Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma
Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma
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DOI：
10.1136/thoraxjnl-2014-206067
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发表时间：
2015-05-01
期刊：
影响因子：
10
通讯作者：
Hansbro, Philip M.
中科院分区：
文献类型：
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作者：
Essilfie, Ama-Tawiah;Horvat, Jay C.;Hansbro, Philip M.
背景激素不敏感型哮喘是一个重要的临床问题，需要有效的治疗。它们与哮喘肺部的细菌感染和非嗜酸性粒细胞炎症反应有关。大环内酯类药物治疗对激素不敏感的内源性哮喘有效，如非嗜酸性粒细胞性哮喘。然而，大环内酯类药物的作用是由于抗菌还是抗炎机制尚不清楚。目的确定和评价大环内酯类药物的疗效（即克拉霉素）和非大环内酯类（即阿莫西林）抗生素治疗感染诱导的重度、类固醇不敏感的嗜酸性过敏性气道疾病（SSIAAD）实验模型，与类固醇敏感的AAD和描绘的抗菌和抗炎作用的大环内酯therapy.Methods我们开发和使用新的小鼠模型衣原体和嗜血杆菌肺部感染诱导的SSIAAD。我们使用这些模型来研究克拉霉素和阿莫西林治疗对免疫应答和气道高反应性（AHR）的影响与地塞米松治疗相比，在卵白诱导的，辅助性T淋巴细胞（Th）2相关的类固醇敏感的AAD和感染诱导的Th 1/Th 17相关的SSIAAD。阿莫西林确实减弱了某些特征，但不能广泛抑制AAD的任何一种形式。它确实通过减少感染恢复了SSIAAD的类固醇敏感性。相比之下，克拉霉素单独使用可广泛抑制类固醇敏感AAD和SSIAAD的炎症和AHR。这是通过减少Th 2反应，驱动类固醇敏感的嗜酸性AAD和肿瘤坏死因子α和白细胞介素17的反应，诱导SSIAAD.Conclusions大环内酯类药物有广泛的抗炎作用AAD可能是独立的抗菌作用。被抑制的特定反应取决于AAD期间占主导地位的反应。
Background Steroid-insensitive endotypes of asthma are an important clinical problem and effective therapies are required. They are associated with bacterial infection and non-eosinophilic inflammatory responses in the asthmatic lung. Macrolide therapy is effective in steroid-insensitive endotypes, such as non-eosinophilic asthma. However, whether the effects of macrolides are due to antimicrobial or anti-inflammatory mechanisms is not known.Objective To determine and assess the efficacy of macrolide (ie, clarithromycin) and non-macrolide (ie, amoxicillin) antibiotic treatments in experimental models of infection-induced, severe, steroid-insensitive neutrophilic allergic airways disease (SSIAAD), compared with steroid-sensitive AAD and to delineate the antimicrobial and anti-inflammatory effects of macrolide therapy.Methods We developed and used novel mouse models of Chlamydia and Haemophilus lung infection-induced SSIAAD. We used these models to investigate the effects of clarithromycin and amoxicillin treatment on immune responses and airways hyper-responsiveness (AHR) in Ova-induced, T helper lymphocyte (Th) 2 -associated steroid-sensitive AAD and infection-induced Th1/Th17-associated SSIAAD compared with dexamethasone treatment.Results Clarithromycin and amoxicillin had similar antimicrobial effects on infection. Amoxicillin did attenuate some features, but did not broadly suppress either form of AAD. It did restore steroid sensitivity in SSIAAD by reducing infection. In contrast, clarithromycin alone widely suppressed inflammation and AHR in both steroid-sensitive AAD and SSIAAD. This occurred through reductions in Th2 responses that drive steroid-sensitive eosinophilic AAD and tumour necrosis factor alpha and interleukin 17 responses that induce SSIAAD.Conclusions Macrolides have broad anti-inflammatory effects in AAD that are likely independent of their antimicrobial effects. The specific responses that are suppressed are dependent upon the responses that dominate during AAD.