Physiological levels of lipoxin A4 inhibit ENaC and restore airway surface liquid height in cystic fibrosis bronchial epithelium.

Mazen Al-Alawi,Gerard Higgins,Valia Verriere,Paul Buchanan,Paul Mcnally,Richard W Costello,Brian J Harvey,Valérie Urbach,Olive Mccabe

doi:10.14814/phy2.12093

Abstract

In cystic fibrosis (CF), the airway surface liquid (ASL) is depleted. We previously demonstrated that lipoxin A4 (LXA4) can modulate ASL height (ASLh) through actions on Cl− transport. Here, we report novel effects of lipoxin on the epithelial Na+ channel ENaC in this response. ASL dynamics and ion transport were studied using live‐cell confocal microscopy and short‐circuit current measurements in CF (CuFi‐1) and non‐CF (NuLi‐1) cell cultures. Low physiological concentrations of LXA4 in the picomolar range produced an increase in ASLh which was dependent on inhibition of an amiloride‐sensitive Na+ current and stimulation of a bumetanide‐sensitive Cl− current. These ion transport and ASLh responses to LXA4 were blocked by Boc‐2 an inhibitor of the specific LXA4 receptor ALX/FPR2. LXA4 affected the subcellular localization of its receptor and enhanced the localization of ALX/FPR2 at the apical membrane of CF cells. Our results provide evidence for a novel effect of low physiological concentrations of LXA4 to inhibit airway epithelial Na+ absorption that results in an ASL height increase in CF airway epithelia.

Highlights

The surface of the bronchi is covered by an airway surface liquid (ASL) layer which is maintained at optimum height by NaCl transport across the epithelium
We have previously shown that high concentrations of lipoxin A4 (LXA4) (100 nmol/L) stimulated airway epithelium tight junction formation (Grumbach et al 2009), produced an intracellular Ca2+ mobilization and ClÀ secretion (Bonnans et al 2003), and enhanced ASL height in bronchial epithelial cells derived from patients with Cystic fibrosis (CF) (Verriere et al 2012)
Airway Surface Liquid height (ASLh) measurements were carried out over a period of 30 h to follow the dynamics of epithelial fluid absorption/secretion and to determine the time course of the generation of a steady-state thin ASL film in CuFi-1 and NuLi-1 cell monolayers cultured under an air–liquid interface

Summary

Introduction

The surface of the bronchi is covered by an airway surface liquid (ASL) layer which is maintained at optimum height by NaCl transport across the epithelium. Sodium absorption through the epithelial Na+ channel (ENaC) induces water absorption and dehydrates the ASL, whereas secretion of ClÀ via the cystic fibrosis transmembrane a 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society. Lipoxin Inhibits ENaC and Restores Airway Surface Liquid Height in CF

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Results

Conclusion