title: Vardenafil reduces macrophage pro-inflammatory overresponses in cystic fibrosis through PDE5- and CFTR-dependent mechanisms.
abstract: Chronic inflammation that progressively disrupts the lung tissue is a hallmark of cystic fibrosis (CF). In mice, vardenafil, an inhibitor of phosphodiesterase type 5 (PDE5), restores transepithelial ion transport and corrects mislocalization of the most common CF mutation, F508del-CFTR. It also reduces lung pro-inflammatory responses in mice and in patients with CF. To test the hypothesis that macrophages are target effector cells of the immunomo-dulatory effect of vardenafil, we isolated lung macrophages from mice homozygous for the F508del mutation or invalidated for thecftrgene and from their corresponding wild-type (WT) littermates. We then evaluated the effect of vardenafil on the classical M1 polarization, mirroring release of pro-inflammatory cytokines. We confirmed that macrophages from different body compartments express CF transmembrane conductance regulator (CFTR) and showed that vardenafil targets the cells through PDE5- and CFTR-dependent mechanisms. In the presence of the F508del mutation, vardenafil down-regulated overresponses of the M1 markers, tumour necrosis factor (TNF)-α and inducible nitric oxide synthase (NOS)-2. Our study identifies lung macrophages as target cells of the anti-inflammatory effect of vardenafil in CF and supports the view that the drug is potentially beneficial for treating CF as it combines rescue of CFTR protein and anti-inflammatory properties.
authors.affiliation: Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Noel
authors.affiliation: Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Nadtha
authors.initials: N
authors.lastname: Panin
authors.affiliation: Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Beka
authors.affiliation: Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dhooghe
authors.affiliation: Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Huaux
authors.affiliation: Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium teresinha.leal@uclouvain.be.
authors.forename: Teresinha
authors.initials: T
authors.lastname: Leal
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D018181:Mice, Inbred CFTR; D058990:Molecular Targeted Therapy / Q000379:methods; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000069058:Vardenafil Dihydrochloride / Q000494:pharmacology*
chemical_list: D018836:Inflammation Mediators; D058986:Phosphodiesterase 5 Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000069058:Vardenafil Dihydrochloride; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse
keywords: CFTR; cystic fibrosis; inflammation; macrophages; mouse model; phosphodiesterase type 5