REGULATION OF NORMAL AND CYSTIC FIBROSIS AIRWAY SURFACE LIQUID VOLUME BY PHASIC SHEAR STRESS

2006 ◽  
Vol 68 (1) ◽  
pp. 543-561 ◽  
Author(s):  
Robert Tarran ◽  
Brian Button ◽  
Richard C. Boucher
Keyword(s):  
Cystic Fibrosis ◽  
Shear Stress ◽  
Liquid Volume ◽  
Airway Surface Liquid ◽  
Cystic Fibrosis Airway ◽  
Surface Liquid

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 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.

Airway Surface Liquid Calcium Modulates Chloride Permeability in the Cystic Fibrosis Airway

2003 ◽  
Vol 168 (10) ◽  
pp. 1223-1226 ◽  
Author(s):  
Peter G. Middleton ◽  
Katy A. Pollard ◽  
Elizabeth Donohoo ◽  
John R. Wheatley ◽  
Duncan M. Geddes ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Airway Surface Liquid ◽  
Chloride Permeability ◽  
Cystic Fibrosis Airway ◽  
Liquid Calcium ◽  
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 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 Measuring Airway Surface Liquid Depth in Ex Vivo Mouse Airways by X-Ray Imaging for the Assessment of Cystic Fibrosis Airway Therapies

PLoS ONE ◽  
2013 ◽  
Vol 8 (1) ◽  
pp. e55822 ◽  
Author(s):  
Kaye S. Morgan ◽  
Martin Donnelley ◽  
David M. Paganin ◽  
Andreas Fouras ◽  
Naoto Yagi ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Ex Vivo ◽  
Airway Surface Liquid ◽  
X Ray ◽  
X Ray Imaging ◽  
Cystic Fibrosis Airway ◽  
Liquid Depth ◽  
Surface Liquid
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