title: The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia.
abstract: Cystic fibrosis (CF), a genetic disease caused by mutations in the CFTR gene, is a life-limiting disease characterized by chronic bacterial airway infection and severe inflammation. Some CFTR mutants have reduced responsiveness to cAMP/PKA signaling; hence, pharmacological agents that elevate intracellular cAMP are potentially useful for the treatment of CF. By inhibiting cAMP breakdown, phosphodiesterase (PDE) inhibitors stimulate CFTR in vitro and in vivo. Here, we demonstrate that PDE inhibition by RPL554, a drug that has been shown to cause bronchodilation in asthma and chronic obstructive pulmonary disease (COPD) patients, stimulates CFTR-dependent ion secretion across bronchial epithelial cells isolated from patients carrying the R117H/F508del CF genotype. RPL554-induced CFTR activity was further increased by the potentiator VX-770, suggesting an additional benefit by the drug combination. RPL554 also increased cilia beat frequency in primary human bronchial epithelial cells. The results indicate RPL554 may increase mucociliary clearance through stimulation of CFTR and increasing ciliary beat frequency and thus could provide a novel therapeutic option for CF.
authors.affiliation: Department of Physiology, McIntyre Medical Sciences Building, McGill University, Montreal, Canada; McGill CF Translational Research Centre, Montreal, Canada; mark.turner2@mail.mcgill.ca.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Turner
authors.affiliation: Department of Physiology, McIntyre Medical Sciences Building, McGill University, Montreal, Canada; McGill CF Translational Research Centre, Montreal, Canada;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Matthes
authors.affiliation: Department of Physiology, McIntyre Medical Sciences Building, McGill University, Montreal, Canada; McGill CF Translational Research Centre, Montreal, Canada;
authors.forename: Arnaud
authors.initials: A
authors.lastname: Billet
authors.affiliation: Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Ferguson
authors.affiliation: McGill CF Translational Research Centre, Montreal, Canada; Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montreal, Canada;
authors.forename: David Y
authors.initials: DY
authors.lastname: Thomas
authors.affiliation: Department of Cell Biology and Physiology and the Marsico Lung Institute/Cystic Fibrosis Center, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Scott H
authors.initials: SH
authors.lastname: Randell
authors.affiliation: Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Ostrowski
authors.affiliation: Verona Pharma plc, London, United Kingdom; and.
authors.forename: Kathy
authors.initials: K
authors.lastname: Abbott-Banner
authors.affiliation: Department of Physiology, McIntyre Medical Sciences Building, McGill University, Montreal, Canada; McGill CF Translational Research Centre, Montreal, Canada; Research Institute of the McGill University Health Centre, Montreal, Canada.
authors.forename: John W
authors.initials: JW
authors.lastname: Hanrahan
mesh_terms: D001249:Asthma / Q000188:drug therapy / Q000378:metabolism; D002478:Cells, Cultured; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology*; D009079:Mucociliary Clearance / Q000187:drug effects; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology*
chemical_list: D007546:Isoquinolines; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D011744:Pyrimidinones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C512996:ensifentrine
keywords: CFTR; RPL554; ciliary beating; cystic fibrosis; phosphodiesterase