Impaired PGE(2)-stimulated Cl(-) and HCO(3)(-) secretion contributes to cystic fibrosis airway disease

BACKGROUND: Airway mucociliary clearance (MCC) is an important defense mechanism against pulmonary infections and is compromised in cystic fibrosis (CF). Cl(-) and HCO(3)(-) epithelial transport are integral to MCC. During pulmonary infections prostaglandin E(2) (PGE(2)) production is abundant. AIM: To determine the effect of PGE(2) on airway Cl(-) and HCO(3)(-) secretion and MCC in normal and CF airways. METHODS: We examined PGE(2) stimulated MCC, Cl(-) and HCO(3)(-) secretion using ferret trachea, human bronchial epithelial cell cultures (CFBE41o- with wildtype CFTR (CFBE41 WT) or homozygous F508del CFTR (CFBE41 CF) and human normal bronchial submucosal gland cell line (Calu-3) in Ussing chambers with or without pH-stat. RESULTS: PGE(2) stimulated MCC in a dose-dependent manner and was partially impaired by CFTR(inh)-172. PGE(2)-stimulated Cl(-) current in ferret trachea was partially inhibited by CFTR(inh)-172, with niflumic acid eliminating the residual current. CFBE41 WT cell monolayers produced a robust Cl(-) and HCO(3)(-) secretory response to PGE(2), both of which were completely inhibited by CFTR(inh)-172. CFBE41 CF cells exhibited no response to PGE(2). In Calu-3 cells, PGE(2) stimulated Cl(-) and HCO(3)(-) secretion. Cl(-) secretion was partially inhibited by CFTR(inh)-172, with additional inhibition by niflumic acid. HCO(3)(-) secretion was completely inhibited by CFTR(inh)-172. CONCLUSIONS: PGE(2) stimulates bronchotracheal MCC and this response is decreased in CF. In CF airway, PGE(2)-stimulated Cl(-) and HCO(3)(-) conductance is impaired and may contribute to decreased MCC. There remains a CFTR-independent Cl(-) current in submucosal glands, which if exploited, could represent a means of improving airway Cl(-) secretion and MCC in CF.