scholarly journals Combined agonists act synergistically to increase mucociliary clearance in a cystic fibrosis airway model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nam Soo Joo ◽  
Hyung-Ju Cho ◽  
Meagan Shinbashi ◽  
Jae Young Choi ◽  
Carlos E. Milla ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Mucociliary Clearance ◽  
Defense Mechanism ◽  
Fluid Secretion ◽  
Adrenergic Agonist ◽  
Anion Secretion ◽  
Innate Defense ◽  
Mucus Clearance ◽  
Cystic Fibrosis Airway ◽  
Submucosal Glands

AbstractMucus clearance, a primary innate defense mechanism of airways, is defective in patients with cystic fibrosis (CF) and CF animals. In previous work, the combination of a low dose of the cholinergic agonist, carbachol with forskolin or a β adrenergic agonist, isoproterenol synergistically increased mucociliary clearance velocity (MCCV) in ferret tracheas. Importantly, the present study shows that synergistic MCCV can also be produced in CF ferrets, with increases ~ 55% of WT. Synergistic MCCV was also produced in pigs. The combined agonists increased MCCV by increasing surface fluid via multiple mechanisms: increased fluid secretion from submucosal glands, increased anion secretion across surface epithelia and decreased Na+ absorption. To avoid bronchoconstriction, the cAMP agonist was applied 30 min before carbachol. This approach to increasing mucus clearance warrants testing for safety and efficacy in humans as a potential therapeutic for muco-obstructive diseases.

scholarly journals Acinar origin of CFTR-dependent airway submucosal gland fluid secretion

2007 ◽  
Vol 292 (1) ◽  
pp. L304-L311 ◽  
Author(s):  
Jin V. Wu ◽  
Mauri E. Krouse ◽  
Jeffrey J. Wine
Keyword(s):  
Cystic Fibrosis ◽  
Fluid Secretion ◽  
Time Lapse ◽  
Airway Disease ◽  
Bulk Flow ◽  
Submucosal Gland ◽  
Mucus Clearance ◽  
Submucosal Glands ◽  
Gland Duct ◽  
Time Lapse Imaging

Cystic fibrosis (CF) airway disease arises from defective innate defenses, especially defective mucus clearance of microorganisms. Airway submucosal glands secrete most airway mucus, and CF airway glands do not secrete in response to VIP or forskolin. CFTR, the protein that is defective in CF, is expressed in glands, but immunocytochemistry finds the highest expression of CFTR in either the ciliated ducts or in the acini, depending on the antibodies used. CFTR is absolutely required for forskolin-mediated gland secretion; we used this finding to localize the origin of forskolin-stimulated, CFTR-dependent gland fluid secretion. We tested the hypothesis that secretion to forskolin might originate from the gland duct rather than or in addition to the acini. We ligated gland ducts at various points, stimulated the glands with forskolin, and monitored the regions of the glands that swelled. The results supported an acinar rather than ductal origin of secretion. We tracked particles in the mucus using Nomarski time-lapse imaging; particles originated in the acini and traveled toward the duct orifice. Estimated bulk flow accelerated in the acini and mucus tubules, consistent with fluid secretion in those regions, but was constant in the unbranched duct, consistent with a lack of fluid secretion or absorption by the ductal epithelium. We conclude that CFTR-dependent gland fluid secretion originates in the serous acini. The failure to observe either secretion or absorption from the CFTR and epithelial Na+ channel (ENaC)-rich ciliated ducts is unexplained, but may indicate that this epithelium alters the composition rather than the volume of gland mucus.

Airway submucosal glands from cystic fibrosis swine suffer from abnormal ion transport across the serous acini, collecting duct, and ciliated duct

2020 ◽  
Vol 318 (5) ◽  
pp. L931-L942 ◽  
Author(s):  
Xiaojie Luan ◽  
Julian S. Tam ◽  
Santosh Jagadeeshan ◽  
Nikolay Grishchenko ◽  
Noman Hassan ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Ion Transport ◽  
Transport Properties ◽  
Defense Mechanism ◽  
Collecting Duct ◽  
Upper Airway ◽  
Wild Type ◽  
Innate Defense ◽  
Collecting Ducts ◽  
Submucosal Glands

The human airway is protected by an efficient innate defense mechanism that requires healthy secretion of airway surface liquid (ASL) to clear pathogens from the lungs. Most of the ASL in the upper airway is secreted by submucosal glands. In cystic fibrosis (CF), the function of airway submucosal glands is abnormal, and these abnormalities are attributed to anomalies in ion transport across the epithelia lining the different sections of the glands that function coordinately to produce the ASL. However, the ion transport properties of most of the anatomical regions of the gland have never been measured, and there is controversy regarding which segments express CFTR. This makes it difficult to determine the glandular abnormalities that may contribute to CF lung disease. Using a noninvasive, extracellular self-referencing ion-selective electrode technique, we characterized ion transport properties in all four segments of submucosal glands from wild-type and CFTR−/− swine. In wild-type airways, the serous acini, mucus tubules, and collecting ducts secrete Cl− and Na+ into the lumen in response to carbachol and forskolin stimulation. The ciliated duct also transports Cl− and Na+ but in the opposite direction, i.e., reabsorption from the ASL, which may contribute to lowering Na+ and Cl− activities in the secreted fluid. In CFTR−/− airways, the serous acini, collecting ducts, and ciliated ducts fail to transport ions after forskolin stimulation, resulting in the production of smaller volumes of ASL with normal Cl−, Na+, and K+ concentration.

scholarly journals TMEM16A: An Alternative Approach to Restoring Airway Anion Secretion in Cystic Fibrosis?

2020 ◽  
Vol 21 (7) ◽  
pp. 2386
Author(s):  
Henry Danahay ◽  
Martin Gosling
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Standard Of Care ◽  
Fluid Secretion ◽  
Airway Epithelial ◽  
Anion Secretion ◽  
Positive Effects ◽  
Mucus Clearance ◽  
Airway Mucosa ◽  
Treat All

The concept that increasing airway hydration leads to improvements in mucus clearance and lung function in cystic fibrosis has been clinically validated with osmotic agents such as hypertonic saline and more convincingly with cystic fibrosis transmembrane conductance regulator (CFTR) repair therapies. Although rapidly becoming the standard of care in cystic fibrosis (CF), current CFTR modulators do not treat all patients nor do they restore the rate of decline in lung function to normal levels. As such, novel approaches are still required to ensure all with CF have effective therapies. Although CFTR plays a fundamental role in the regulation of fluid secretion across the airway mucosa, there are other ion channels and transporters that represent viable targets for future therapeutics. In this review article we will summarise the current progress with CFTR-independent approaches to restoring mucosal hydration, including epithelial sodium channel (ENaC) blockade and modulators of SLC26A9. A particular emphasis is given to modulation of the airway epithelial calcium-activated chloride channel (CaCC), TMEM16A, as there is controversy regarding whether it should be positively or negatively modulated. This is discussed in light of a recent report describing for the first time bona fide TMEM16A potentiators and their positive effects upon epithelial fluid secretion and mucus clearance.

Effect of anion transport inhibition on mucus secretion by airway submucosal glands

1997 ◽  
Vol 272 (2) ◽  
pp. L372-L377 ◽  
Author(s):  
S. K. Inglis ◽  
M. R. Corboz ◽  
A. E. Taylor ◽  
S. T. Ballard
Keyword(s):  
Cystic Fibrosis ◽  
Anion Transport ◽  
Mucus Secretion ◽  
Disulfonic Acid ◽  
Pathological Changes ◽  
Submucosal Gland ◽  
Anion Secretion ◽  
Submucosal Glands ◽  
Gland Duct

To model the airway glandular defect in cystic fibrosis (CF), the effect of anion secretion blockers on submucosal gland mucus secretion was investigated. Porcine distal bronchi were isolated, pretreated with a Cl- secretion blocker (bumetanide) and/or a combination of blockers to inhibit HCO3- secretion (dimethylamiloride, acetazolamide, and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid), and then treated with acetylcholine (ACh), a glandular liquid and mucus secretagogue. Bronchi were then fixed, sectioned, and stained for mucins. Each gland duct was ranked for mucin content from zero (no mucin) to five (duct completely occluded with mucin). Untreated bronchi, bronchi treated only with ACh, and ACh-treated bronchi that received either bumetanide or the HCO3- secretion blockers all exhibited low gland duct mucin content (1.18 +/- 0.34, 0.59 +/- 0.07, 0.65 +/- 0.03, and 0.83 +/- 0.11, respectively). However, pretreatment with both Cl- and HCO3- secretion blockers before ACh addition resulted in substantial and significant ductal mucus accumulation (3.57 +/- 0.22). In situ videomicroscopy studies of intact airways confirmed these results. Thus inhibition of the anion (and presumably liquid) secretion response to ACh leads to mucus obstruction of submucosal gland ducts that resembles the early pathological changes observed in CF.

Mucus clearance: in vivo canine tracheal vs. in vitro bullfrog palate studies

1977 ◽  
Vol 42 (5) ◽  
pp. 761-766 ◽  
Author(s):  
A. Giordano ◽  
C. K. Shih ◽  
D. S. Holsclaw ◽  
M. A. Khan ◽  
M. Litt
Keyword(s):  
Cystic Fibrosis ◽  
Mucociliary Clearance ◽  
Objective Method ◽  
Flow Properties ◽  
Therapeutic Modalities ◽  
Mucus Clearance ◽  
Clearance Studies ◽  
Frog Palate

Tracheal mucociliary clearance was studied by a radioisotope technique in pentothal-anesthetized beagles in the control, atropinized, or dehydrated state. Mucus collected from a tracheal pouch in each dog was used for in vitro bullfrog (Rana cantesbiana) palate clearance studies and compared to the in vivo clearance rates. In all three experimental states, there was a significant correlation between in vivo and in vitro rates, suggesting that tracheal pouch mucus is a good model for investigating the mucociliary flow properties of intact airway mucus. When compared to matched controls, atropine appeared to cause a slowing of the in vivo clearance rate but not of the in vitro rate. Dehydration had no effect on either. The appropriateness of the frog palate method in the study of human respiratory disease (e.g., chronic bronchitis, cystic fibrosis) as well as its potential as an objective method of assessing the effects of various therapeutic modalities in these diseases is discussed.

scholarly journals Epinephrine stimulation of anion secretion in the Calu-3 serous cell model

2014 ◽  
Vol 306 (10) ◽  
pp. L937-L946 ◽  
Author(s):  
Amiraj Banga ◽  
Stephanie Flaig ◽  
Shanta Lewis ◽  
Seth Winfree ◽  
Bonnie L. Blazer-Yost
Keyword(s):  
Adrenergic Receptor ◽  
Mucociliary Clearance ◽  
Cell Model ◽  
Transmembrane Protein ◽  
Intracellular Camp ◽  
Anion Secretion ◽  
Dual Channel ◽  
Submucosal Glands ◽  
Serous Cell ◽  
Well Differentiated

Calu-3 is a well-differentiated human bronchial cell line with the characteristics of the serous cells of airway submucosal glands. The submucosal glands play a major role in mucociliary clearance because they secrete electrolytes that facilitate airway hydration. Given the significance of both long- and short-term β-adrenergic receptor agonists in the treatment of respiratory diseases, it is important to determine the role of these receptors and their ligands in normal physiological function. The present studies were designed to characterize the effect of epinephrine, the naturally occurring β-adrenergic receptor agonist, on electrolyte transport of the airway serous cells. Interestingly, epinephrine stimulated two anion secretory channels, the cystic fibrosis transmembrane conductance regulator and a Ca2+-activated Cl− channel, with the characteristics of transmembrane protein 16A, thereby potentially altering mucociliary clearance via multiple channels. Consistent with the dual channel activation, epinephrine treatment resulted in increases in both intracellular cAMP and Ca2+. Furthermore, the present results extend previous reports indicating that the two anion channels are functionally linked.

scholarly journals Mucus clearance as a primary innate defense mechanism for mammalian airways

2002 ◽  
Vol 109 (5) ◽  
pp. 571-577 ◽  
Author(s):  
Michael R. Knowles ◽  
Richard C. Boucher
Keyword(s):  
Defense Mechanism ◽  
Innate Defense ◽  
Mucus Clearance

Differentiation of immortalized epithelial cells derived from cystic fibrosis airway submucosal glands

1994 ◽  
Vol 30 (8) ◽  
pp. 539-546 ◽  
Author(s):  
D. P. Chora ◽  
L. Reddy ◽  
S. K. Gupta ◽  
L. Wan ◽  
P. A. Mathieu ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Cystic Fibrosis Airway ◽  
Submucosal Glands

Mucociliary clearance and submucosal gland secretion in the ex vivo ferret trachea

2014 ◽  
Vol 307 (1) ◽  
pp. L83-L93 ◽  
Author(s):  
Jin Hyeok Jeong ◽  
Nam Soo Joo ◽  
Peter H. Hwang ◽  
Jeffrey J. Wine
Keyword(s):  
Mucociliary Clearance ◽  
Ex Vivo ◽  
Fluid Secretion ◽  
Gland Secretion ◽  
Intracellular Camp ◽  
Low Concentrations ◽  
Submucosal Glands ◽  
Intracellular Ca ◽  
Tracheal Mucus ◽  
Intracellular Camp Concentration

In many species submucosal glands are an important source of tracheal mucus, but the extent to which mucociliary clearance (MCC) depends on gland secretion is unknown. To explore this relationship, we measured basal and agonist-stimulated MCC velocities in ex vivo tracheas from adult ferrets and compared the velocities with previously measured rates of ferret glandular mucus secretion (Cho HJ, Joo NS, Wine JJ. Am J Physiol Lung Cell Mol Physiol 299: L124–L136, 2010). Stimulated MCC velocities (mm/min, means ± SE for 10- to 35-min period poststimulation) were as follows: 1 μM carbachol: 19.1 ± 3.3 > 10 μM phenylephrine: 15.3 ± 2.4 ≈ 10 μM isoproterenol: 15.0 ± 1.9 ≈ 10 μM forskolin: 14.6 ± 3.1 > 1 μM vasoactive intestinal peptide (VIP): 10.2 ± 2.2 >> basal ( t15): 1.8 ± 0.3; n = 5–10 for each condition. Synergistic stimulation of MCC was observed between low concentrations of carbachol (100 nM) and isoproterenol (300 nM). Bumetanide inhibited carbachol-stimulated MCC by ∼70% and abolished the increase in MCC stimulated by forskolin + VIP, whereas HCO3−-free solutions did not significantly inhibit MCC to either intracellular Ca2+ concentration or intracellular cAMP concentration ([cAMP]i)-elevating agonists. Stimulation and inhibition of MCC and gland secretion differed in several respects: most importantly, elevating [cAMP]i increased MCC much more effectively than expected from its effects on gland secretion, and bumetanide almost completely inhibited [cAMP]i-stimulated MCC while it had a smaller effect on gland secretion. We conclude that changes in glandular fluid secretion are complexly related to MCC and discuss possible reasons for this.

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