Abstract
Cystic fibrosis (CF) is a genetic disease characterized by the lack of cystic fibrosis transmembrane conductance regulator (CFTR) protein expressed in epithelial cells. The resulting defective chloride and bicarbonate secretion and imbalance of the transepithelial homeostasis lead to abnormal airway surface liquid (ASL) composition and properties. The reduced ASL volume impairs ciliary beating with the consequent accumulation of sticky mucus. This situation prevents the normal mucociliary clearance, favouring the survival and proliferation of bacteria and contributing to the genesis of CF lung disease. Here, we have explored the potential of small molecules capable of facilitating the transmembrane transport of chloride and bicarbonate in order to replace the defective transport activity elicited by CFTR in CF airway epithelia. Primary human bronchial epithelial cells obtained from CF and non-CF patients were differentiated into a mucociliated epithelia in order to assess the effects of our compounds on some key properties of ASL. The treatment of these functional models with non-toxic doses of the synthetic anionophores improved the periciliary fluid composition, reducing the fluid re-absorption, correcting the ASL pH and reducing the viscosity of the mucus, thus representing promising drug candidates for CF therapy.
Highlights
Transepithelial ions and water transport, which are essential for the proper functioning of epithelial tissues, are controlled by different proteins distributed non-symmetrically to the two sides of the epithelium [1]
The thickness and ion concentrations of airway surface liquid (ASL) are carefully maintained through the chloride and bicarbonate secretion, predominantly via the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and the sodium absorption mediated by the epithelial sodium channel (ENaC) [4]
This results in the lack of a functional CFTR protein expressed in epithelial cells and defective chloride and bicarbonate secretion affects the upper and lower airway, intestine, endocrine and reproductive organs [5,6]
Summary
Transepithelial ions and water transport, which are essential for the proper functioning of epithelial tissues, are controlled by different proteins distributed non-symmetrically to the two sides of the epithelium [1]. Cystic fibrosis (CF) is a genetic disease caused by mutations in the CFTR gene This results in the lack of a functional CFTR protein expressed in epithelial cells and defective chloride and bicarbonate secretion affects the upper and lower airway, intestine, endocrine and reproductive organs [5,6]. Loss of CFTR protein function imbalances the transepithelial homeostasis, which as a direct consequence generates a reduced and more acidic ASL. This in turn impairs the beat of the cilia ending in an accumulation of sticky mucus in the affected area [7,8]. This environment inhibits the antimicrobial activity favouring the survival and proliferation of bacteria and contributing to the genesis of CF lung disease [9,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
