scholarly journals Regulation of Murine Airway Surface Liquid Volume by CFTR and Ca2+-activated Cl− Conductances

2002 ◽  
Vol 120 (3) ◽  
pp. 407-418 ◽  
Author(s):  
Robert Tarran ◽  
Matthew E. Loewen ◽  
Anthony M. Paradiso ◽  
John C. Olsen ◽  
Micheal A. Gray ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Driving Force ◽  
Apical Membrane ◽  
Critical Role ◽  
Liquid Volume ◽  
Airway Surface Liquid ◽  
Airway Epithelia ◽  
Molecular Identity ◽  
Surface Liquid ◽  
Cl Conductance

Two Cl− conductances have been described in the apical membrane of both human and murine proximal airway epithelia that are thought to play predominant roles in airway hydration: (1) CFTR, which is cAMP regulated and (2) the Ca2+-activated Cl− conductance (CaCC) whose molecular identity is uncertain. In addition to second messenger regulation, cross talk between these two channels may also exist and, whereas CFTR is absent or defective in cystic fibrosis (CF) airways, CaCC is preserved, and may even be up-regulated. Increased CaCC activity in CF airways is controversial. Hence, we have investigated the effects of CFTR on CaCC activity and have also assessed the relative contributions of these two conductances to airway surface liquid (ASL) height (volume) in murine tracheal epithelia. We find that CaCC is up-regulated in intact murine CF tracheal epithelia, which leads to an increase in UTP-mediated Cl−/volume secretion. This up-regulation is dependent on cell polarity and is lost in nonpolarized epithelia. We find no role for an increased electrical driving force in CaCC up-regulation but do find an increased Ca2+ signal in response to mucosal nucleotides that may contribute to the increased Cl−/volume secretion seen in intact epithelia. CFTR plays a critical role in maintaining ASL height under basal conditions and accordingly, ASL height is reduced in CF epithelia. In contrast, CaCC does not appear to significantly affect basal ASL height, but does appear to be important in regulating ASL height in response to released agonists (e.g., mucosal nucleotides). We conclude that both CaCC and the Ca2+ signal are increased in CF airway epithelia, and that they contribute to acute but not basal regulation of ASL height.

scholarly journals Thick airway surface liquid volume and weak mucin expression in pendrin-deficient human airway epithelia

2015 ◽  
Vol 3 (8) ◽  
pp. e12480 ◽  
Author(s):  
Hyun Jae Lee ◽  
Jee Eun Yoo ◽  
Wan Namkung ◽  
Hyung-Ju Cho ◽  
Kyubo Kim ◽  
...  
Keyword(s):  
Liquid Volume ◽  
Airway Surface Liquid ◽  
Airway Epithelia ◽  
Human Airway ◽  
Mucin Expression ◽  
Surface Liquid ◽  
Human Airway Epithelia

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 Functional Apical Large Conductance, Ca2+-activated, and Voltage-dependent K+ Channels Are Required for Maintenance of Airway Surface Liquid Volume

2011 ◽  
Vol 286 (22) ◽  
pp. 19830-19839 ◽  
Author(s):  
Dahis Manzanares ◽  
Carlos Gonzalez ◽  
Pedro Ivonnet ◽  
Ren-Shiang Chen ◽  
Monica Valencia-Gattas ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Ion Transport ◽  
Apical Membrane ◽  
Airway Epithelial Cells ◽  
Bk Channels ◽  
Liquid Volume ◽  
Airway Surface Liquid ◽  
Airway Epithelial ◽  
Voltage Dependent ◽  
Surface Liquid

Large conductance, Ca2+-activated, and voltage-dependent K+ (BK) channels control a variety of physiological processes in nervous, muscular, and renal epithelial tissues. In bronchial airway epithelia, extracellular ATP-mediated, apical increases in intracellular Ca2+ are important signals for ion movement through the apical membrane and regulation of water secretion. Although other, mainly basolaterally expressed K+ channels are recognized as modulators of ion transport in airway epithelial cells, the role of BK in this process, especially as a regulator of airway surface liquid volume, has not been examined. Using patch clamp and Ussing chamber approaches, this study reveals that BK channels are present and functional at the apical membrane of airway epithelial cells. BK channels open in response to ATP stimulation at the apical membrane and allow K+ flux to the airway surface liquid, whereas no functional BK channels were found basolaterally. Ion transport modeling supports the notion that apically expressed BK channels are part of an apical loop current, favoring apical Cl− efflux. Importantly, apical BK channels were found to be critical for the maintenance of adequate airway surface liquid volume because continuous inhibition of BK channels or knockdown of KCNMA1, the gene coding for the BK α subunit (KCNMA1), lead to airway surface dehydration and thus periciliary fluid height collapse revealed by low ciliary beat frequency that could be fully rescued by addition of apical fluid. Thus, apical BK channels play an important, previously unrecognized role in maintaining adequate airway surface hydration.

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 Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion

2013 ◽  
Vol 304 (11) ◽  
pp. L746-L756 ◽  
Author(s):  
Robert Tarran ◽  
Juan R. Sabater ◽  
Tainya C. Clarke ◽  
Chong D. Tan ◽  
Catrin M. Davies ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Bacterial Resistance ◽  
Liquid Volume ◽  
Human Neutrophil Elastase ◽  
Airway Surface Liquid ◽  
Volume Depletion ◽  
Innate Defense ◽  
Mucus Clearance ◽  
Surface Liquid

Mucus clearance is an important component of the lung's innate defense system. A failure of this system brought on by mucus dehydration is common to both cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Mucus clearance rates are regulated by the volume of airway surface liquid (ASL) and by ciliary beat frequency (CBF). Chronic treatment with macrolide antibiotics is known to be beneficial to both CF and COPD patients. However, chronic macrolide usage may induce bacterial resistance. We have developed a novel macrolide, 2′-desoxy-9-( S)-erythromycylamine (GS-459755), that has significantly diminished antibiotic activity against Staphylococcus aureus, Streptococcus pneumonia, Moraxella catarrhalis, and Haemophilus influenzae. Since neutrophilia frequently occurs in chronic lung disease and human neutrophil elastase (HNE) induces mucus stasis by activating the epithelial sodium channel (ENaC), we tested the ability of GS-459755 to protect against HNE-induced mucus stasis. GS-459755 had no effect on HNE activity. However, GS-459755 pretreatment protected against HNE-induced ASL volume depletion in human bronchial epithelial cells (HBECs). The effect of GS-459755 on ASL volume was dose dependent (IC50 ∼3.9 μM) and comparable to the antibacterial macrolide azithromycin (IC50 ∼2.4 μM). Macrolides had no significant effect on CBF or on transepithelial water permeability. However, the amiloride-sensitive transepithelial voltage, a marker of ENaC activity, was diminished by macrolide pretreatment. We conclude that GS-459755 may limit HNE-induced activation of ENaC and may be useful for the treatment of mucus dehydration in CF and COPD without inducing bacterial resistance.

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