PT  - JOURNAL ARTICLE
AU  - Yan Shin J. Liao
AU  - Shin Ping Kuan
AU  - Maria V. Guevara
AU  - Emily N. Collins
AU  - Kalina R. Atanasova
AU  - Joshua S. Dadural
AU  - Kevin Vogt
AU  - Veronica Schurmann
AU  - Leah R. Reznikov
TI  - Acid exposure impairs mucus secretion and disrupts mucus transport in neonatal piglet airways
AID  - 10.1101/669879
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 669879
4099  - http://biorxiv.org/content/early/2019/06/13/669879.short
4100  - http://biorxiv.org/content/early/2019/06/13/669879.full
AB  - 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 summary Early life airway acidification has profound impacts on mucus secretion and transport.