Clarithromycin targets neutrophilic airway inflammation in refractory asthma
Clarithromycin targets neutrophilic airway inflammation in refractory asthma
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DOI：
10.1164/rccm.200707-1134oc
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发表时间：
2008-01-15
影响因子：
24.7
通讯作者：
Gibson, Peter G.
中科院分区：
文献类型：
--
作者：
Simpson, Jodie L.;Powell, Heather;Gibson, Peter G.
理由：尽管使用吸入皮质类固醇和长效支气管扩张剂进行最大程度的治疗，难治性哮喘患者的症状仍持续存在。附加疗法的可用性是有限的，需要针对非嗜酸性粒细胞性气道炎症的有效附加疗法。大环内酯类抗生素，如克拉霉素，对非嗜酸性粒细胞性哮喘的关键炎症介质 IL-8 和中性粒细胞具有体外疗效。 目的： 确定克拉霉素对严重难治性哮喘患者，特别是非嗜酸性粒细胞性哮喘亚组患者的疗效。 方法： 患有严重难治性哮喘的受试者 (n = 45) 被随机分配接受克拉霉素（500 mg，两次）每天）或安慰剂，持续 8 周。测量和主要结果：本研究的主要结果是痰液 IL-8 浓度。评估的其他炎症结果包括痰中性粒细胞数量以及中性粒细胞弹性蛋白酶和基质金属蛋白酶 (MMP)-9 的浓度。还评估了临床结果，包括肺功能、气道对高渗盐水的高反应性、哮喘控制、生活质量和症状。与安慰剂相比，克拉霉素治疗显着降低了气道 IL-8 浓度和中性粒细胞数量，并改善了生活质量评分。还观察到中性粒细胞弹性蛋白酶和 MMP-9 浓度降低。炎症的减轻在难治性非嗜酸性粒细胞性哮喘患者中最为明显。结论：克拉霉素治疗可以调节难治性哮喘患者气道中 IL-8 水平以及中性粒细胞积聚和活化。大环内酯疗法可能是一种重要的附加疗法，可用于减少哮喘中的非嗜酸性粒细胞气道炎症，特别是中性粒细胞炎症。临床试验已在澳大利亚临床试验注册中心 www.actr.org.au 注册（编号：12605000318684）。
Rationale: Patients with refractory asthma have persistent symptoms despite maximal treatment with inhaled corticosteroids and long-acting bronchodilators. The availability of add-on therapies is limited, and effective add-on therapies that target noneosinophilic airway inflammation are needed. Macrolide antibiotics, such as clarithromycin, have in vitro efficacy against IL-8 and neutrophils, key inflammatory mediators in noneosinophilic asthma.Objectives: To determine the efficacy of clarithromycin in patients with severe refractory asthma and specifically in a subgroup of patients with noneosinophilic asthma.Methods: Subjects with severe refractory asthma (n = 45) were randomized to receive clarithromycin (500 mg twice daily) or placebo for 8 weeks.Measurements and Main Results: The primary outcome for this study was sputum IL-8 concentration. Other inflammatory outcomes assessed included sputum neutrophil numbers and concentrations of neutrophil elastase and matrix metalloproteinase (MMP)-9. Clinical outcomes were also assessed, including lung function, airway hyper-responsiveness to hypertonic saline, asthma control, quality of life, and symptoms. Clarithromycin therapy significantly reduced airway concentrations of IL-8 and neutrophil numbers and improved quality-of-life scores compared with placebo. Reductions in neutrophil elastase and MMP-9 concentrations were also observed. These reductions in inflammation were most marked in those with refractory noneosinophilic asthma.Conclusions: Clarithromycin therapy can modulate IL-8 levels and neutrophil accumulation and activation in the airways of patients with refractory asthma. Macrolide therapy may be an important additional therapy that could be used to reduce noneosinophilic airway inflammation, particularly neutrophilic inflammation, in asthma. Clinical trial registered with the Australian Clinical Trials Registry www.actr.org.au (No. 12605000318684).