| Now COPD is defined as a disease state characterized by airflow limitation that is not fully reversible.The airflow is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious paticles or gases.Inflammation plays a key role in the pathogenesis of COPD. Anti-inflammatory effects of drugs such as corticosteroids and theophyllines are not favorable. Cilomilast is a potent and selective phosphodiesterase 4 inhibitor.The rationale for the use of cilomilast in the treatment of COPD is based upon the role of cyclic adenosine monophosphate (cyclic AMP) as a second messenger that mediates a broad suppression of immune and inflammatory cell activities, along with the knowledge that PDE4 is the major cyclic AMP-hydrolyzing isozyme in these cells.Clinical data suggests that cilomilast can improve the clinical symptoms and pulmonary functions.And cilomilast can inhibit the release of inflammatory cytokines in vitro. This study was performed to observe the effect of cilomilast on the inflammatory mediators and cytokines in vitro and in vivo in order to testify anti-inflammatory activity of cilomilast and provide the basis for clinical therapy.MethodsThis study was divided to two parts.The first part is experiment in vitro.Alveolar macrophages(AM) separated from BALF of patients with COPD were cultured in the presence of different concentrations of cilomilast,methylprednisolone and aminophylline for 24 hours.After the incubation the absolute values of LTB4 and IL-6 in supernatants were assessed using ELISA. Peripheral blood mononuclear cells (PBMC) separated from blood of patients with COPD were also cultured in the presence of different concentrations of cilomilast,methylprednisolone and aminophylline for 24 hours. After the incubation the absolute values of IL-8 and TNF-α in supernatants were assessed using ELISA. The effects on the inflammatory mediators and cytokines of different drugs and different concentrations were compared. The second part is experiment in vivo.31 patients with COPD were randomly treated with either cilomilast 15mg bid (cilomilast group) (n=20) or placebo 15mg bid (the control group) (n=11) for 24 weeks. At the start and end of the treatment period the levels of LTB4 and IL-6 in induced sputum were assessed using ELISA.Results1.The effect of cilomilast on release of LTB4 and IL-6 by AM.(1) All three concentrations of cilomilast (0.1μM,1μM,10μM) significantly reduced LTB4 release by AM(p<0.01).And all three concentrations of aminophylline (5μg/ml,15μg/ml,25μg/ml) significantly reduced LTB4 release by AM(p<0.01).But all three concentrations of methylprednisolone (0.05μM,0.10μM,0.15μM) did not significantly reduce LTB4 release by AM. Cilomilast (1μM) reduced the release of LTB4 by 48%.And aminophylline (15μg/ml) reduced the release of LTB4 by 32%.Significant difference was observed (p<0.01).(2) All three concentrations of cilomilast (0.1μM,1μM,10μM) significantly reduced IL-6 release by AM(p<0.01).And all three concentrations of aminophylline (5μg/ml,15μg/ml,25μg/ml) significantly reduced IL-6 release by AM(p<0.01).But all three concentrations of methylprednisolone (0.05μM,0.10μM,0.15μM) did not significantly reduce IL-6 release by AM. Cilomilast (1μM) reduced the release of IL-6 by 45%. And aminophylline (15μg/ml) reduced the release of IL-6 by 33%.Significant difference was observed (p<0.05).2.The effect of cilomilast on release of IL-8 and TNF-α by PBMC.(1) All three concentrations of cilomilast (0.1μM,1μM,10μM) significantly reduced IL-8 release by PBMC(p<0.01).And all three concentrations of aminophylline (5μg/ml,15μg/ml,25μg/ml) significantly reduced IL-8 release by PBMC (p<0.01).But all three concentrations of methylprednisolone (0.05μM,0.10μM,0.15μM) did not significantly reduce IL-8 release by PBMC. Cilomilast (1μM) reduced the release of IL-8 by 54%. And aminophylline (15μg/ml) reduced the release of IL-8 by 39%. Significant difference was observed (p<0.01).(2) All three concentrations of c... |
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