Comparison of the anti-inflammatory effects of Cilomilast, Budesonide and a p38 Mitogen activated protein kinase inhibitor in COPD lung tissue macrophages

COPD is an increasingly prevalent disease, affecting up to 10% of adults aged over 40 years [1]. Current therapies include long acting β2-receptor agonists (LABAs) and muscarinic receptor antagonists, which increase lung function by relaxing airway smooth muscle. Corticosteroids are also used, and have been shown to decrease exacerbations as well as improving other clinical parameters such as FEV1[2]. However, the use of inhaled steroids in COPD is somewhat controversial due to inconsistent clinical effects and reports that these agents have limited effects on lung inflammation in COPD patients. For example, a meta-analysis of the effects of inhaled corticosteroids on inflammatory cells in the sputum of stable COPD patients showed evidence of reductions in neutrophils and lymphocytes but no effect on macrophages [3]. A similar analysis conducted recently on bronchial biopsies and bronchoalveolar lavage (BAL) fluid from stable patients showed reductions in neutrophils and lymphocytes in BAL but an increase in macrophages. The biopsy analysis indicated no effect on neutrophil and macrophage counts but a reduction in CD4+ and CD8+ lymphocytes [4]. In accordance with these results, macrophages from COPD patients have been reported to be insensitive to steroids [5,6]. Various mechanisms for this steroid insensitivity have been proposed, including up-regulation of NF-kB signaling and increased oxidative stress [7]. If specific mechanisms are indeed responsible for the poor efficacy of steroids in COPD, then alternative anti-inflammatory approaches may be more successful. One such approach currently being considered is inhibition of PDEIV, by drugs such as Roflumilast and Cilomilast. The former drug has recently been approved as an add-on therapy for the maintenance treatment of severe COPD in the European Union and as a treatment to reduce the risk of exacerbations in the United States. These cAMP elevating agents have been shown to reduce recruitment of macrophages and C