Impaired PGE2-stimulated Cl- and HCO3- 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 HCO3- 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 HCO3-secretion and MCC in normal and CF airways. Methods We examined PGE(2) stimulated MCC, Cl- and HCO3- 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 CFTRinh-172. PGE(2)-stimulated Cl- current in ferret trachea was partially inhibited by CFTRinh-172, with niflumic acid eliminating the residual current. CFBE41 WT cell monolayers produced a robust Cl- and HCO3- secretory response to PGE(2), both of which were completely inhibited by CFTRinh-172. CFBE41 CF cells exhibited no response to PGE(2). In Calu-3 cells, PGE(2) stimulated Cl- and HCO3- secretion. Cl- secretion was partially inhibited by CFTRinh-172, with additional inhibition by niflumic acid. HCO3- secretion was completely inhibited by CFTRinh-172. Conclusions PGE(2) stimulates bronchotracheal MCC and this response is decreased in CF. In CF airway, PGE(2)-stimulated Cl- and HCO3- 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.