Abstract
Rationale The majority of chronic obstructive pulmonary disease (COPD) patients have chronic bronchitis, for which specific therapies are unavailable. Acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is observed in chronic bronchitis, but has not been proven in a controlled animal model with airway disease. Furthermore, the potential of CFTR as a therapeutic target has not been tested in vivo, given limitations to rodent models of COPD. Ferrets exhibit cystic fibrosis-related lung pathology when CFTR is absent and COPD with bronchitis following cigarette smoke exposure.
Objectives To evaluate CFTR dysfunction induced by smoking and test its pharmacological reversal by a novel CFTR potentiator, GLPG2196, in a ferret model of COPD with chronic bronchitis.
Methods Ferrets were exposed for 6 months to cigarette smoke to induce COPD and chronic bronchitis and then treated with enteral GLPG2196 once daily for 1 month. Electrophysiological measurements of ion transport and CFTR function, assessment of mucociliary function by one-micron optical coherence tomography imaging and particle-tracking microrheology, microcomputed tomography imaging, histopathological analysis and quantification of CFTR protein and mRNA expression were used to evaluate mechanistic and pathophysiological changes.
Measurements and main results Following cigarette smoke exposure, ferrets exhibited CFTR dysfunction, increased mucus viscosity, delayed mucociliary clearance, airway wall thickening and airway epithelial hypertrophy. In COPD ferrets, GLPG2196 treatment reversed CFTR dysfunction, increased mucus transport by decreasing mucus viscosity, and reduced bronchial wall thickening and airway epithelial hypertrophy.
Conclusions The pharmacologic reversal of acquired CFTR dysfunction is beneficial against pathological features of chronic bronchitis in a COPD ferret model.
Abstract
These studies provide the first in vivo data evaluating CFTR potentiation in an experimental animal model of chronic bronchitis, an approach being pursued in COPD. Findings support targeting CFTR in COPD with drugs that potentiate CFTR. https://bit.ly/3nSCkQu
Footnotes
Author contributions: S.V. Raju and S.M. Rowe conceived of and designed the research; N. Kaza, V.Y. Lin, D. Stanford, S.S. Hussain, V. Mutyam, S.A. Byzek, L.P. Tang, J.E. Trombley, L. Rasmussen, T. Schoeb, S.V. Raju and S.M. Rowe performed the experiments; N. Kaza, V.Y. Lin, D. Stanford, S.S. Hussain, M. Borgonovi, K. Conrath, E. Falk Libby, H. Kim, V. Mutyam, S.V. Raju and S.M. Rowe analysed data and interpreted results; H.M. Leung and G.J. Tearney provided experimental technology and procedures; N. Kaza, V.Y. Lin, S.V. Raju and S.M. Rowe prepared figures; E. Falk Libby and S.M. Rowe wrote the manuscript; S.V. Raju and S.M. Rowe supervised the project; all authors had an opportunity to edit the manuscript and approved of its submission.
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Conflict of interest: S.M. Rowe has received consulting fees from Abbvie related to the design and conduct of clinical trials in cystic fibrosis. M. Borgonovi and K. Conrath are employees of Galapagos. All other authors declare no competing interests.
Support statement: These studies were supported by NIH National Heart, Lung, and Blood Institute (NHLBI) Grant R35HL135816 (to S.M.R.) and National Institute of Diabetes and Digestive and Kidney Diseases Grant P30 DK072482 (to S.M.R). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received June 4, 2021.
- Accepted November 21, 2021.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org