Hyperinflammation and airway surface liquid dehydration in cystic fibrosis: purinergic system as therapeutic target

2021 ◽  
Author(s):  
Thiago Inácio Teixeira do Carmo ◽  
Victor Emanuel Miranda Soares ◽  
Jonatha Wruck ◽  
Fernanda dos Anjos ◽  
Débora Tavares de Resende e Silva ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Therapeutic Target ◽  
Airway Surface Liquid ◽  
Purinergic System ◽  
Surface Liquid

Development of Confocal Reflection Microscopy for the Study of Airway Surface Liquid Dysregulation in Cystic Fibrosis

Pneumologie ◽  
2015 ◽  
Vol 69 (07) ◽  
Author(s):  
A Seyhan Agircan ◽  
M Lampe ◽  
J Duerr ◽  
R Pepperkok ◽  
MA Mall
Keyword(s):  
Cystic Fibrosis ◽  
Airway Surface Liquid ◽  
Surface Liquid

scholarly journals SPLUNC1 degradation by the cystic fibrosis mucosal environment drives airway surface liquid dehydration

2018 ◽  
Vol 52 (4) ◽  
pp. 1800668 ◽  
Author(s):  
Megan J. Webster ◽  
Boris Reidel ◽  
Chong D. Tan ◽  
Arunava Ghosh ◽  
Neil E. Alexis ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Airway Surface Liquid ◽  
The Novel ◽  
Pulmonary Tissue ◽  
Tissue Samples ◽  
Protein Levels ◽  
Surface Liquid ◽  
Protease Degradation ◽  
Mucosal Secretions ◽  
Cystic Fibrosis Transmembrane

The multi-organ disease cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane regulator gene (CFTR) that lead to diminished transepithelial anion transport. CF lungs are characterised by airway surface liquid (ASL) dehydration, chronic infection/inflammation and neutrophilia. Dysfunctional CFTR may upregulate the epithelial Na+ channel (ENaC), further exacerbating dehydration. We previously demonstrated that short palate lung and nasal epithelial clone 1 (SPLUNC1) negatively regulates ENaC in normal airway epithelia.Here, we used pulmonary tissue samples, sputum and human bronchial epithelial cells (HBECs) to determine whether SPLUNC1 could regulate ENaC in a CF-like environment.We found reduced endogenous SPLUNC1 in CF secretions, and rapid degradation of recombinant SPLUNC1 (rSPLUNC1) by CF secretions. Normal sputum, containing SPLUNC1 and SPLUNC1-derived peptides, inhibited ENaC in both normal and CF HBECs. Conversely, CF sputum activated ENaC, and rSPLUNC1 could not reverse this phenomenon. Additionally, we observed upregulation of ENaC protein levels in human CF bronchi. Unlike SPLUNC1, the novel SPLUNC1-derived peptide SPX-101 resisted protease degradation, bound apically to HBECs, inhibited ENaC and prevented ASL dehydration following extended pre-incubation with CF sputum.Our data indicate that CF mucosal secretions drive ASL hyperabsorption and that protease-resistant peptides, e.g. SPX-101, can reverse this effect to rehydrate CF ASL.

scholarly journals Hypertonic Saline in Treatment of Pulmonary Disease in Cystic Fibrosis

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Emer P. Reeves ◽  
Kevin Molloy ◽  
Kerstin Pohl ◽  
Noel G. McElvaney
Keyword(s):  
Cystic Fibrosis ◽  
Hypertonic Saline ◽  
Mucociliary Clearance ◽  
Inflammatory Cells ◽  
Liquid Volume ◽  
Airway Surface Liquid ◽  
Beneficial Effects ◽  
Therapeutic Benefits ◽  
Surface Liquid ◽  
Subsequent Failure

The pathogenesis of lung disease in cystic fibrosis is characterised by decreased airway surface liquid volume and subsequent failure of normal mucociliary clearance. Mucus within the cystic fibrosis airways is enriched in negatively charged matrices composed of DNA released from colonizing bacteria or inflammatory cells, as well as F-actin and elevated concentrations of anionic glycosaminoglycans. Therapies acting against airway mucus in cystic fibrosis include aerosolized hypertonic saline. It has been shown that hypertonic saline possesses mucolytic properties and aids mucociliary clearance by restoring the liquid layer lining the airways. However, recent clinical and bench-top studies are beginning to broaden our view on the beneficial effects of hypertonic saline, which now extend to include anti-infective as well as anti-inflammatory properties. This review aims to discuss the described therapeutic benefits of hypertonic saline and specifically to identify novel models of hypertonic saline action independent of airway hydration.

scholarly journals Paracellular bicarbonate flux across human cystic fibrosis airway epithelia tempers changes in airway surface liquid pH

2020 ◽  
Vol 598 (19) ◽  
pp. 4307-4320 ◽  
Author(s):  
Ian M. Thornell ◽  
Tayyab Rehman ◽  
Alejandro A. Pezzulo ◽  
Michael J. Welsh
Keyword(s):  
Cystic Fibrosis ◽  
Airway Surface Liquid ◽  
Airway Epithelia ◽  
Cystic Fibrosis Airway ◽  
Surface Liquid

scholarly journals Inhibition of ATP hydrolysis restores airway surface liquid production in cystic fibrosis airway epithelia

2020 ◽  
Vol 318 (2) ◽  
pp. L356-L365 ◽  
Author(s):  
Catharina van Heusden ◽  
Brian Button ◽  
Wayne H. Anderson ◽  
Agathe Ceppe ◽  
Lisa C. Morton ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Steady State ◽  
Atp Hydrolysis ◽  
Fluid Secretion ◽  
Pathological Feature ◽  
Airway Surface Liquid ◽  
Airway Epithelial ◽  
Airway Epithelia ◽  
Atp Levels ◽  
Surface Liquid

Airway surface dehydration is a pathological feature of cystic fibrosis (CF) lung disease. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR), a cyclic AMP-regulated Cl− channel controlled in part by the adenosine A2B receptor. An alternative CFTR-independent mechanism of fluid secretion is regulated by ATP via the P2Y2 receptor (P2Y2R) that activates Ca2+-regulated Cl− channels (CaCC/TMEM16) and inhibits Na+ absorption. However, due to rapid ATP hydrolysis, steady-state ATP levels in CF airway surface liquid (ASL) are inadequate to maintain P2Y2R-mediated fluid secretion. Therefore, inhibiting airway epithelial ecto-ATPases to increase ASL ATP levels constitutes a strategy to restore airway surface hydration in CF. Using [γ32P]ATP as radiotracer, we assessed the effect of a series of ATPase inhibitory compounds on the stability of physiologically occurring ATP concentrations. We identified the polyoxometalate [Co4(H2O)2(PW9O34)2]10− (POM-5) as the most potent and effective ecto-ATPase inhibitor in CF airway epithelial cells. POM-5 caused long-lasting inhibition of ATP hydrolysis in airway epithelia, which was reversible upon removal of the inhibitor. Importantly, POM-5 markedly enhanced steady-state levels of released ATP, promoting increased ASL volume in CF cell surfaces. These results provide proof of concept for ecto-ATPase inhibitors as therapeutic agents to restore hydration of CF airway surfaces. As a test of this notion, cell-free sputum supernatants from CF subjects were studied and found to have abnormally elevated ATPase activity, which was markedly inhibited by POM-5.

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

2020 ◽  
Vol 21 (4) ◽  
pp. 1488 ◽  
Author(s):  
Ambra Gianotti ◽  
Valeria Capurro ◽  
Livia Delpiano ◽  
Marcin Mielczarek ◽  
María García-Valverde ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Fluid Composition ◽  
Airway Surface Liquid ◽  
Airway Epithelia ◽  
Drug Candidates ◽  
Cystic Fibrosis Airway ◽  
Functional Models ◽  
Cftr Protein ◽  
Surface Liquid

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.

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