PBA increases CFTR expression but at high doses inhibits Cl- secretion in Calu-3 airway epithelial cells

Sodium 4-phenylbutyrate (PBA), a short-chain fatty acid, has been approved to treat patients with urea cycle enzyme deficiencies and is being evaluate d in the management of sickle cell disease, thalassemia, cancer, and cystic fibrosis (CF). Because relatively little is known about the effects of PEA on the expression and function of the wild-type CF transmembrane conductan ce regulator (wt CFTR), the goal of this study was to examine the effects o f PEA and related compounds on wt CFTR-mediated Cl- secretion. To this end, we studied Calu-3 cells, a human airway cell line that expresses endogenou s wt CFTR and has a serous cell phenotype. We report that chronic treatment of Calu-3 cells with a high concentration (5 mM) of PBA, sodium butyrate, or sodium valproate but not of sodium acetate reduced basal and 8-(4-chloro phenylthio)-cAMP-stimulated Cl- secretion. Paradoxically, PEA enhanced CFTR protein expression 6- to 10-fold and increased the intensity of CFTR stain ing in the apical plasma membrane. PEA also increased protein expression of Na+-K+-ATPase. PEA reduced CFTR Cl- currents across the apical membrane bu t had no effect on Na+-K+-ATPase activity in the basolateral membrane. Thus a high concentration of PBA(5 mM) reduces Cl- secretion by inhibiting CFTR Cl- currents across the apical membrane. In contrast, lower therapeutic co ncentrations of PEA (0.05-2 mM) had no effect on cAMP-stimulated Cl- secret ion across Calu-3 cells. We conclude that PEA concentrations in the therape utic range are unlikely to have a negative effect on Cl- secretion. However , concentrations >5 mM might reduce transepithelial Cl- secretion by serous cells in submucosal glands in individuals expressing wt CFTR.