(402) Inhibiting the neurogenic component of the response to hypertonic saline treatment increases mucociliary clearance in CF swine

Background: Nebulized hypertonic saline (HTS) is a well-established treatment aimed at restoring airway hydration and improving mucus clearance, which has been shown to improve lung health in patients with cystic fibrosis [1-3]. Recently, we reported that HTS nebulization triggers a neurogenic response that accounts for ~50% of its airway rehydration effect [4]. These results suggest that it may be possible to modulate the duration and intensity of HTS treatment by recruiting the airway nervous system. Our objective is to examine the role of the nervous system in HTS’ treatment response in CF airways.

Methods: We used CFTR-/- swine to study the response to nebulized HTS on airway surface liquid (ASL) secretion in vivo using synchrotron-based high-resolution assays and the effect of HTS on mucociliary clearance (MCC) in an isolated tracheal preparation assay.

Results: We found that HTS nebulization triggers an increase in ASL compared to isotonic saline nebulization. The hydration effect of HTS was reduced by ~50% by blocking the nervous system. These results suggest that HTS treatment triggers glandular secretion. MCC assays showed that HTS treatment induced clearance of tantalum discs in CF airway preparations. Interestingly, inhibiting the nervous system with tetrodotoxin, a blocker of voltage-dependent Na⁺ channels, increased HTS’ effect on the clearance of tantalum discs in airway preparations.

Conclusions: Overall, our findings suggest that HTS nebulization stimulates submucosal gland secretion; blocking glandular secretion improves MCC in CFTR-/- swine trachea. This is consistent with recent reports that in glandular secretions are abnormal in CF and fail to detach from the glands thus impairing MCC. Blocking HTS-triggered glandular secretion in CF would still permit osmotically driven airway hydration, while inhibiting the production of the abnormal CF mucus that diminishes MCC.

Acknowledgements: Supported by Cystic Fibrosis Canada, Cystic Fibrosis Foundation,, Canadian Institutes of Health Research, and the University of Saskatchewan Respiratory Research Centre.

References: [1] Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med. 2006;354(3):241-50. DOI: 10.1056/NEJMoa043891

[2] Elkins MR, Bye PT. Inhaled hypertonic saline as a therapy for cystic fibrosis. Curr Opin Pulm Med. 2006;12(6):445-52. doi: 10.1097/01.mcp.0000245714.89632.b2
[3] Tildy BE, Rogers DF. Therapeutic options for hydrating airway mucus in cystic fibrosis. Pharmacology. 2015;95(3-4):117-32. DOI: 10.1159/000377638

[4] Luan X, Tam JS, Belev G, Jagadeeshan S, Murray B, Hassan N, et al. Nebulized hypertonic saline triggers nervous system-mediated active liquid secretion in cystic fibrosis swine trachea. Sci Rep. 2019;9(1):540. DOI: 10.1038/s41598-018-36695-4