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 4

Prolonged increases of MCCV in an in vivo sheep model of inflamed CF airways following nebulization of formoterol and methacholine.

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Prolonged increases of MCCV in an in vivo sheep model of inflamed CF air...
(A) Time courses of in vivo MCCV showing dose-dependent increases of tracheal MCCV by SA in a sheep model of inflamed CF airways. Symbols and abbreviations: black squares, no agonist (NA); red triangles, 20 μg formoterol (Fmt or F) alone; green diamonds and blue circles, 20 μg Fmt + either 1 or 12 μg methacholine (M); hNE, recombinant human neutrophil elastase; D-Tx, drug treatment. (B) Summary of in vivo sheep data: no agonist, 20 μg formoterol alone, SA (formoterol + 1 μg methacholine/M 1 or formoterol + 12 μg methacholine/M 12) (n = 3–4 sheep). Note that while formoterol alone was not different in MCCV from vehicle-treated sheep (NA), F + M12 and F + M1 produced significantly larger MCCV than F + M1 and Fmt alone, respectively. A 1-way ANOVA with Bonferroni’s post hoc test was used.