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

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.

Lipopolysaccharides induce a RAGE-mediated sensitization of sensory neurons and fluid hypersecretion in the upper airways

“…The fact that we can stimulate liquid secretion in isolated trachea preparations, which lack tDRG and jugular/nodose ganglia, indicates that the sensory fibers remain viable/active for at least 60 min (the duration of the experiment) after euthanizing the animal and that the effects of LPS on CAP-mediated secretory responses are the result of local mechanisms, such as axon reflex. The latter is consistent with previous reports by Ianowski and coworkers, indicating that nerve conduction blockers impaired secretory responses in trachea isolated from mice 43 and swine 77 . Because sensory neurons from the tDRG and jugular/nodose ganglia are virtually identical regarding responses to CAP, we cannot discard the contribution of vagal afferents to the secretory responses obtained in our study.…”

Tromethamine improves mucociliary clearance in cystic fibrosis pigs

“…However, this discrepancy of decreased MCT may be explained by understanding how HS is affecting the airway epithelium within our experimental context. First, HS is an osmotic mucolytic and as such it may draw liquid into ASL and improve MCT by increasing ASL height (Goralski et al, 2018; Luan et al, 2019). However, in the presence of cholinergic stimulation, fluid secretion is already maximally stimulated (Lee & Foskett, 2014).…”

Considerations for and Mechanisms of Adjunct Therapy in COPD

“…The exact mechanism of action of HTS remains unclear, but current understanding points to a multimodal effect. HTS creates an endobronchial osmotic gradient, leading to increased passive secretion of water into the airways through apical aquaporin channels [ 42 ], while also stimulating airway neurons to trigger epithelial secretion of ASL [ 43 ]. HTS also has mucolytic properties which decrease mucous viscosity, allowing for the reformation of mucous as it ascends the bronchial tree and promoting overall clearance.…”