Airway Disease Section, National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, United Kingdom.
J Allergy Clin Immunol. 2013 Nov;132(5):1166-73. doi: 10.1016/j.jaci.2013.07.038. Epub 2013 Sep 23.
Combination inhaled therapy with long-acting β2 agonists (LABAs) and corticosteroids is beneficial in treating asthma and chronic obstructive pulmonary disease (COPD).
In asthma, LABAs enhance glucocorticoid receptor (GR) nuclear translocation in the presence of corticosteroids. Whether this biological mechanism occurs in COPD, a relatively corticosteroid-resistant disease, is uncertain.
Eight patients with mild/moderate COPD participated in a double-blind, placebo-controlled, crossover study and inhaled single doses of fluticasone propionate (FP) 100 μg, FP 500 μg, salmeterol xinafoate (SLM) 50 μg, and combination FP 100 μg + SLM 50 μg. One hour postinhalation, sputum was induced, nuclear proteins isolated from purified macrophages, and levels of activated nuclear GR quantified by using a GR-glucocorticoid response element ELISA-based assay.
Nuclear GR significantly increased after the inhalation of FP 500 μg (P < .01), but not after the inhalation of FP 100 μg or SLM 50 μg, compared with placebo. Interestingly, SLM in combination with FP 100 μg increased nuclear GR levels equivalent to those of FP 500 μg alone. This was significantly greater than either FP 100 μg (P < .05) or SLM 50 μg (P < .01) alone. In vitro in a human macrophage cell line, SLM (10(-8) mol/L) enhanced FP (10(-9) mol/L)-induced mitogen-activated protein kinase phosphatase-1 mRNA (5.8 ± 0.6 vs 8.4 ± 1.1 × 10(-6) copies, P < .05) and 2 × glucocorticoid response element-luciferase reporter gene activity (250.1 ± 15.6 vs 103.1 ± 23.6-fold induction, P < .001). Addition of SLM (10(-9) mol/L) to FP (10(-11) mol/L) significantly enhanced FP-mediated suppression of IL-1β-induced CXCL8 (P < .05).
Addition of SLM 50 μg to FP 100 μg enhanced GR nuclear translocation equivalent to that seen with a 5-fold higher dose of FP in sputum macrophages from patients with COPD. This may account for the superior clinical effects of combination LABA/corticosteroid treatment compared with either as monotherapy observed in COPD.
长效β2 激动剂（LABA）和皮质类固醇联合吸入疗法有益于治疗哮喘和慢性阻塞性肺疾病（COPD）。
在哮喘中，LABA 在皮质类固醇存在的情况下增强糖皮质激素受体（GR）核易位。这种生物学机制是否发生在 COPD 中，一种相对的皮质类固醇抵抗性疾病，尚不确定。
8 例轻度/中度 COPD 患者参加了一项双盲、安慰剂对照、交叉研究，并吸入单剂量丙酸氟替卡松（FP）100μg、FP500μg、沙美特罗昔萘酸（SLM）50μg 和 FP100μg+SLM50μg 联合用药。吸入后 1 小时，诱导痰液，从纯化的巨噬细胞中分离核蛋白，并使用基于 GR-糖皮质激素反应元件 ELISA 的测定法定量测定激活的核 GR 水平。
与安慰剂相比，吸入 FP500μg 后（P<0.01），GR 核显著增加，但吸入 FP100μg 或 SLM50μg 后无此变化。有趣的是，SLM 与 FP100μg 联合使用可使核 GR 水平增加，与单独使用 FP500μg 相当。这明显大于 FP100μg（P<0.05）或 SLM50μg（P<0.01）单独使用。在人巨噬细胞系的体外研究中，SLM（10-8mol/L）增强了 FP（10-9mol/L）诱导的丝裂原激活蛋白激酶磷酸酶-1 mRNA（5.8±0.6 对 8.4±1.1×10-6 拷贝，P<0.05）和 2×糖皮质激素反应元件-荧光素酶报告基因活性（250.1±15.6 对 103.1±23.6 倍诱导，P<0.001）。在 FP（10-11mol/L）中加入 SLM（10-9mol/L）可显著增强 FP 对 IL-1β 诱导的 CXCL8 的抑制作用（P<0.05）。
在 COPD 患者的痰巨噬细胞中，与 FP 100μg 联合使用 SLM 50μg 可增强 GR 核易位，其效果与 FP 5 倍高剂量相当。这可能解释了与 COPD 中观察到的单一疗法相比，联合 LABA/皮质类固醇治疗的临床效果更优的原因。
