Acid exposure impairs mucus secretion and disrupts mucus transport in neonatal piglet airways
| Autor: | Leah R. Reznikov, Kalina R. Atanasova, Shin Ping Kuan, Emily N. Collins, Veronica Schurmann, Yan Shin J. Liao, Joshua S. Dadural, Maria V. Guevara, Kevin Vogt |
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| Rok vydání: | 2019 |
| Předmět: |
Submucosal glands
0303 health sciences medicine.medical_specialty Chemistry Stimulation respiratory system Airway obstruction medicine.disease Mucus Cystic fibrosis 03 medical and health sciences fluids and secretions 0302 clinical medicine Endocrinology 030228 respiratory system Internal medicine medicine Cholinergic Secretion Ex vivo 030304 developmental biology |
| DOI: | 10.1101/669879 |
| Popis: | Tenacious 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. |
| Databáze: | OpenAIRE |
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