Abstract
Simple SummaryCystic fibrosis (CF) is a multi-organ disease that affects the epithelia and exocrine glands, particularly the lungs, but also the pancreas, liver, kidneys, and intestines. Respiratory disease is the most common cause of death. Many of the problems in respiratory disease can be attributed to the viscous nature of the mucus. Indeed, thick mucus in the airways leads to reduced mucociliary clearance, chronic bacterial infections and inflammation followed by destruction of the lung parenchyma. The composition of the periciliary fluid (ASL) is regulated by the transport of water and ions through different ion channels and transporters distributed in a non-symmetrical way to the two parts of the epithelium. Mucus is the first line of defense against inhaled particles and protects the epithelium by trapping and eliminating harmful substances through the blink of the cells that push them towards the nose. In patients with CF the malfunction of the mutated CFTR causes a reduction in bicarbonate secretion with consequent reduction in the expansion of mucins and the formation of thick mucus. In this work we have shown that, in vitro, the administration of a solution containing bicarbonate ion would act not only on the osmotic component of the mucus, but directly on the expansion of the mucins by acting on its viscoelastic properties.Cystic fibrosis (CF) is a genetic disease associated with the defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein that causes obstructive disease and chronic bacterial infections in airway epithelia. Deletion of phenylalanine at position 508, p.F508del, the most frequent mutation among CF patients, causes a folding and traffic defect, resulting in a dramatic reduction in the CFTR expression. To investigate whether the direct application of bicarbonate could modify the properties of the airway surface liquid (ASL), we measured the micro-viscosity, fluid transport and pH of human bronchial epithelial cells monolayers. We have demonstrated that the treatment of a CF-epithelia with an iso-osmotic solution containing bicarbonate is capable of reducing both, the ASL viscosity and the apical fluid re-absorption. We suggest the possibility of design a supportive treatment based on topical application of bicarbonate, or any other alkaline buffer.
Highlights
Cystic fibrosis (CF) is a monogenic disease caused by the lack of function of the cystic fibrosis transmembrane conductance regulator protein (CFTR), an anion-permeable channel involved in fluid transport through epithelia [1]
In CF patients, the reduced bicarbonate secretion causes a lowering of the airway surface liquid (ASL) pH which is involved in the change of the epithelia equilibrium with alterations in the ciliary function, mucus formation and antimicrobial activity [11,12]
The valuation of micro-rheology properties of the fluid recovered from the apical side of CF and non-CF epithelia has shown that, in vitro, the viscosity of the CF human bronchial primary epithelial cells (HBEC) ASL
Summary
Cystic fibrosis (CF) is a monogenic disease caused by the lack of function of the cystic fibrosis transmembrane conductance regulator protein (CFTR), an anion-permeable channel involved in fluid transport through epithelia [1]. In CF patients, the reduced bicarbonate secretion causes a lowering of the ASL pH which is involved in the change of the epithelia equilibrium with alterations in the ciliary function, mucus formation and antimicrobial activity [11,12]. When CF human bronchial primary epithelial cells (HBEC) were treated with lumacaftor, 25% of the ion transport of p.F508del-CFTR was rescued, and, even if the rate of fluid re-absorption was not modified, this functional correction was enough to reduce significantly the ASL mucus viscosity [13]. Dobay and colleagues [19] demonstrated that, in vitro, the application of bicarbonate causes a reduction in bacterial growth and blocks the formation of the biofilm from P. aeruginosa, and the authors suggested the an aerosol inhalation therapy with HCO3- solutions can help improve respiratory hygiene in patients with cystic fibrosis and possibly other chronically infected lung diseases [19]. Biology 2021, 10, 278 translated in a treatment for CF patients, representing a mutation-independent therapy to clear the airways of thickened mucus and improve lung function [13,21,23]
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