Journal article
Therapeutic potential of synergistic mucociliary clearance for cystic fibrosis airways by combined 𝜷-adrenergic + cholinergic agonists
The Journal of clinical investigation, Vol.136(11), e201541
06/01/2026
DOI: 10.1172/JCI201541
PMCID: PMC13221217
PMID: 41926225
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. The present study extends and underpins our earlier findings by showing for the first time, in vivo synergistic MCC in WT rats and in CF sheep models and CF rats using inhalable β-adrenergic and cholinergic drugs approved for human use when delivered to the apical surface and a single dose 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 increased ASL depth. They also increased net base secretion and increased ciliary beat frequency. Additional ex vivo and in vitro experiments show that the combined agonists have additive effects when combined with highly effective CF transmembrane conductance regulator (CFTR) modulator therapy (HEMT). The synergistic increase in MCCV induced by this combination of agonists offers therapeutic potential for treating muco-obstructive pulmonary diseases including CF.
Details
- Title: Subtitle
- Therapeutic potential of synergistic mucociliary clearance for cystic fibrosis airways by combined 𝜷-adrenergic + cholinergic agonists
- Creators
- Nam Soo Joo - Cystic Fibrosis FoundationSusan E Birket - University of Alabama at BirminghamJohnathan D Keith - University of Alabama at BirminghamJuan P Ianowski - University of SaskatchewanXiaojie Luan - University of SaskatchewanJacquelyn Spano - Stanford UniversityJennifer B Bollyky - Stanford UniversityMarissa N Dobry - SLAC National Accelerator LaboratoryJuan R Sabater - Mount Sinai Medical CenterRyan W Williams - University of IowaJohn F Engelhardt - University of IowaJeffrey J Wine - Cystic Fibrosis FoundationCarlos E Milla - Stanford University
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.136(11), e201541
- DOI
- 10.1172/JCI201541
- PMID
- 41926225
- PMCID
- PMC13221217
- NLM abbreviation
- J Clin Invest
- ISSN
- 1558-8238
- eISSN
- 1558-8238
- Publisher
- American Society for Clinical Investigation
- Grant note
- NIH: R01 HL165404, 75N92025C00007 Cystic Fibrosis Foundation: Joo19G0, MILLA23G0, CFF BIRKET23XX0, IMA-1070 Cystic Fibrosis Research Inc., Ross Mosier CF Research Laboratories gift fund Galper Family CF fund
This work is the result of NIH funding, in whole or in part, and is subject to the NIH Public Access Policy. Through acceptance of this federal funding, the NIH has been given a right to make the work publicly available in PubMed Central. JFE by NIH (R01 HL165404 and NHLBI Federal Contract 75N92025C00007) .NSJ, CEM, and SEB by Cystic Fibrosis Foundation (Joo19G0, MILLA23G0, and CFF BIRKET23XX0) .Stanford Innovative Medicines Accelerator (IMA-1070) , Cystic Fibrosis Research Inc., Ross Mosier CF Research Laboratories gift fund, and Galper Family CF fund.
- Language
- English
- Electronic publication date
- 04/02/2026
- Date published
- 06/01/2026
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9985149524502771
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