Sarir Hadi, Mortaz Esmaeil, Karimi Khalil, Johnson Malcolm, Nijkamp Frans P, Folkerts Gert
Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, The Netherlands.
Eur J Pharmacol. 2007 Sep 24;571(1):55-61. doi: 10.1016/j.ejphar.2007.05.034. Epub 2007 Jun 5.
Cigarette smoke is the major risk factor for the development of chronic obstructive pulmonary disease (COPD). Macrophages are suggested to orchestrate the chronic inflammatory response and tissue destruction associated with COPD by secreting interleukin (IL)-8, a major neutrophil chemoattractant. The combination of inhaled corticosteroids and long-acting beta(2)-adrenoceptor agonists are increasingly used as maintenance therapy in patients with COPD. The aim of this study was to determine whether combined fluticasone propionate, a corticosteroid, and salmeterol, a long-acting beta(2)-adrenoceptor agonist, can suppress IL-8 production by human macrophages. To mimic resident macrophages in the lung, human monocytes were cultured for 5 days in medium containing Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) and Macrophage Colony Stimulating Factor (M-CSF). In human Monocyte-Derived Macrophages, we found that cigarette smoke medium strongly enhanced IL-8 release in a time- and concentration-dependent manner. IL-8 release by cigarette smoke was significantly suppressed in a concentration-dependent manner by fluticasone and salmeterol. Coincubation of the drugs potentiated the inhibitory effect on cigarette smoke medium-induced IL-8 production and longer preincubation times resulted in more IL-8 inhibition. Interestingly, preincubation of cells with suboptimal concentration of salmeterol for 4 h before fluticasone administration for 30 min potentiates the inhibitory effect of fluticasone on IL-8 release. In conclusion, combination therapy may provide benefits over monotherapy for the treatment of COPD patients.
香烟烟雾是慢性阻塞性肺疾病（COPD）发生的主要危险因素。巨噬细胞被认为通过分泌白细胞介素（IL）-8（一种主要的中性粒细胞趋化因子）来协调与COPD相关的慢性炎症反应和组织破坏。吸入性糖皮质激素和长效β2肾上腺素受体激动剂的联合用药越来越多地被用作COPD患者的维持治疗。本研究的目的是确定皮质类固醇丙酸氟替卡松和长效β2肾上腺素受体激动剂沙美特罗的联合用药是否能抑制人巨噬细胞产生IL-8。为模拟肺内的驻留巨噬细胞，将人单核细胞在含有粒细胞巨噬细胞集落刺激因子（GM-CSF）和巨噬细胞集落刺激因子（M-CSF）的培养基中培养5天。在人单核细胞衍生的巨噬细胞中，我们发现香烟烟雾培养基能以时间和浓度依赖的方式强烈增强IL-8的释放。丙酸氟替卡松和沙美特罗能以浓度依赖的方式显著抑制香烟烟雾诱导的IL-8释放。两种药物共同孵育可增强对香烟烟雾培养基诱导的IL-8产生的抑制作用，且预孵育时间越长，对IL-8的抑制作用越强。有趣的是，在给予丙酸氟替卡松30分钟前，先用次优浓度的沙美特罗预孵育人单核细胞衍生的巨噬细胞4小时，可增强丙酸氟替卡松对IL-8释放的抑制作用。总之，联合治疗可能比单一治疗更有利于COPD患者的治疗。
