Scientific Reports (Sep 2021)

Combined agonists act synergistically to increase mucociliary clearance in a cystic fibrosis airway model

  • Nam Soo Joo,
  • Hyung-Ju Cho,
  • Meagan Shinbashi,
  • Jae Young Choi,
  • Carlos E. Milla,
  • John F. Engelhardt,
  • Jeffrey J. Wine

DOI
https://doi.org/10.1038/s41598-021-98122-5
Journal volume & issue
Vol. 11, no. 1
pp. 1 – 13

Abstract

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Abstract Mucus clearance, a primary innate defense mechanism of airways, is defective in patients with cystic fibrosis (CF) and CF animals. In previous work, the combination of a low dose of the cholinergic agonist, carbachol with forskolin or a β adrenergic agonist, isoproterenol synergistically increased mucociliary clearance velocity (MCCV) in ferret tracheas. Importantly, the present study shows that synergistic MCCV can also be produced in CF ferrets, with increases ~ 55% of WT. Synergistic MCCV was also produced in pigs. The combined agonists increased MCCV by increasing surface fluid via multiple mechanisms: increased fluid secretion from submucosal glands, increased anion secretion across surface epithelia and decreased Na+ absorption. To avoid bronchoconstriction, the cAMP agonist was applied 30 min before carbachol. This approach to increasing mucus clearance warrants testing for safety and efficacy in humans as a potential therapeutic for muco-obstructive diseases.