Therapeutic potential of synergistic mucociliary clearance for cystic fibrosis airways by β-adrenergic plus cholinergic agonists
Nam Soo Joo, Susan E. Birket, Johnathan D. Keith, Juan P. Ianowski, Xiaojie Luan, Jacquelyn Spano, Jennifer B. Bollyky, Marissa N. Dobry, Juan R. Sabater, Ryan W. Williams, John F. Engelhardt, Jeffrey J. Wine, Carlos E. Milla
Nam Soo Joo, Susan E. Birket, Johnathan D. Keith, Juan P. Ianowski, Xiaojie Luan, Jacquelyn Spano, Jennifer B. Bollyky, Marissa N. Dobry, Juan R. Sabater, Ryan W. Williams, John F. Engelhardt, Jeffrey J. Wine, Carlos E. Milla
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Research Article Cell biology Clinical Research Pulmonology

Therapeutic potential of synergistic mucociliary clearance for cystic fibrosis airways by β-adrenergic plus cholinergic agonists

Abstract

Mucociliary clearance (MCC) is an innate defense mechanism that normally keeps airways clean but is dysfunctional in cystic fibrosis (CF) and other muco-obstructive pulmonary diseases. Previously we discovered that activating adenyl cyclase in combination with a cholinergic agonist increased MCC velocity (MCCV) synergistically in ex vivo WT and CF ferret and WT piglets. For what we believe is the first time, we show in vivo synergistic MCC using FDA approved β-adrenergic and cholinergic drugs delivered to the apical surface of WT and CF rats and a CF sheep model. Also, a single dose of the combined drugs is tolerated by humans. As for mechanisms, via ex vivo experiments, we show the combined agonists increased net fluid secretion mainly by stimulating gland secretion and by inhibiting surface absorption, consequently increasing airway surface liquid depth. They also increased net base secretion and increased ciliary beat frequency. Additional ex vivo and in vitro experiments show that the combined agonists had additive effects when combined with highly effective CF transmembrane conductance regulator modulator therapy. The synergistic increase in MCCV induced by this combination of agonists offers therapeutic potential for treating muco-obstructive pulmonary diseases, including CF.

Authors

Nam Soo Joo, Susan E. Birket, Johnathan D. Keith, Juan P. Ianowski, Xiaojie Luan, Jacquelyn Spano, Jennifer B. Bollyky, Marissa N. Dobry, Juan R. Sabater, Ryan W. Williams, John F. Engelhardt, Jeffrey J. Wine, Carlos E. Milla

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Figure 3

Formoterol and methacholine increase net base secretion, inhibit fluid absorption, and increase ASL depth.

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Formoterol and methacholine increase net base secretion, inhibit fluid a...
(A) Base secretion was assessed by pH-stat method. SA significantly increases net base production compared with baseline in freshly isolated WT pig tracheal mucosa (n = 23 tracheal tissue preparations from 16 pigs). A 2-tailed paired t test was used. (B) Time courses of ex vivo MCCV showing ENaC inhibition by 10 μM benzamil (Bz) significantly increased baseline MCCV with no additional effect on MCCV induced by SA regardless of benzamil treatment in ex vivo tracheal MCCV measurements in piglets (*P = 0.02, n = 4 each condition). SA†,(P = 0.97 with a 2-tailed unpaired t test) or simply not significant. (C) SA (10 μM formoterol + 0.3 μM methacholine) significantly increased the rates of ASL depth changes from baseline (Bs) in ex vivo pig tracheae, assessed by phase contrast imaging using synchrotron x-rays (P = 0.05 with a 2-tailed paired t test, 24 beads from n = 4 pigs). The ASL depth change (in μm): 102.4 ± 8.7 during T20 baseline period and 251.4 ± 19.6 during T30 SA treatment period.