Acidic Submucosal Gland pH and Elevated Protein Concentration Produce Abnormal Cystic Fibrosis Mucus

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.

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Attenuation of IL-2-induced multisystem organ edema by phalloidin and antamanide

Journal of Applied Physiology ◽

10.1152/jappl.1991.70.3.1364 ◽

1991 ◽

Vol 70 (3) ◽

pp. 1364-1368 ◽

Cited By ~ 12

Author(s):

R. Welbourn ◽

G. Goldman ◽

L. Kobzik ◽

C. R. Valeri ◽

H. B. Hechtman ◽

...

Keyword(s):

Endothelial Cell ◽

Side Effects ◽

Bronchoalveolar Lavage ◽

Protein Concentration ◽

Interleukin 2 ◽

Cell Junction ◽

Elevated Protein ◽

Intravenous Saline

Interleukin 2 (IL-2) is a potent cytokine with diverse effects, including the ability to stimulate lymphocyte differentiation into cells capable of lysing tumor. Its therapeutic efficacy is limited because of side effects such as breakdown of the microvascular barrier and edema. Control of the microvascular barrier is in part regulated by endothelial cell cytoskeletal contractile proteins. This study tests whether the cyclopeptides that maintain actin filament organization and distribution and reduce macromolecular flux across the endothelial cell junction in vitro would similarly maintain barrier tightness and prevent early edema produced by IL-2 in vivo. Anesthetized rats were treated at 30-min periods with intravenous saline (0.5 ml, n = 41), phalloidin (20 micrograms in 0.5 ml, n = 21), or antamanide, (20 micrograms in 0.5 ml, n = 21), starting 30 min before the 1-h infusion of 10(6) U of recombinant human IL-2 or saline. Six hours after the start of IL-2, there was edema in the saline/IL-2 group, as measured by increased wet-to-dry ratios (W/D) in the lungs, heart, and kidney. With saline/IL-2, bronchoalveolar lavage (BAL) fluid contained an elevated protein concentration and higher plasma thromboxane levels compared with controls. The number of neutrophils sequestered in the lungs was more than twice that of saline controls. Phalloidin significantly attenuated edema in lung and reduced BAL protein leak. Antamanide treatment was as effective in limiting lung and heart edema, but, in contrast to phalloidin, antamanide prevented kidney edema and did not lead to an alteration in the liver W/D. Antamanide also prevented BAL fluid protein leak.(ABSTRACT TRUNCATED AT 250 WORDS)

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1997.272.2.l372 ◽

1997 ◽

Vol 272 (2) ◽

pp. L372-L377 ◽

Cited By ~ 16

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.

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Characterization of Novel Airway Submucosal Gland Cell Models for Cystic Fibrosis

Cellular Physiology and Biochemistry ◽

10.1159/000087235 ◽

2005 ◽

Vol 15 (6) ◽

pp. 251-262 ◽

Cited By ~ 12

Author(s):

Ana da Paula ◽

Anabela Ramalho ◽

Carlos Farinha ◽

Judy Cheung ◽

Rosalie Maurisse ◽

...

Keyword(s):

Cystic Fibrosis ◽

Gland Cell ◽

Cell Models ◽

Submucosal Gland

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Sputum club cell protein concentration is associated with pulmonary exacerbation in cystic fibrosis

Journal of Cystic Fibrosis ◽

10.1016/j.jcf.2014.10.002 ◽

2015 ◽

Vol 14 (3) ◽

pp. 334-340 ◽

Cited By ~ 5

Author(s):

Theresa A. Laguna ◽

Cynthia B. Williams ◽

Kyle R. Brandy ◽

Cole Welchlin-Bradford ◽

Catherine E. Moen ◽

...

Keyword(s):

Cystic Fibrosis ◽

Protein Concentration ◽

Cell Protein ◽

Pulmonary Exacerbation ◽

Club Cell

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Evaluation Of Candidate Genes Implicated In Submucosal Gland Hyperplasia/Hypertrophy In The Sinus Mucosa Of Chronic Rhinosinusitis Patients With Or Without Cystic Fibrosis

10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a5511 ◽

2010 ◽

Author(s):

Xiaofang Wu ◽

Jennifer Peters-Hall ◽

Mary C. Rose ◽

Maria T. Pena

Keyword(s):

Cystic Fibrosis ◽

Candidate Genes ◽

Chronic Rhinosinusitis ◽

Submucosal Gland ◽

Sinus Mucosa

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Acinar origin of CFTR-dependent airway submucosal gland fluid secretion

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00286.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. L304-L311 ◽

Cited By ~ 26

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.

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