Impaired PGE2-stimulated Cl- and HCO3- secretion contributes to cystic fibrosis airway disease.

Zachary M Sellers,Marcelo M Morales,Beate Illek,Gopika Hari,Nam Soo Joo,Jeffrey J Wine,Miriam Frankenthal Figueira,Horst Fischer,Eric Sibley,Jackson Souza-Menezes,Shama Ahmad

doi:10.1371/journal.pone.0189894

Abstract

BackgroundAirway 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 E2 (PGE2) production is abundant.AimTo determine the effect of PGE2 on airway Cl- and HCO3- secretion and MCC in normal and CF airways.MethodsWe examined PGE2 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.ResultsPGE2 stimulated MCC in a dose-dependent manner and was partially impaired by CFTRinh-172. PGE2-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 PGE2, both of which were completely inhibited by CFTRinh-172. CFBE41 CF cells exhibited no response to PGE2. In Calu-3 cells, PGE2 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.ConclusionsPGE2 stimulates bronchotracheal MCC and this response is decreased in CF. In CF airway, PGE2-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.

Highlights

Cystic fibrosis, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), is characterized by defective Cl- and HCO3- epithelial ion transport
CFBE41 WT cell monolayers produced a robust Cl- and HCO3- secretory response to prostaglandin E2 (PGE2), both of which were completely inhibited by CFTRinh-172
PGE2 stimulates bronchotracheal mucociliary clearance (MCC) and this response is decreased in CF

Summary

Introduction

Cystic fibrosis, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), is characterized by defective Cl- and HCO3- epithelial ion transport. In the airways this results in thick, sticky mucus, impairing airway surface liquid (ASL) height and mucociliary clearance (MCC). In cystic fibrosis (CF), defective MCC leads to bronchiectasis, chronic infections, and progressive loss of lung function. In the model put forth by Haq et al, defective Cl- and HCO3- transport in CF leads to a dehydrated and acidic ASL. Airway mucociliary clearance (MCC) is an important defense mechanism against pulmonary infections and is compromised in cystic fibrosis (CF).

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