title: Comparison of the anti-inflammatory effects of Cilomilast, Budesonide and a p38 Mitogen activated protein kinase inhibitor in COPD lung tissue macrophages.
abstract: Chronic Obstructive Pulmonary Disease (COPD) is a disease characterized by a largely irreversible airflow obstruction and a persistent, excessive inflammatory response. Alveolar macrophages (AMs) are increased in the lungs of COPD patients, and act as orchestrators of the inflammatory response, releasing a range of mediators to coordinate recruitment and activation of leukocytes. Attempts to treat the inflammatory component of COPD with anti-inflammatory drugs such as steroids has met with limited success. In this study, we compared the ability of the phosphodiesterase IV (PDEIV) inhibitor Cilomilast, the steroid Budesonide, and the p38 mitogen activated protein kinase inhibitor BIRB-796 to inhibit tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) releases from AMs isolated from COPD lung transplant tissue. All studies were carried out with appropriate ethical approval and written, informed consent was obtained from each subject. Cilomilast had little effect on cytokine release from AMs. There was considerable variability in the responsiveness of AMs to Budesonide, with a subset of AMs responding poorly to Budesonide. BIRB-796 inhibited TNFα release from all AM donors, including those that responded poorly to steroids. Treatment with BIRB-796 and Budesonide together gave an additive decrease in TNFa release. These results suggest that a p38 inhibitor may provide advantages over existing anti-inflammatory treatments for COPD, either as an add-on to existing therapy, or to treat patients who respond poorly to steroids.
authors.affiliation: Personalised Healthcare and Biomarkers, AstraZeneca R&D Alderley Park, Cheshire, SK, 10 4TG, UK. Marianne.ratcliffe@astrazeneca.com
authors.forename: Marianne Jennifer
authors.initials: MJ
authors.lastname: Ratcliffe
authors.forename: Iain Gordon
authors.initials: IG
authors.lastname: Dougall
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D019819:Budesonide / Q000494:pharmacology; D002478:Cells, Cultured; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D008070:Lipopolysaccharides; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive; D011720:Pyrazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010671:Phenylurea Compounds
chemical_list: D000893:Anti-Inflammatory Agents; D019819:Budesonide; D003509:Cyclohexanecarboxylic Acids; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009281:Naphthalenes; D009570:Nitriles; D058988:Phosphodiesterase 4 Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C433247:Cilomilast; C452139:doramapimod; D010671:Phenylurea Compounds