Small Molecule Anion Carriers Correct Abnormal Airway Surface Liquid Properties in Cystic Fibrosis Airway Epithelia

Ambra Gianotti, Valeria Capurro, Livia Delpiano, Marcin Mielczarek, María García-Valverde, Israel Carreira-Barral, Alessandra Ludovico, Michele Fiore, Debora Baroni, Oscar Moran, Roberto Quesada, Emanuela Caci

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalInt J Mol Sci
Volume21
Issue number4
DOIs
Publication statusPublished - Feb 21 2020

Keywords

  • Cell Line
  • Cystic Fibrosis/drug therapy
  • Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
  • Epithelial Cells/metabolism
  • Humans
  • Ion Transport/drug effects
  • Ionophores/chemical synthesis
  • Mucus/metabolism
  • Respiratory Mucosa/metabolism

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