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 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 Soluble Mediators, Not Cilia, Determine Airway Surface Liquid Volume in Normal and Cystic Fibrosis Superficial Airway Epithelia

2006 ◽  
Vol 127 (5) ◽  
pp. 591-604 ◽  
Author(s):  
Robert Tarran ◽  
Laura Trout ◽  
Scott H. Donaldson ◽  
Richard C. Boucher
Keyword(s):  
Cystic Fibrosis ◽  
Volume Regulation ◽  
Liquid Volume ◽  
Airway Surface Liquid ◽  
Airway Epithelia ◽  
Innate Defense ◽  
Cl Secretion ◽  
Immotile Cilia ◽  
Glandular Secretion ◽  
Surface Liquid

A key aspect of the lung's innate defense system is the ability of the superficial epithelium to regulate airway surface liquid (ASL) volume to maintain a 7-μm periciliary liquid layer (PCL), which is required for cilia to beat and produce mucus flow. The mechanisms whereby airway epithelia regulate ASL height to ≥7 μm are poorly understood. Using bumetanide as an inhibitor of Cl− secretion, and nystatin as an activator of Na+ absorption, we found that a coordinated “blending” of both Cl− secretion and Na+ absorption must occur to effect ASL volume homeostasis. We then investigated how ASL volume status is regulated by the underlying epithelia. Cilia were not critical to this process as (a) ASL volume was normal in cultures from patients with primary ciliary dyskinesia with immotile cilia, and (b) in normal cultures that had not yet undergone ciliogenesis. However, we found that maneuvers that mimic deposition of excess ASL onto the proximal airways, which occurs during mucociliary clearance and after glandular secretion, acutely stimulated Na+ absorption, suggesting that volume regulation was sensitive to changes in concentrations of soluble mediators in the ASL rather than alterations in ciliary beating. To investigate this hypothesis further, we added potential “soluble mediators” to the ASL. ASL volume regulation was sensitive to a channel-activating protein (CAP; trypsin) and a CAP inhibitor (aprotinin), which regulated Na+ absorption via changes in epithelial Na+ channel (ENaC) activity in both normal and cystic fibrosis cultures. ATP was also found to acutely regulate ASL volume by inducing secretion in normal and cystic fibrosis (CF) cultures, while its metabolite adenosine (ADO) evoked secretion in normal cultures but stimulated absorption in CF cultures. Interestingly, the amount of ASL/Cl− secretion elicited by ATP/ADO was influenced by the level of CAP-induced Na+ absorption, suggesting that there are important interactions between the soluble regulators which finely tune ASL volume.

scholarly journals Thickness of the airway surface liquid layer in the lung is affected in cystic fibrosis by compromised synergistic regulation of the ENaC ion channel

2019 ◽  
Vol 16 (157) ◽  
pp. 20190187 ◽  
Author(s):  
Daniel V. Olivença ◽  
Luis L. Fonseca ◽  
Eberhard O. Voit ◽  
Francisco R. Pinto
Keyword(s):  
Cystic Fibrosis ◽  
Steady State ◽  
Phosphoinositide Metabolism ◽  
Airway Surface Liquid ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Therapeutic Benefits ◽  
Synergistic Regulation ◽  
Surface Liquid ◽  
Cf Transmembrane Conductance Regulator

The lung epithelium is lined with a layer of airway surface liquid (ASL) that is crucial for healthy lung function. ASL thickness is controlled by two ion channels: epithelium sodium channel (ENaC) and cystic fibrosis (CF) transmembrane conductance regulator (CFTR). Here, we present a minimal mathematical model of ENaC, CFTR and ASL regulation that sheds light on the control of ENaC by the short palate lung and nasal epithelial clone 1 (SPLUNC1) protein and by phosphatidylinositol 4,5-biphosphate (PI(4,5)P 2 ). The model, despite its simplicity, yields a good fit to experimental observations and is an effective tool for exploring the interplay between ENaC, CFTR and ASL. Steady-state data and dynamic information constrain the model's parameters without ambiguities. Testing the hypothesis that PI(4,5)P 2 protects ENaC from ubiquitination suggests that this protection does not improve the model results and that the control of the ENaC opening probability by PI(4,5)P 2 is sufficient to explain all available data. The model analysis further demonstrates that ASL at the steady state is sensitive to small changes in PI(4,5)P 2 abundance, particularly in CF conditions, which suggests that manipulation of phosphoinositide metabolism may promote therapeutic benefits for CF patients.

scholarly journals Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis

2008 ◽  
Vol 294 (5) ◽  
pp. L932-L941 ◽  
Author(s):  
Mike M. Myerburg ◽  
Erin E. McKenna ◽  
Cliff J. Luke ◽  
Raymond A. Frizzell ◽  
Thomas R. Kleyman ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Airway Epithelial Cells ◽  
Proteolytic Processing ◽  
Surface Epithelium ◽  
Liquid Volume ◽  
Osmotic Gradient ◽  
Airway Surface Liquid ◽  
Epithelial Surface ◽  
Proteolytic Activation ◽  
Surface Liquid

Airway surface liquid (ASL) absorption is initiated by Na+ entry via epithelial Na+ channels (ENaC), which establishes an osmotic gradient that drives fluid from the luminal to serosal airway surface. We and others have recently reported that a protease/anti-protease balance regulates ENaC in human airway epithelial cells (HAEC) and provides a mechanism for autoregulation of ASL volume. In cystic fibrosis (CF), this balance is disturbed, leading to constitutive proteolytic activation of ENaC and the pathological Na+ hyperabsorption characteristic of this airway disease. Prostasin is a glycosylphosphatidylinositol-anchored serine protease that activates ENaC and is expressed on the surface epithelium lining the airway. In this report we present evidence that prostasin expression is regulated by the ASL volume, allowing for increased proteolytic activation of ENaC when the ASL volume is high. Prostasin activity is further regulated by the cognate serpin protease nexin-1 (PN-1), which is expressed in HAEC and inhibits Na+ absorption by forming an inactive complex with prostasin and preventing the proteolytic processing of prostasin. Whereas these mechanisms regulate prostasin expression in response to ASL volume in non-CF epithelia, HAEC cultured from CF patients express >50% more prostasin on the epithelial surface. These findings suggest that a proteolytic cascade involving prostasin, an upstream prostasin-activating protease, and PN-1 regulate Na+ absorption in the airway and that abnormal prostasin expression contributes to excessive proteolytic activation of ENaC in CF patients.

scholarly journals Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

2016 ◽  
Vol 30 (6) ◽  
pp. 2187-2197 ◽  
Author(s):  
Peter M. Haggie ◽  
Puay‐Wah Phuan ◽  
Joseph‐Anthony Tan ◽  
Lorna Zlock ◽  
Walter E. Finkbeiner ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Anion Exchange ◽  
Small Molecule ◽  
Liquid Volume ◽  
Airway Surface Liquid ◽  
Small Molecule Screen ◽  
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
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