Submucosal gland dysfunction as a primary defect in cystic fibrosis

2004 ◽  
Vol 19 (3) ◽  
pp. 1-13 ◽  
Author(s):  
Danieli Salinas ◽  
Peter M. Haggie ◽  
Jay R. Thiagarajah ◽  
Yuanlin Song ◽  
Kristina Rosbe ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Submucosal Gland ◽  
Primary Defect

CFTR involvement in chloride, bicarbonate, and liquid secretion by airway submucosal glands

1999 ◽  
Vol 277 (4) ◽  
pp. L694-L699 ◽  
Author(s):  
Stephen T. Ballard ◽  
Laura Trout ◽  
Zsuzsa Bebök ◽  
E. J. Sorscher ◽  
Angela Crews
Keyword(s):  
Cystic Fibrosis ◽  
Channel Blocker ◽  
Polyclonal Antibodies ◽  
Surface Epithelium ◽  
Transmembrane Conductance Regulator ◽  
Submucosal Gland ◽  
Transmembrane Conductance ◽  
Active Secretion ◽  
Submucosal Glands ◽  
Cystic Fibrosis Transmembrane

Previous studies demonstrated that ACh-induced liquid secretion by porcine bronchi is driven by active Cl− and H[Formula: see text] secretion. The present study was undertaken to determine whether this process was localized to submucosal glands and mediated by the cystic fibrosis transmembrane conductance regulator (CFTR). When excised, cannulated, and treated with ACh, porcine bronchi secreted 15.6 ± 0.6 μl ⋅ cm−2 ⋅ h−1. Removal of the surface epithelium did not significantly affect the rate of secretion, indicating that the source of the liquid was the submucosal glands. Pretreatment with diphenylamine-2-carboxylate, a relatively nonselective Cl−-channel blocker, significantly reduced liquid secretion by 86%, whereas pretreatment with DIDS, which inhibits a variety of Cl− channels but not CFTR, had no effect. When bronchi were pretreated with glibenclamide or 5-nitro-2-(3-phenylpropylamino)benzoic acid (both inhibitors of CFTR), the rate of ACh-induced liquid secretion was significantly reduced by 39 and 91%, respectively, compared with controls. Agents that blocked liquid secretion also caused disproportionate reductions in H[Formula: see text] secretion. Polyclonal antibodies to the CFTR bound preferentially to submucosal gland ducts and the surface epithelium, suggesting that this channel was localized to these sites. These data suggest that ACh-induced gland liquid secretion by porcine bronchi is driven by active secretion of both Cl− and H[Formula: see text] and is mediated by the CFTR.

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.

Airway β-adrenoceptor number in cystic fibrosis and asthma

1990 ◽  
Vol 78 (4) ◽  
pp. 409-417 ◽  
Author(s):  
Rajiev K. Sharma ◽  
Peter K. Jeffery
Keyword(s):  
Cystic Fibrosis ◽  
Smooth Muscle ◽  
Binding Capacity ◽  
Statistical Significance ◽  
Bronchial Carcinoma ◽  
Bronchial Epithelium ◽  
Alveolar Wall ◽  
Primary Defect ◽  
Bronchial Smooth Muscle ◽  
Level 1

1. Maximal binding capacity (Bmax.) and the dissociation constant (KD) for the β-adrenoceptor antagonist 125I-cyanopindol were estimated in membrane preparations of hilar, lobar/main bronchi (level 1) and peripheral lung (level 11) of grossly normal lungs resected for bronchial carcinoma. The tissue distribution of 125I-cyanopindol-binding sites was assessed by autoradiography of complementary cryostat sections. The data obtained from the resections for carcinoma and bronchiectasis were used as disease controls for comparison with those obtained from patients with cystic fibrosis and asthma. 2. In carcinoma controls, mean Bmax. values (± sem) for airway levels 1 and 11 were 89 ± 4 and 133 ± 6 fmol/mg of protein, respectively (P <0.01). The corresponding KD values at each airway level were similar, i.e. 29 ± 2 and 33 ± 1 pmol/l, respectively. Autoradiography revealed that there was dense labelling of bronchial and bronchiolar epithelium and most strikingly of the alveolar wall. 3. Compared with carcinoma controls, mean Bmax. values in cystic fibrosis were significantly reduced in membrane preparations of both airway levels 1 and 11 (P <0.01). Autoradiography showed the reduction was most apparent in alveolar wall and bronchial epithelium. 4. There was a tendency to reduction of Bmax. in membrane preparations from patients with bronchiectasis at airway level I, but this failed to reach statistical significance. Autoradiography demonstrated that the density of labelling was significantly reduced in bronchial epithelium and bronchial smooth muscle as compared with carcinoma controls (P <0.01). 5. The Bmax. values were not significantly altered in membranes prepared from both airway levels in asthma, albeit there was a tendency towards reduction in Bmax. at level 1. At this level autoradiography demonstrated significantly reduced labelling of bronchial epithelium (P>0.01) and submucosal glands (P>0.05) but not of bronchial smooth muscle. 6. It is most likely that the reduction in β-adrenoceptor number that we have found in cystic fibrosis is secondary to pulmonary infection and airway inflammation. Its relationship to the primary defect remains unclear.

scholarly journals Characterization of Novel Airway Submucosal Gland Cell Models for Cystic Fibrosis

2005 ◽  
Vol 15 (6) ◽  
pp. 251-262 ◽  
Author(s):  
Ana da Paula ◽  
Anabela Ramalho ◽  
Carlos Farinha ◽  
Judy Cheung ◽  
Rosalie Maurisse ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gland Cell ◽  
Cell Models ◽  
Submucosal Gland

scholarly journals A new platform for high-throughput therapy testing on iPSC-derived, immature airway from Cystic Fibrosis Patients

2021 ◽  
Author(s):  
Jia Xin Jiang ◽  
Leigh Wellhauser ◽  
Onofrio Laselva ◽  
Irina Utkina ◽  
Zoltan Bozoky ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Stem Cell ◽  
High Throughput ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Functional Responses ◽  
Primary Defect ◽  
Epithelial Cultures ◽  
Therapy Development ◽  
Induced Pluripotent

Induced pluripotent, stem cell (iPSC)-derived models of airway tissue have successfully modeled the primary defect in regulated chloride conductance caused by the major Cystic Fibrosis causing mutation, F508del. However, it remains unclear if iPSC-derived airway cultures can be used in high-throughput therapy development for F508del and rarer mutations. There is an urgent need for airway tissue models that reflect the variability of patient-specific responses and are scalable for therapy development. In the current work, we describe a robust, high-throughput fluorescence assay of mutant CFTR function in iPSCs differentiated to immature airway epithelium. This assay measures reproducible functional responses to modulators targeting either the major CF mutant F508del or the nonsense mutant: W1282X-CFTR. We show that the ranking of patient-specific responses to interventions in this stem-cell based model recapitulates the ranking observed in primary nasal epithelial cultures obtained from the same individuals. In summary, these proof-of-concept studies show that this novel platform has the potential to support therapy development and precision medicine for Cystic Fibrosis patients.

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.

scholarly journals COPII-dependent export of cystic fibrosis transmembrane conductance regulator from the ER uses a di-acidic exit code

2004 ◽  
Vol 167 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Xiaodong Wang ◽  
Jeanne Matteson ◽  
Yu An ◽  
Bryan Moyer ◽  
Jin-San Yoo ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Hereditary Disease ◽  
Mutant Form ◽  
Transmembrane Conductance Regulator ◽  
Wild Type ◽  
Transmembrane Conductance ◽  
Primary Defect ◽  
Cf Transmembrane Conductance Regulator ◽  
Er Export ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) is a childhood hereditary disease in which the most common mutant form of the CF transmembrane conductance regulator (CFTR) ΔF508 fails to exit the endoplasmic reticulum (ER). Export of wild-type CFTR from the ER requires the coat complex II (COPII) machinery, as it is sensitive to Sar1 mutants that disrupt normal coat assembly and disassembly. In contrast, COPII is not used to deliver CFTR to ER-associated degradation. We find that exit of wild-type CFTR from the ER is blocked by mutation of a consensus di-acidic ER exit motif present in the first nucleotide binding domain. Mutation of the code disrupts interaction with the COPII coat selection complex Sec23/Sec24. We propose that the di-acidic exit code plays a key role in linking CFTR to the COPII coat machinery and is the primary defect responsible for CF in ΔF508-expressing patients.

Primary inflammation in human cystic fibrosis small airways

2002 ◽  
Vol 283 (2) ◽  
pp. L445-L451 ◽  
Author(s):  
Rabindra Tirouvanziam ◽  
Ibrahim Khazaal ◽  
Bruno Péault
Keyword(s):  
Cystic Fibrosis ◽  
Severe Combined Immunodeficiency ◽  
In Vivo Model ◽  
Small Airways ◽  
Combined Immunodeficiency ◽  
Tissue Destruction ◽  
Primary Defect ◽  
Clear Cut ◽  
Lung Failure

Most cystic fibrosis (CF) patients die of lung failure, due to the combined effects of bacterial infection, neutrophil-mediated inflammation, and airway obstruction by hyperviscous mucus. To this day, it remains unclear where and how this pathological vicious circle is initiated in vivo. In particular, it has proven difficult to investigate whether inflammatory pathways are dysregulated in CF airways independently of infection. Also, the relative involvement of large (tracheobronchial) vs. small (bronchiolar) airways in CF pathophysiology is still unclear. To help address these issues, we used an in vivo model based on the maturation of human fetal CF and non-CF small airways in severe combined immunodeficiency mice. We show that uninfected mature CF small airway grafts, but not matched non-CF controls, undergo time-dependent neutrophil-mediated inflammation, leading to progressive lung tissue destruction. This model of mature human small airways provides the first clear-cut evidence that, in CF, inflammation may arise at least partly from a primary defect in the regulation of neutrophil recruitment, independently of infection.

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