Persdotter Sofia, Lindahl Maria, Malm-Erjefalt Monika, von Wachenfeldt Karin, Korn Solange H, Stevens Tim, Miller-Larsson Anna
AstraZeneca R&D Lund, Lund, Sweden.
Int Arch Allergy Immunol. 2007;143(3):201-10. doi: 10.1159/000099463. Epub 2007 Feb 9.
Improved asthma control by combinations of inhaled glucocorticosteroids (GCs) and long-acting beta(2)-agonists (LABAs) includes a reduced frequency and severity of exacerbations. In view of the association of exacerbations with increased airway inflammation, the question has arisen as to whether LABAs are able to complement the known anti-inflammatory activity of GCs. To address this, we studied the effects of a LABA, formoterol (FORM), and a GC, budesonide (BUD), alone and in combination, on bronchial epithelial cell-mediated eosinophil superoxide production in vitro.
We employed 2 experimental approaches. First, superoxide production by human eosinophils incubated with conditioned medium (CM) from human bronchial epithelial cells cultured for 24 h with vehicle, BUD, FORM or BUD + FORM was measured (Epi/Eos assay). Second, eosinophils were stimulated with vehicle-CM to which the drugs were added (Eos assay). Superoxide production was determined as the superoxide dismutase-inhibitable reduction of ferricytochrome C.
CM increased eosinophil superoxide generation (p < 0.01) and epithelial-derived granulocyte macrophage colony-stimulating factor was the mediator responsible. In both assays, FORM dose-dependently inhibited eosinophil superoxide similarly and in the same concentration range as BUD. The BUD + FORM combination was more effective than BUD alone, and it completely inhibited CM-induced superoxide production in the Epi/Eos assay, suggesting complementary effects of both drugs on bronchial epithelial cells and eosinophils.
The cooperative, inhibitory effects of BUD and FORM on eosinophils and bronchial epithelial cells, in terms of their effects on eosinophil superoxide production, may represent a possible mechanism for the enhanced anti-inflammatory efficacy of BUD and FORM combination therapy of asthma.
吸入性糖皮质激素（GCs）与长效β₂受体激动剂（LABAs）联合使用改善哮喘控制包括减少发作的频率和严重程度。鉴于发作与气道炎症增加相关，LABAs是否能够补充GCs已知的抗炎活性这一问题已经出现。为解决这一问题，我们在体外研究了一种LABA福莫特罗（FORM）和一种GC布地奈德（BUD）单独及联合使用对支气管上皮细胞介导的嗜酸性粒细胞超氧化物产生的影响。
我们采用了2种实验方法。首先，测量与用赋形剂、BUD、FORM或BUD + FORM培养24小时的人支气管上皮细胞的条件培养基（CM）孵育的人嗜酸性粒细胞的超氧化物产生（上皮细胞/嗜酸性粒细胞测定）。其次，用添加了药物的赋形剂-CM刺激嗜酸性粒细胞（嗜酸性粒细胞测定）。超氧化物产生被确定为超氧化物歧化酶可抑制的铁细胞色素C的还原。
CM增加了嗜酸性粒细胞超氧化物生成（p < 0.01），并且上皮细胞衍生的粒细胞巨噬细胞集落刺激因子是负责的介质。在两种测定中，FORM在与BUD相同的浓度范围内以剂量依赖性方式类似地抑制嗜酸性粒细胞超氧化物。BUD + FORM组合比单独使用BUD更有效，并且在Epi/Eos测定中它完全抑制了CM诱导的超氧化物产生，表明两种药物对支气管上皮细胞和嗜酸性粒细胞具有互补作用。
就其对嗜酸性粒细胞超氧化物产生的影响而言，BUD和FORM对嗜酸性粒细胞和支气管上皮细胞的协同抑制作用可能代表了BUD和FORM联合治疗哮喘增强抗炎疗效的一种可能机制。
