Airway surface liquid pH is not acidic in children with cystic fibrosis

André Schultz,Peter B Noble,Brian Button,Anthony Kicic,Nicole C Shaw,Stephen M Stick,Samuel T Montgomery,Thien Nguyen,Ramaa Puvvadi,Silvia M Kreda,Luke J Berry,Sergey M Borisov,Ingo Klimant

doi:10.1038/s41467-017-00532-5

Abstract

Modulation of airway surface liquid (ASL) pH has been proposed as a therapy for cystic fibrosis (CF). However, evidence that ASL pH is reduced in CF is limited and conflicting. The technical challenges associated with measuring ASL pH in vivo have precluded accurate measurements in humans. In order to address this deficiency, ASL pH was measured in vivo in children using a novel luminescent technology integrated with fibre-optic probes. Here we show that ASL pH in children with CF is similar to that of children without CF. Findings were supported by highly controlled direct pH measurements in primary human airway epithelial cell culture models, which also suggest that the potential ASL pH gradient produced by defective apical ion transport is balanced out by paracellular shunting of acid/base. Thus, reduced baseline ASL pH is unlikely to be an important pathobiological factor in early CF lung disease.

Highlights

Modulation of airway surface liquid (ASL) pH has been proposed as a therapy for cystic fibrosis (CF)
CF airway disease results from dysfunction of the CF transmembrane regulator (CFTR) protein located on the apical surface of airway epithelial cells where it functions as an anion channel, regulator of other epithelial transport proteins, e.g., the epithelial sodium channel, and mediator of intracellular signalling pathways[6, 7]
The lower pH in CF was associated with impaired bacterial killing that was restored by raising ASL pH12

Summary

Introduction

Modulation of airway surface liquid (ASL) pH has been proposed as a therapy for cystic fibrosis (CF). CFTR-mediated transepithelial chloride and sodium transport are important for the regulation of airway surface liquid (ASL) hydration and mucociliary clearance[6] and there is evidence that impaired CFTR-related bicarbonate transport results in reduced ASL pH in CF8–13. A controversial issue is whether CF lung disease is initiated by a CFTR-mediated reduction in ASL pH as a result of reduced bicarbonate transport. The only study that measured lower airway pH in children found no difference in ASL pH between children with and without CF21

Methods

Results

Conclusion