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

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

doi:10.1038/s41598-021-98122-5

Nam Soo Joo, Carlos E Milla + Show 5 more

Open Access

https://doi.org/10.1038/s41598-021-98122-5

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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.

Highlights

Mucus clearance, a primary innate defense mechanism of airways, is defective in patients with cystic fibrosis (CF) and CF animals
During experiments to quantify how CFTR and ENaC modulators alter mucociliary clearance in ex vivo ferret tracheas, we discovered that combinations of a β-adrenergic agonist with a low dose of cholinergic agonist promoted dramatic increases in mucociliary clearance velocity (MCCV) that were significantly greater than the sum of the increases produced by either agonist separately[16]
To determine if synergistic increases of MCCV could be produced in CF ferret tracheas, we tested tracheas from 7 transgenic adult CF ferrets of mixed genotype

Summary

Introduction

A primary innate defense mechanism of airways, is defective in patients with cystic fibrosis (CF) and CF animals. During experiments to quantify how CFTR and ENaC (the epithelial sodium channel) modulators alter mucociliary clearance in ex vivo ferret tracheas, we discovered that combinations of a β-adrenergic agonist (we used forskolin as a surrogate, but isoproterenol is effective) with a low dose of cholinergic agonist promoted dramatic increases in MCCV that were significantly greater than the sum of the increases produced by either agonist separately[16]. It was not known if these results would generalize, nor if they could be produced in CF. We investigate the potential mechanism that leads to synergistic MCCV by studying the roles of airway submucosal glands, airway surface epithelia, and cilia

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