scholarly journals Physiological levels of lipoxin A4 inhibit ENaC and restore airway surface liquid height in cystic fibrosis bronchial epithelium

2014 ◽  
Vol 2 (8) ◽  
pp. e12093 ◽  
Author(s):  
Mazen Al-Alawi ◽  
Paul Buchanan ◽  
Valia Verriere ◽  
Gerard Higgins ◽  
Olive McCabe ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Bronchial Epithelium ◽  
Airway Surface Liquid ◽  
Lipoxin A4 ◽  
Liquid Height ◽  
Surface Liquid

scholarly journals Lipoxin A4 Stimulates Calcium-Activated Chloride Currents and Increases Airway Surface Liquid Height in Normal and Cystic Fibrosis Airway Epithelia

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e37746 ◽  
Author(s):  
Valia Verrière ◽  
Gerard Higgins ◽  
Mazen Al-Alawi ◽  
Richard W. Costello ◽  
Paul McNally ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Airway Surface Liquid ◽  
Lipoxin A4 ◽  
Airway Epithelia ◽  
Chloride Currents ◽  
Liquid Height ◽  
Cystic Fibrosis Airway ◽  
Surface Liquid

scholarly journals Evaluation of a SPLUNC1-derived peptide for the treatment of cystic fibrosis lung disease

2018 ◽  
Vol 314 (1) ◽  
pp. L192-L205 ◽  
Author(s):  
Shawn T. Terryah ◽  
Robert C. Fellner ◽  
Saira Ahmad ◽  
Patrick J. Moore ◽  
Boris Reidel ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Animal Models ◽  
Renal Toxicity ◽  
Morbidity And Mortality ◽  
Liquid Volume ◽  
Airway Surface Liquid ◽  
Naturally Occurring ◽  
Liquid Height ◽  
Surface Liquid ◽  
Target Effects

In cystic fibrosis (CF) lungs, epithelial Na+ channel (ENaC) hyperactivity causes a reduction in airway surface liquid volume, leading to decreased mucocilliary clearance, chronic bacterial infection, and lung damage. Inhibition of ENaC is an attractive therapeutic option. However, ENaC antagonists have failed clinically because of off-target effects in the kidney. The S18 peptide is a naturally occurring short palate lung and nasal epithelial clone 1 (SPLUNC1)-derived ENaC antagonist that restores airway surface liquid height for up to 24 h in CF human bronchial epithelial cultures. However, its efficacy and safety in vivo are unknown. To interrogate the potential clinical efficacy of S18, we assessed its safety and efficacy using human airway cultures and animal models. S18-mucus interactions were tested using superresolution microscopy, quartz crystal microbalance with dissipation, and confocal microscopy. Human and murine airway cultures were used to measure airway surface liquid height. Off-target effects were assessed in conscious mice and anesthetized rats. Morbidity and mortality were assessed in the β-ENaC-transgenic (Tg) mouse model. Restoration of normal mucus clearance was measured in cystic fibrosis transmembrane conductance regulator inhibitor 172 [CFTR(inh)-172]-challenged sheep. We found that S18 does not interact with mucus and rapidly penetrated dehydrated CF mucus. Compared with amiloride, an early generation ENaC antagonist, S18 displayed a superior ability to slow airway surface liquid absorption, reverse CFTR(inh)-172-induced reduction of mucus transport, and reduce morbidity and mortality in the β-ENaC-Tg mouse, all without inducing any detectable signs of renal toxicity. These data suggest that S18 is the first naturally occurring ENaC antagonist to show improved preclinical efficacy in animal models of CF with no signs of renal toxicity.

scholarly journals Non-Genomic Estrogen Regulation of Ion Transport and Airway Surface Liquid Dynamics in Cystic Fibrosis Bronchial Epithelium

PLoS ONE ◽  
2013 ◽  
Vol 8 (11) ◽  
pp. e78593 ◽  
Author(s):  
Vinciane Saint-Criq ◽  
Sung Hoon Kim ◽  
John A. Katzenellenbogen ◽  
Brian J. Harvey
Keyword(s):  
Cystic Fibrosis ◽  
Ion Transport ◽  
Bronchial Epithelium ◽  
Airway Surface Liquid ◽  
Estrogen Regulation ◽  
Surface Liquid ◽  
Liquid Dynamics

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

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

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
Sign in / Sign up

Export Citation Format

Share Document