Sputum and blood transcriptomics characterisation of the inhaled PDE4 inhibitor CHF6001 on top of triple therapy in patients with chronic bronchitis
Autor: | Brendan Colgan, Michele Bassi, Stefano Vezzoli, Mirco Govoni, Germano Lucci, Oliver Kornmann, Ebenezer K. Afolabi, Aida Emirova, Gera L. Jellema, Kai Michael Beeh, Dave Singh, Marie Anna Nandeuil, Brian Leaker, Stefano Petruzzelli, Henrik Watz |
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Rok vydání: | 2019 |
Předmět: |
Male
medicine.medical_specialty Chronic bronchitis Anti-Inflammatory Agents Inflammation Placebo Gastroenterology Pulmonary Disease Chronic Obstructive Internal medicine Administration Inhalation para-Aminobenzoates Medicine Humans ddc:610 Whole blood Aged lcsh:RC705-779 COPD Sulfonamides Lung Cross-Over Studies business.industry Research Chronic obstructive pulmonary disease Sputum lcsh:Diseases of the respiratory system medicine.disease Crossover study Phosphodiesterase 4 inhibitors Bronchitis Chronic medicine.anatomical_structure Female Gene expression medicine.symptom Inflammation Mediators business Transcriptome Biomarkers |
Zdroj: | Respiratory Research Respiratory Research, Vol 21, Iss 1, Pp 1-11 (2020) |
ISSN: | 1465-993X |
Popis: | Background Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to characterise the whole genome gene expression profile of the inhaled PDE4-inhibitor CHF6001 on top of triple therapy in sputum cells and whole blood of patients with COPD and chronic bronchitis. Methods Whole genome gene expression analysis was carried out by microarray in 54 patients before and after 32 days treatment with CHF6001 800 and 1600 μg and placebo twice daily (BID) in a randomised crossover study. Results CHF6001 had a strong effect in sputum, with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-adjusted for False Discovery Rate 87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. The effect in blood was not significant. Conclusions Inhaled PDE4 inhibition by CHF6001 on top of triple therapy in patients with COPD and chronic bronchitis significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimising unwanted systemic class-effects. Trial registration ClinicalTrial.gov, EudraCT, 2015–005550-35. Registered 15 July 2016. |
Databáze: | OpenAIRE |
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