paracellular HCO3- flux becomes absorptive, tempering the alkaline pH generated by transcellular HCO3- secretion. This article is protected by copyright. All rights reserved.