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 6

Formoterol and methacholine provide additional benefits when combined with HEMT.

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Formoterol and methacholine provide additional benefits when combined wi...
(A) Time courses of ex vivo MCCV showing synergistic MCC by SA (10 μM formoterol + 0.3 μM methacholine) in CFTRG551D CF ferret tracheae ± ivacaftor (n = 3–4 CF ferrets). Note that when CF ferrets had been off ivacaftor (>30 days, Iva-OFF at the bottom MCCV trace), formoterol did not have an effect on MCCV (red squares), while ferrets continuously administered ivacaftor until their euthanasia showed increased MCCV by 10 μM formoterol (Iva-ON at the top MCCV trace). Also notice that SA increased MCCV in both groups of ferrets, while Iva-ON ferrets produced larger MCCV increases compared with those of Iva-OFF ferrets. (B) Measured in vitro particle Deff (in μm2/msec) from primary human nasal CF (CFTRdelF508 homozygous) cells with and without HEMT, ETI (3 μM elexa/3 μM teza/10 μM ivacaftor). Increasing Deff represents actively transported particles by the mucus flow, with steeper tracings reflecting increasingly facilitated transport by a more fluid system. Note that SA (10 μM forskolin + 0.3 μM carbachol) further increased Deff when combined with ETI (n = 3).