Role of airway surface liquid and submucosal glands in cystic fibrosis lung disease

2003 ◽  
Vol 284 (1) ◽  
pp. C2-C15 ◽  
Author(s):  
A. S. Verkman ◽  
Yuanlin Song ◽  
Jay R. Thiagarajah
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Model Systems ◽  
Airway Surface Liquid ◽  
Cystic Fibrosis Lung Disease ◽  
Submucosal Glands ◽  
Cftr Protein ◽  
Surface Liquid ◽  
Gland Function ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein, an epithelial chloride channel expressed in the airways, pancreas, testis, and other tissues. A central question is how defective CFTR function in CF leads to chronic lung infection and deterioration of lung function. Several mechanisms have been proposed to explain lung disease in CF, including abnormal airway surface liquid (ASL) properties, defective airway submucosal gland function, altered inflammatory response, defective organellar acidification, loss of CFTR regulation of plasma membrane ion transporters, and others. This review focuses on the physiology of the ASL and submucosal glands with regard to their proposed role in CF lung disease. Experimental evidence for defective ASL properties and gland function in CF is reviewed, and deficiencies in understanding ASL/gland physiology are identified as areas for further investigation. New model systems and measurement technologies are being developed to make progress in establishing lung disease mechanisms in CF, which should facilitate mechanism-based design of therapies for CF.

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.

scholarly journals Engineered mutant α-ENaC subunit mRNA delivered by lipid nanoparticles reduces amiloride currents in cystic fibrosis–based cell and mice models

2020 ◽  
Vol 6 (47) ◽  
pp. eabc5911
Author(s):  
Anindit Mukherjee ◽  
Kelvin D. MacDonald ◽  
Jeonghwan Kim ◽  
Michael I. Henderson ◽  
Yulia Eygeris ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Therapeutic Potential ◽  
Lipid Nanoparticles ◽  
Sodium Absorption ◽  
Airway Surface Liquid ◽  
Surface Liquid ◽  
Cf Transmembrane Conductance Regulator ◽  
Airway Cells

Cystic fibrosis (CF) results from mutations in the chloride-conducting CF transmembrane conductance regulator (CFTR) gene. Airway dehydration and impaired mucociliary clearance in CF is proposed to result in tonic epithelial sodium channel (ENaC) activity, which drives amiloride-sensitive electrogenic sodium absorption. Decreasing sodium absorption by inhibiting ENaC can reverse airway surface liquid dehydration. Here, we inhibit endogenous heterotrimeric ENaC channels by introducing inactivating mutant ENaC α mRNA (αmutENaC). Lipid nanoparticles carrying αmutENaC were transfected in CF-based airway cells in vitro and in vivo. We observed a significant decrease in macroscopic as well as amiloride-sensitive ENaC currents and an increase in airway surface liquid height in CF airway cells. Similarly, intranasal transfection of αmutENaC mRNA decreased amiloride-sensitive nasal potential difference in CFTRKO mice. These data suggest that mRNA-based ENaC inhibition is a powerful strategy for reducing mucus dehydration and has therapeutic potential for treating CF in all patients, independent of genotype.

scholarly journals The Application of Bicarbonate Recovers the Chemical-Physical Properties of Airway Surface Liquid in Cystic Fibrosis Epithelia Models

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 278
Author(s):  
Loretta Ferrera ◽  
Valeria Capurro ◽  
Livia Delpiano ◽  
Ambra Gianotti ◽  
Oscar Moran
Keyword(s):  
Cystic Fibrosis ◽  
Bacterial Infections ◽  
Fluid Transport ◽  
Airway Surface Liquid ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Osmotic Solution ◽  
Cftr Protein ◽  
Surface Liquid ◽  
Cystic Fibrosis Transmembrane

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.

Hyperacidity of secreted fluid from submucosal glands in early cystic fibrosis

2006 ◽  
Vol 290 (3) ◽  
pp. C741-C749 ◽  
Author(s):  
Yuanlin Song ◽  
Danieli Salinas ◽  
Dennis W. Nielson ◽  
A. S. Verkman
Keyword(s):  
Cystic Fibrosis ◽  
Ionic Composition ◽  
Airway Disease ◽  
Bicarbonate Transport ◽  
Surface Epithelium ◽  
Transmembrane Conductance Regulator ◽  
Airway Pathology ◽  
Submucosal Glands ◽  
Cftr Protein ◽  
Cf Transmembrane Conductance Regulator

Prior studies have shown that fluid secretions from airway submucosal glands in cystic fibrosis (CF) are reduced and hyperviscous, possibly contributing to the pathogenesis of CF airway disease. Because the CF transmembrane conductance regulator (CFTR) protein can transport both chloride and bicarbonate, we investigated whether gland fluid pH is abnormal in early CF, using nasal biopsies from pediatric subjects having minimal CF lung disease. Gland fluid pH, measured in freshly secreted droplets under oil stained with BCECF-dextran, was 6.57 ± 0.09 (mean ± SE) in biopsies from six CF subjects, significantly lower than 7.18 ± 0.06 in eight non-CF biopsies ( P < 0.01). To rule out the possibility that the apparent gland fluid hyperacidity in CF results from modification of fluid pH by the airway surface, a microcannulation method was used to measure pH in fluid exiting gland orifices. In pig trachea and human bronchi, gland fluid pH was reduced by up to 0.45 units by CFTR inhibitors, but was not affected by amiloride. Acid base transport in the surface epithelium of pig trachea was studied from pH changes in 300-nl fluid droplets deposited onto the oil-covered airway surface. The droplets had specified ionic composition/pH and/or contained transporter activators/inhibitors. We found evidence for CFTR-dependent bicarbonate transport by the tracheal surface epithelium as well as ATP/histamine-stimulated proton secretion, but not for sodium/proton or chloride/bicarbonate exchange. These results provide evidence for intrinsic hyperacidity in CF gland fluid secretions, which may contribute to CF airway pathology.

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 SLC6A14Is a Genetic Modifier of Cystic Fibrosis That RegulatesPseudomonas aeruginosaAttachment to Human Bronchial Epithelial Cells

mBio ◽  
2017 ◽  
Vol 8 (6) ◽  
Author(s):  
Michelle Di Paola ◽  
Amber J. Park ◽  
Saumel Ahmadi ◽  
Elyse J. Roach ◽  
Yu-Sheng Wu ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Genetic Factors ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Airway Surface Liquid ◽  
Airway Epithelia ◽  
Genome Wide ◽  
Surface Liquid

ABSTRACTCystic fibrosis (CF) is caused by mutations in theCFTRgene and is associated with progressive and ultimately fatal infectious lung disease. There can be considerable variability in disease severity among individuals with the sameCFTRmutations, and recent genome-wide association studies have identified secondary genetic factors that contribute to this. One of these modifier genes isSLC6A14, which encodes an amino acid transporter. Importantly, variants of this gene have been associated with age at first acquisition ofPseudomonas aeruginosa. In this study, we aimed to determine the function of SLC6A14 in airway epithelia and how it might affect colonization byP. aeruginosa. We show thatSLC6A14is expressed in respiratory epithelial cells and transportsl-arginine out of the airway surface liquid (ASL). Exposure of airway epithelia to flagellin fromP. aeruginosaled to upregulation ofSLC6A14expression and increased SLC6A14-dependent uptake ofl-arginine from the ASL. In support of the hypothesis thatl-arginine affectsP. aeruginosaattachment, we showed thatl-arginine supplementation promotedP. aeruginosaattachment to an abiotic surface in a dose-dependent manner. In a coculture model, we found that inhibition of SLC6A14-dependentl-arginine transport enhancedP. aeruginosaattachment. InSlc6a14−/y(knockout) mice,P. aeruginosaattachment to lung tissue was also significantly enhanced. Together, these findings suggest that SLC6A14 activity plays a role in the modification of the initial stages of airway infection by altering the level ofl-arginine in the ASL, which in turn affects the attachment ofP. aeruginosa.IMPORTANCECF patients with sharedCFTRgene mutations show significant variability in their clinical presentation of infectious lung disease. Genome-wide association studies have been used to identify secondary genetic factors that may explain the variable susceptibility to infection by opportunistic pathogens, includingP. aeruginosa, the leading cause of pathogen-induced lung damage in nonpediatric CF patients. Once identified and characterized, these secondary genetic modifiers may allow for the development of personalized medicine for patients and ultimately the extension of life. In this study, we interrogated the biological role of one of these modifiers,SLC6A14, and showed that it contributes to host defense by depleting extracellular arginine (an attachment-promoting metabolite forP. aeruginosa) from the airway 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

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
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