Nebulized hypertonic saline triggers nervous system-mediated active liquid secretion in cystic fibrosis swine trachea

Xiaojie Luan,L Dean Chapman,Brendan Murray,Santosh Jagadeeshan,Terry E Machen,George Belev,Julian S Tam,Noman Hassan,Juan P Ianowski

doi:10.1038/s41598-018-36695-4

Abstract

Inhaled hypertonic saline (HTS) treatment is used to improve lung health in patients with cystic fibrosis (CF). The current consensus is that the treatment generates an osmotic gradient that draws water into the airways and increases airway surface liquid (ASL) volume. However, there is evidence that HTS may also stimulate active secretion of ASL by airway epithelia through the activation of sensory neurons. We tested the contribution of the nervous system and airway epithelia on HTS-stimulated ASL height increase in CF and wild-type swine airway. We used synchrotron-based imaging to investigate whether airway neurons and epithelia are involved in HTS treatment-triggered ASL secretion in CFTR−/− and wild-type swine. We showed that blocking parasympathetic and sensory neurons in airway resulted in ~50% reduction of the effect of HTS treatment on ASL volume in vivo. Incubating tracheal preparations with inhibitors of epithelial ion transport across airway decreased secretory responses to HTS treatment. CFTR−/− swine ex-vivo tracheal preparations showed substantially decreased secretory response to HTS treatment after blockage of neuronal activity. Our results indicated that HTS-triggered ASL secretion is partially mediated by the stimulation of airway neurons and the subsequent activation of active epithelia secretion; osmosis accounts for only ~50% of the effect.

Highlights

Inhaled hypertonic saline (HTS) is a well-established treatment for patients with cystic fibrosis (CF) and patients with non-CF bronchiectasis[1,2]
These results suggest that approximately 50% of the airway surface liquid (ASL) produced by HTS treatment in wild-type and CF airway is mediated by the activation of the nervous system and stimulation of active epithelial ASL secretion
Our results showed that amiloride did not affect HTS treatment in the pig airway (Fig. 2E), which indicates that HTS-triggered increase in ASL layer height results from the production of liquid into the airway lumen, and not by blocking liquid absorption

Summary

Introduction

Inhaled hypertonic saline (HTS) is a well-established treatment for patients with cystic fibrosis (CF) and patients with non-CF bronchiectasis[1,2]. The current consensus understanding of the mechanism of action of HTS inhalation is that the treatment generates an osmotic gradient that draws water into the airways[11,12]. This increases the volume of airway surface liquid (ASL), which improves mucus rheological properties and accelerates mucus transport rates[3,4]. The goal of the present study was to test the role of airway neurons and epithelia in HTS-stimulated ASL production in the tracheas of wild-type and CFTR−/− swine using a novel synchrotron-based imaging method, which we developed to measure and quantify ASL secretion in live animals and ex vivo trachea preparations[23,24,25]. These results suggest that approximately 50% of the ASL produced by HTS treatment in wild-type and CF airway is mediated by the activation of the nervous system and stimulation of active epithelial ASL secretion

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