scholarly journals Acid exposure disrupts mucus secretion and impairs mucociliary transport in neonatal piglet airways

2020 ◽  
Vol 318 (5) ◽  
pp. L873-L887 ◽  
Author(s):  
Yan Shin J. Liao ◽  
Shin Ping Kuan ◽  
Maria V. Guevara ◽  
Emily N. Collins ◽  
Kalina R. Atanasova ◽  
...  
Keyword(s):  
Airway Obstruction ◽  
Chloride Transport ◽  
Ex Vivo ◽  
Mucus Secretion ◽  
Mucociliary Transport ◽  
Cholinergic Stimulation ◽  
Diminazene Aceturate ◽  
Airway Pathology ◽  
Submucosal Glands ◽  
Airway Acidification

Tenacious mucus produced by tracheal and bronchial submucosal glands is a defining feature of several airway diseases, including cystic fibrosis (CF). Airway acidification as a driving force of CF airway pathology has been controversial. Here we tested the hypothesis that transient airway acidification produces pathologic mucus and impairs mucociliary transport. We studied pigs challenged with intra-airway acid. Acid had a minimal effect on mucus properties under basal conditions. However, cholinergic stimulation in acid-challenged pigs revealed retention of mucin 5B (MUC5B) in the submucosal glands, decreased concentrations of MUC5B in the lung lavage fluid, and airway obstruction. To more closely mimic a CF-like environment, we also examined mucus secretion and transport following cholinergic stimulation under diminished bicarbonate and chloride transport conditions ex vivo. Under these conditions, airways from acid-challenged pigs displayed extensive mucus films and decreased mucociliary transport. Pretreatment with diminazene aceturate, a small molecule with ability to inhibit acid detection through blockade of the acid-sensing ion channel (ASIC) at the doses provided, did not prevent acid-induced pathologic mucus or transport defects but did mitigate airway obstruction. These findings suggest that transient airway acidification early in life has significant impacts on mucus secretion and transport properties. Furthermore, they highlight diminazene aceturate as an agent that might be beneficial in alleviating airway obstruction.

scholarly journals Acid exposure impairs mucus secretion and disrupts mucus transport in neonatal piglet airways

2019 ◽  
Author(s):  
Yan Shin J. Liao ◽  
Shin Ping Kuan ◽  
Maria V. Guevara ◽  
Emily N. Collins ◽  
Kalina R. Atanasova ◽  
...  
Keyword(s):  
Chloride Transport ◽  
Ex Vivo ◽  
Lavage Fluid ◽  
Mucus Secretion ◽  
Submucosal Gland ◽  
Cholinergic Stimulation ◽  
Diminazene Aceturate ◽  
Gland Duct ◽  
Airway Acidification

ABSTRACTTenacious mucus produced by tracheal and bronchial submucosal glands is a defining feature of cystic fibrosis (CF). Although airway acidification occurs early in CF, whether transient acidification is sufficient to initiate mucus abnormalities is unknown. We studied mucus secretion and mucus transport in piglets forty-eight hours following an intra-airway acid challenge. Acid-challenged piglet airways were distinguished by increased mucin 5B (MUC5B) in the submucosal gland but decreased lung lavage fluid MUC5B, following in vivo cholinergic stimulation, suggesting a failure in submucosal gland secretion. Concomitantly, intrapulmonary airways were obstructed with glycoprotein rich material under both basal and methacholine-stimulated conditions. To mimic a CF-like environment, we also studied mucus secretion and transport under diminished bicarbonate and chloride transport conditions ex vivo. Cholinergic stimulation in acid-challenged piglet airways induced extensive mucus films, greater mucus strand formation, increased dilation of submucosal gland duct openings and decreased mucociliary transport. Finally, to elucidate potential mediators of acid-induced mucus defects, we investigated diminazene aceturate, a small molecule that inhibits the acid-sensing ion channel (ASIC). Diminazene aceturate restored surface MUC5B in acid-challenged piglet airways under basal conditions, mitigated acid-induced airway obstruction, and magnified the number of dilated submucosal gland duct openings. These findings suggest that even transient airway acidification early in life might have profound impacts on mucus secretion and transport properties. Further they highlight diminazene aceturate as an agent that might be beneficial in alleviating certain mucus defects in CF airway disease.One sentence summaryEarly life airway acidification has profound impacts on mucus secretion and transport.

scholarly journals Durable Changes to Airway Mucus and Fluid Secretion Following Cholinergic Challenge

2020 ◽  
Author(s):  
Yan Shin J. Liao ◽  
Emily N. Collins ◽  
Maria Valentina Guevara ◽  
Veronica Schurmann ◽  
Kalina R. Atanasova ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Fluid Secretion ◽  
Mucus Secretion ◽  
Cholinergic Innervation ◽  
Mucociliary Transport ◽  
Cholinergic Stimulation ◽  
Ussing Chambers ◽  
Airway Mucus ◽  
Antibody Labeling ◽  
Air Liquid Interface

AbstractPurposeMucus abnormalities are central to the pathophysiology of several chronic airway diseases. Mucus secretion and clearance are regulated, in part, by cholinergic innervation. Prolonged cholinergic stimulation may contribute to mucus abnormalities in disease. Thus, we tested the hypothesis that prolonged cholinergic stimulation gives rise to lasting mucus abnormalities in airways.MethodsWe delivered aerosolized bethanechol, a cholinergic agonist, to pig airways. Forty-eight hours later, we measured mucus secretion and mucociliary transport in tracheal segments ex vivo. Tracheal and bronchoalveolar lavage concentrations of the major secreted mucus glycoproteins, mucin5B (MUC5B) or mucin5AC (MUC5AC), were measured with ELISA and antibody labeling. Pig airway epithelia were cultured at the air-liquid interface and treated with bethanechol for forty-eight hours. Stimulated fluid secretion was measured with reflected microscopy and Ussing chambers were used to measure ion transport.ResultsAirways from bethanechol-challenged pigs exhibited sheet-like mucus films, which were not associated with a greater abundance of MUC5AC or MUC5B. Epithelia treated with bethanechol had diminished fluid secretion and decreased Cl- transport. However, mucus and fluid alterations were not associated with impaired mucociliary transport.ConclusionsThese data suggest that cholinergic transmission induces sustained alterations in airway mucus properties. Such defects might compound and/or contribute to persistent mucus phenotypes found after the resolution of airway inflammation.

scholarly journals Lack of airway submucosal glands impairs respiratory host defenses

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Lynda S Ostedgaard ◽  
Margaret P Price ◽  
Kristin M Whitworth ◽  
Mahmoud H Abou Alaiwa ◽  
Anthony J Fischer ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Airway Surface Liquid ◽  
Mucociliary Transport ◽  
Direct Test ◽  
Host Defenses ◽  
Bacterial Challenge ◽  
Wild Type ◽  
Submucosal Glands ◽  
Surface Liquid

Submucosal glands (SMGs) are a prominent structure that lines human cartilaginous airways. Although it has been assumed that SMGs contribute to respiratory defense, that hypothesis has gone without a direct test. Therefore, we studied pigs, which have lungs like humans, and disrupted the gene for ectodysplasin (EDA-KO), which initiates SMG development. EDA-KO pigs lacked SMGs throughout the airways. Their airway surface liquid had a reduced ability to kill bacteria, consistent with SMG production of antimicrobials. In wild-type pigs, SMGs secrete mucus that emerges onto the airway surface as strands. Lack of SMGs and mucus strands disrupted mucociliary transport in EDA-KO pigs. Consequently, EDA-KO pigs failed to eradicate a bacterial challenge in lung regions normally populated by SMGs. These in vivo and ex vivo results indicate that SMGs are required for normal antimicrobial activity and mucociliary transport, two key host defenses that protect the lung.

Correlations among Mucociliary Transport, Ciliary Function, and Ciliary Structure

1998 ◽  
Vol 12 (1) ◽  
pp. 53-58 ◽  
Author(s):  
Mark Jorissen
Keyword(s):  
Defense Mechanisms ◽  
Ex Vivo ◽  
Beat Frequency ◽  
Ciliary Beat Frequency ◽  
Preliminary Evidence ◽  
Relevant Parameter ◽  
Mucociliary Transport ◽  
Ciliary Dyskinesia ◽  
Ciliary Beat

Mucociliary transport is one of the most important defense mechanisms of the airway. Mucociliary transport time or rate, as measured using the saccharin test or the radioisotope technique, respectively, is clinically the most relevant parameter, although subject to large intra- and interindividual variability. There is no correlation between mucociliary transport in vivo and ciliary beat frequency ex vivo. Preliminary evidence demonstrates that mucociliary transport correlates with ciliary structure and orientation as investigated with transmission and scanning electron microscopy. A correlation is presented between ciliary beat frequency and secondary ciliary abnormalities. This correlation can best be described according to the logistic sigmoid model (r = 0.69). Based on these functional data, an ultrastructural distinction is proposed among normal (less than 5%), light (5 to 15%), moderate (15 to 25%), and severe (more than 25%) secondary ciliary dyskinesia.

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.

Acute Airway Acidification Modifies Mucus Secretion and Transport Properties

2019 ◽  
Author(s):  
L. Reznikov ◽  
S.-P. Kuan ◽  
Y.S. Liao ◽  
J. Dadural ◽  
E. Collins ◽  
...  
Keyword(s):  
Transport Properties ◽  
Mucus Secretion ◽  
Airway Acidification

VIP augments cholinergic-induced glycoconjugate secretion in tracheal submucosal glands

1988 ◽  
Vol 65 (6) ◽  
pp. 2537-2544 ◽  
Author(s):  
S. Shimura ◽  
T. Sasaki ◽  
K. Ikeda ◽  
H. Sasaki ◽  
T. Takishima
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Secretory Cells ◽  
Cholinergic Stimulation ◽  
Low Concentration ◽  
Mucus Glycoprotein ◽  
Submucosal Glands ◽  
Glycoprotein Secretion ◽  
Dose Dependent Increase ◽  
Dose Dependent

Using isolated submucosal glands from feline trachea, we examined the effect of vasoactive intestinal peptide (VIP) on mucus glycoprotein secretion and glandular contraction by measuring released radiolabeled glycoconjugates and induced tension, respectively. VIP (10(-10) to 10(-6) M) produced a dose-dependent increase in [3H]glycoconjugate release of up to 300% of controls, which was inhibited by VIP antiserum and not inhibited by atropine, propranolol, or phentolamine. VIP at a low concentration (10(-9) M), which did not produce any significant increases over controls, produced a 2.4- to 5-fold augmentation of the glycoconjugate release induced by 10(-9) to 10(-7) M methacholine (MCh). Atropine or VIP antiserum abolished the augmentation. VIP did not produce any alteration in isoproterenol- or phenylephrine-evoked glycoconjugate secretion. VIP (up to 10(-5) M) did not produce any alteration in the tension, even when the gland had contracted with MCh, or any augmentation of contraction induced by MCh (10(-9) to 10(-7) M). These results indicate that VIP induces mucus glycoprotein release from secretory cells and also that it potentiates the secretion induced by cholinergic stimulation.

Airway responses to esophageal acidification

2008 ◽  
Vol 294 (1) ◽  
pp. R211-R219 ◽  
Author(s):  
Ivan M. Lang ◽  
Steven T. Haworth ◽  
Bidyut K. Medda ◽  
David L. Roerig ◽  
Hubert V. Forster ◽  
...  
Keyword(s):  
Dynamic Compliance ◽  
Mucus Secretion ◽  
Transport Rate ◽  
Mucociliary Transport ◽  
Airway Constriction ◽  
Airway Function ◽  
Lung Resistance ◽  
Airway Response ◽  
Airway Responses ◽  
Total Lung Resistance

The effects of esophageal acidification on airway function are unclear. Some have found that the esophageal acidification causes a small increase in airway resistance, but this change is too small to cause significant symptoms. The aims of this study were to investigate the effects of esophageal acidification on multiple measures of airway function in chloralose-anesthetized cats. The esophagus was cannulated and perfused with either 0.1 M PBS or 0.1 N HCl at 1 ml/min as the following parameters were quantified in separate experiments: diameter of bronchi ( n = 5), tracheal mucociliary transport rate ( n = 4), tracheobronchial mucus secretion ( n = 7), and lung function ( n = 6). We found that esophageal acidification for 10–30 min decreased bronchial diameters primarily of the smaller low-resistance airways (10–22%, P < 0.05), decreased tracheal mucociliary transport (53%, 8.7 ± 2.4 vs. 4.1 ± 1.3 mm/min, P < 0.05), increased tracheobronchial mucus secretion (147%, 3.4 ± 0.7 vs. 8.4 ± 2.6 mg/10 min, P < 0.05), and caused no change in total lung resistance or dynamic compliance ( P > 0.05). Considering that tracheal mucociliary transport rate is governed in part by mucus secretion, we concluded that the primary airway response to esophageal acidification observed is increased mucus secretion. Airway constriction may act to assist in rapid secretion of mucus and to increase the effectiveness of coughing while not affecting lung resistance or compliance. Given the buffering capabilities of mucus, esophageal acidification activates appropriate physiological responses that may act to neutralize gastroesophageal reflux that reaches the larynx, pharynx, or lower airways.

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