Therapeutic Options for Hydrating Airway Mucus in Cystic Fibrosis

Abstract

Background: In cystic fibrosis (CF), genetic mutations in the CF transmembrane conductance regulator (CFTR) gene cause reduced chloride efflux from ciliated airway epithelial cells. This results in a reduction in periciliary liquid (PCL) depth of the airway surface liquid due to associated reduced water efflux. PCL layer dehydration reduces mucociliary clearance (MCC), leading to airway obstruction (reduced airflow and inflammation due to pathogen invasion) with mucus plug formation. Summary: Rehydrating mucus increases MCC. Mucus hydration can be achieved by direct hydration (administering osmotic agents to set up an osmotic gradient), using CFTR modulators to correct dysfunctional CFTR, or it can be achieved pharmacologically (targeting other ion channels on airway epithelial cells). Key Messages: The molecular mechanisms of several therapies are discussed in the context of pre-clinical and clinical trial studies. Currently, only the osmotic agent 7% hypertonic saline and the CFTR ‘potentiator' VX-770 (ivacaftor) are used clinically to hydrate mucus. Emerging therapies include the osmotic agent mannitol (Bronchitol), the intracellular Ca²⁺-raising agent Moli1901/lancovutide, the CFTR potentiator sildenafil [phosphodiesterase type 5 (PDE5) inhibitor] and the CFTR ‘corrector' VX-809 (lumacaftor). Other CFTR correctors (e.g. ‘chemical chaperones') are also showing pre-clinical promise.

Hyper-osmolarity and calcium chelation: Effects on cystic fibrosis mucus

“…The literature suggests that increased osmolarity may help normalize mucus by increasing the hydration of the mucus gel (Tildy and Rogers, 2015). Therefore we added 69 or 115 mM bicarbonate to the apical Krebs buffer without removing NaCl, giving a hypertonic solution.…”

Influence of the Surfactant Tyloxapol on Mucociliary Clearance in Human Respiratory Cystic Fibrosis Cells

“…The cells used for this experiment were taken from 3 CF patients and cultivated for 60 days. Tissues originate from patients belonging to the homozygons ρF508 mutation, where 70% of CF-patients belong to [3]. In this study, the effect of tyloxapol on mucociliary clearance was evaluated on 3 independent batches from these CF patients of MucilAir™-CF (CF_MD0220; CF_MD0437; CF_MD0485) and measurements of the movements of microbeads were performed in triplicates.…”

“…In the tracheobronchial tree, mucus is always moved toward and through the larynx and then swallowed. PCL dehydration reduces mucociliary clearance, leading to airway obstruction [3]. Mucus hypersecretion with abnormal mucus consistency and reduced mucociliary clearance occurs in respiratory diseases like cystic fibrosis (CF), respiratory distress syndrome (RDS) of the newborn, chronic obstructive pulmonary disease, asthma and also in heavy smokers.…”

Novel Therapies to Inhibit Mucus Synthesis and Secretion in Airway Hypersecretory Diseases

“…Strategies to improve mucus hydration are relatively effective in cystic fibrosis [9]. However, mucus dehydration is not a notable pathophysiological feature of asthma and COPD.…”