Airway Disease, National Heart and Lung Institute, Imperial College, Dovehouse street, London SW3 6LY, UK.
Respir Med. 2011 Dec;105(12):1784-9. doi: 10.1016/j.rmed.2011.08.020. Epub 2011 Sep 7.
Combination therapy with inhaled corticosteroids (ICS) and long-acting β(2)-adrenergic agonists (LABA) is reported to have superior effects on controlling asthma symptoms to ICS alone; however, there is no molecular-based evidence to explain the clinical effects. Here, the effect of the ICS/LABA combination was compared with ICS on glucocorticoid receptor (GR) activation in sputum macrophages.
In a randomised, double-blind cross-over placebo-controlled 6-visit study, 10 patients with mild asthma were given placebo, formoterol (Oxis(®) 12 μg), budesonide (Pulmicort(®) 200 μg :BUD200, or 800 μg :BUD800), or budesonide/formoterol combination (Symbicort(®)) as a single 100/6 μg (SYM100) or double 200/12 μg (SYM200) dose. Sputum macrophages were separated by plate adhesion from induced sputum. GR binding to the glucocorticoid-response elements on oligonucleotides (GR-GRE binding) was evaluated by ELISA. mRNA expression of MAP-kinase phosphatase (MKP)-1 and IL-8 were measured by quantitative RT-PCR.
GR-GRE binding was significantly increased after treatment with SYM100 (3.5 OD/10 μg protein, median, p < 0.05) versus placebo (1.3) and BUD200 (1.6), and the induction was higher than that of BUD800 (2.4). MKP-1 mRNA was increased and IL-8 mRNA was significantly inhibited by BUD800, SYM100 and SYM200 versus placebo.
The effects of SYM100 and SYM200 on GR activation were not different from that of BUD800 and superior to BUD200. Thus, it has been confirmed at a molecular level that inhaled combination therapy with a lower dose of budesonide has an equivalent effect to a high dose of budesonide alone. In addition, GR-GRE binding is found to be a valuable pharmacodynamic marker for steroid efficacy in clinical studies.
与单独使用吸入性皮质类固醇（ICS）相比，ICS 联合长效β2 激动剂（LABA）的联合治疗对控制哮喘症状具有更好的效果，但目前尚无基于分子的证据来解释其临床疗效。在此，我们比较了ICS/LABA 联合用药与 ICS 对痰巨噬细胞中糖皮质激素受体（GR）激活的影响。
在一项随机、双盲、交叉安慰剂对照的 6 次就诊研究中，10 例轻度哮喘患者分别接受安慰剂、福莫特罗（Oxis(®) 12 μg）、布地奈德（Pulmicort(®) 200 μg：BUD200 或 800 μg：BUD800）或布地奈德/福莫特罗联合制剂（Symbicort(®)）（SYM100 单剂量 100/6 μg，SYM200 双剂量 200/12 μg）。通过平板黏附法从诱导痰中分离痰巨噬细胞。通过 ELISA 评估 GR 与寡核苷酸上糖皮质激素反应元件（GR-GRE 结合）的结合。通过实时定量 RT-PCR 测量 MAP-激酶磷酸酶（MKP）-1 和 IL-8 的 mRNA 表达。
与安慰剂（1.3）和 BUD200（1.6）相比，SYM100 治疗后 GR-GRE 结合显著增加（3.5 OD/10 μg 蛋白，中位数，p < 0.05），而 BUD800 的诱导作用更高（2.4）。与安慰剂相比，BUD800、SYM100 和 SYM200 均能增加 MKP-1 mRNA 的表达，并显著抑制 IL-8 mRNA 的表达。
SYM100 和 SYM200 对 GR 激活的作用与 BUD800 相似，优于 BUD200。因此，在分子水平上证实了低剂量布地奈德吸入联合治疗与高剂量布地奈德单独治疗具有等效疗效。此外，GR-GRE 结合被发现是评估临床研究中类固醇疗效的有价值的药效学标志物。
