Hypertonic Saline Activates Neurons that Contribute to Airway Surface Liquid Production in CF, Study Suggests

Stimulation of neurons accounts for approximately half of the beneficial production of airway surface liquid (ASL) induced by hypertonic saline (HTS), a therapeutic agent used for cystic fibrosis (CF) treatment, according to research.

The study, “Nebulized hypertonic saline triggers nervous system-mediated active liquid secretion in cystic fibrosis swine trachea,” was published in the journal Scientific Reports.

Inhaled HTS, a concentrated salt solution, is a well-established therapy for CF patients and those with non-CF bronchiectasis. Among other benefits, this treatment lowers the frequency of CF exacerbation and improves lung function regardless of genotype, with evidence also indicating that it halts progression of mild CF lung disease.

Although the underlying mechanism of HTS is unknown, the scientific belief is that it passively pulls fluid from the tissue spaces into the airways via osmosis (a process by which molecules tend to pass from a less concentrated solution into a more concentrated one). This increases the volume of ASL, a thin liquid lining, thereby promoting mucus clearance.

However, studies have suggested that HTS may also stimulate sensory nerves in the airways, leading to ASL secretion.

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A team from University of Saskatchewan, in Canada, and University of California, Berkeley, used a new synchrotron (a powerful source of X-rays)-based imaging method to investigate the role of airway neurons and epithelia ­­­­— the surface layer ­­­­— in HTS-stimulated ASL production in a pig model of CF, characterized by a mutation of the CFTR gene.

Results showed that HTS significantly increased the ASL layer height, compared with isotonic saline, both in vivo and in isolated tracheas from the pigs. The researchers added the epithelial sodium channel inhibitor amiloride ­­­­— which blocks ASL reabsorption ­­­­— and showed that amiloride did not affect HTS treatment in the pig airway, which indicates that HTS-triggered increase in ASL layer height results from the production of liquid into the airways.

However, blocking the autonomic nervous system with atropine and using lidocaine to inhibit sensory neurons was found to lower the effect of HTS on ASL volume to about 50 percent, “suggesting that activation of airway neurons contributes to fluid secreted into the airway during HTS nebulization,” the scientists wrote.

“The game changer we found is that only about half of the airway surface liquid production is caused by the osmotic process. The other half of the liquid secretion is caused through the saline mist stimulating the airway neurons to act,” Julian Tam, MD, a co-leader of the team and director of the Saskatoon Adult Cystic Fibrosis Clinic, said in a press release.

In isolated tracheas, blocking neuronal function with lidocaine and the sodium channel blocker tetrodotoxin also reduced the effect of HTS treatment.

“The key finding in this study is that nebulized HTS treatment causes ASL production through the stimulation of the nervous system,” the scientists wrote. Overall, the experiments suggest that “it may be possible to modulate the duration and intensity of HTS treatment by pharmacologically modulating the contribution of the nervous system,” they added.

“Though we’re still at an early stage for developing new treatments, this is a major discovery of considerable potential relevance to CF patients,” said Juan Ianowski, PhD, the study’s senior author.

Later this year, the scientists will compare the effects of HTS by osmosis alone and with the neuronal response. The researchers will also look at which of the two components ­­­­— neural and osmotic ­­­­— causes airway irritation in some patients (HTS is known to cause excessive airway irritation in some patients).

“If by next year we can say the irritation is caused by a specific process and we can actually control that pharmacologically, then that could be hugely important,” Ianowski said, adding that clinical trials could be started in five years. “In my mind’s eye, I can see many doors that can lead to better treatments for patients.”