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ResearchIn-Press PreviewCell biologyClinical ResearchPulmonology Open Access | 10.1172/JCI201541

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

Nam Soo Joo,1 Susan E. Birket,2 Johnathan D. Keith,2 Juan P. Ianowski,3 Xiaojie Luan,3 Jacquelyn Spano,4 Jennifer B. Bollyky,5 Marissa N. Dobry,6 Juan R. Sabater,7 Ryan W. Williams,8 John F. Engelhardt,8 Jeffrey J. Wine,1 and Carlos E. Milla4

1The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, United States of America

2Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada

4Center for Excellence in Pulmonary Biology, Stanford University, Stanford, United States of America

5Department of Medicine, Stanford University, Stanford, United States of America

6Innovative Medicines Accelerator Program, Stanford University, Stanford, United States of America

7Friedman Advanced Research Institute, Mount Sinai Medical Center, Miami, United States of America

8Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States of America

Find articles by Joo, N. in: PubMed | Google Scholar

1The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, United States of America

2Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada

4Center for Excellence in Pulmonary Biology, Stanford University, Stanford, United States of America

5Department of Medicine, Stanford University, Stanford, United States of America

6Innovative Medicines Accelerator Program, Stanford University, Stanford, United States of America

7Friedman Advanced Research Institute, Mount Sinai Medical Center, Miami, United States of America

8Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States of America

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1The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, United States of America

2Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada

4Center for Excellence in Pulmonary Biology, Stanford University, Stanford, United States of America

5Department of Medicine, Stanford University, Stanford, United States of America

6Innovative Medicines Accelerator Program, Stanford University, Stanford, United States of America

7Friedman Advanced Research Institute, Mount Sinai Medical Center, Miami, United States of America

8Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States of America

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1The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, United States of America

2Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada

4Center for Excellence in Pulmonary Biology, Stanford University, Stanford, United States of America

5Department of Medicine, Stanford University, Stanford, United States of America

6Innovative Medicines Accelerator Program, Stanford University, Stanford, United States of America

7Friedman Advanced Research Institute, Mount Sinai Medical Center, Miami, United States of America

8Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States of America

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1The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, United States of America

2Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada

4Center for Excellence in Pulmonary Biology, Stanford University, Stanford, United States of America

5Department of Medicine, Stanford University, Stanford, United States of America

6Innovative Medicines Accelerator Program, Stanford University, Stanford, United States of America

7Friedman Advanced Research Institute, Mount Sinai Medical Center, Miami, United States of America

8Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States of America

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1The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, United States of America

2Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada

4Center for Excellence in Pulmonary Biology, Stanford University, Stanford, United States of America

5Department of Medicine, Stanford University, Stanford, United States of America

6Innovative Medicines Accelerator Program, Stanford University, Stanford, United States of America

7Friedman Advanced Research Institute, Mount Sinai Medical Center, Miami, United States of America

8Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States of America

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1The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, United States of America

2Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada

4Center for Excellence in Pulmonary Biology, Stanford University, Stanford, United States of America

5Department of Medicine, Stanford University, Stanford, United States of America

6Innovative Medicines Accelerator Program, Stanford University, Stanford, United States of America

7Friedman Advanced Research Institute, Mount Sinai Medical Center, Miami, United States of America

8Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States of America

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1The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, United States of America

2Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada

4Center for Excellence in Pulmonary Biology, Stanford University, Stanford, United States of America

5Department of Medicine, Stanford University, Stanford, United States of America

6Innovative Medicines Accelerator Program, Stanford University, Stanford, United States of America

7Friedman Advanced Research Institute, Mount Sinai Medical Center, Miami, United States of America

8Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States of America

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1The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, United States of America

2Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada

4Center for Excellence in Pulmonary Biology, Stanford University, Stanford, United States of America

5Department of Medicine, Stanford University, Stanford, United States of America

6Innovative Medicines Accelerator Program, Stanford University, Stanford, United States of America

7Friedman Advanced Research Institute, Mount Sinai Medical Center, Miami, United States of America

8Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States of America

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1The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, United States of America

2Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada

4Center for Excellence in Pulmonary Biology, Stanford University, Stanford, United States of America

5Department of Medicine, Stanford University, Stanford, United States of America

6Innovative Medicines Accelerator Program, Stanford University, Stanford, United States of America

7Friedman Advanced Research Institute, Mount Sinai Medical Center, Miami, United States of America

8Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States of America

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1The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, United States of America

2Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada

4Center for Excellence in Pulmonary Biology, Stanford University, Stanford, United States of America

5Department of Medicine, Stanford University, Stanford, United States of America

6Innovative Medicines Accelerator Program, Stanford University, Stanford, United States of America

7Friedman Advanced Research Institute, Mount Sinai Medical Center, Miami, United States of America

8Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States of America

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1The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, United States of America

2Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada

4Center for Excellence in Pulmonary Biology, Stanford University, Stanford, United States of America

5Department of Medicine, Stanford University, Stanford, United States of America

6Innovative Medicines Accelerator Program, Stanford University, Stanford, United States of America

7Friedman Advanced Research Institute, Mount Sinai Medical Center, Miami, United States of America

8Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States of America

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1The Cystic Fibrosis Research Laboratory, Stanford University, Stanford, United States of America

2Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America

3Department of Anatomy Physiology and Pharmacology, University of Saskatchewan, Saskatoon, Canada

4Center for Excellence in Pulmonary Biology, Stanford University, Stanford, United States of America

5Department of Medicine, Stanford University, Stanford, United States of America

6Innovative Medicines Accelerator Program, Stanford University, Stanford, United States of America

7Friedman Advanced Research Institute, Mount Sinai Medical Center, Miami, United States of America

8Department of Anatomy and Cell Biology, University of Iowa, Iowa City, United States of America

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Published April 2, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI201541.
Copyright © 2026, Joo et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 2, 2026 - Version history
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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.

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