Azithromycin and Clarithromycin Inhibit Lipopolysaccharide-Induced Murine Pulmonary Neutrophilia Mainly through Effects on Macrophage-Derived Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-1β
Azithromycin and Clarithromycin Inhibit Lipopolysaccharide-Induced Murine Pulmonary Neutrophilia Mainly through Effects on Macrophage-Derived Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-1β
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DOI：
10.1124/jpet.109.155838
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发表时间：
2009-10-01
影响因子：
3.5
通讯作者：
Haber, Vesna Erakovic
中科院分区：
文献类型：
--
作者：
Bosnar, Martina;Bosnjak, Berislav;Haber, Vesna Erakovic
大环内酯类抗生素具有免疫调节/抗炎特性。这些特性被认为是大环内酯类抗生素治疗弥漫性全细支气管炎和囊性纤维化等慢性炎症性疾病的功效的基础。然而，抗炎/免疫调节大环内酯活性的分子机制和细胞靶点仍不完全清楚。为了更详细地描述大环内酯类药物的抗炎作用并确定其活性的潜在生物标志物，我们研究了阿奇霉素和克拉霉素对小鼠鼻内脂多糖攻击后导致中性粒细胞浸润至肺部的炎症级联反应的影响。阿奇霉素和克拉霉素预处理降低了支气管肺泡灌洗液中的总细胞和中性粒细胞数量以及肺组织中的髓过氧化物酶浓度。此外，大环内酯类药物治疗后，肺匀浆中多种炎症介质的浓度降低，包括CCL2、粒细胞-巨噬细胞集落刺激因子（GM-CSF）、白介素-1β（IL-1β）、肿瘤坏死因子α和sE-选择素。体内观察到的细胞因子产生的抑制也在体外脂多糖刺激的单核细胞/巨噬细胞中得到证实，但在上皮细胞系中没有得到证实。总之，本文提出的结果证实大环内酯类药物可以抑制中性粒细胞为主的肺部炎症，并表明该作用是通过抑制肺泡巨噬细胞产生 GMCSF 和 IL-1β 来介导的。除了 GM-CSF 和 IL-1 beta 之外，CCL2 和 sE-选择素也被确定为肺部大环内酯类抗炎活性的潜在生物标志物。
Macrolide antibiotics possess immunomodulatory/anti-inflammatory properties. These properties are considered fundamental for the efficacy of macrolide antibiotics in the treatment of chronic inflammatory diseases like diffuse panbronchiolitis and cystic fibrosis. However, the molecular mechanisms and cellular targets of anti-inflammatory/immunomodulatory macrolide activity are still not fully understood. To describe anti-inflammatory effects of macrolides in more detail and to identify potential biomarkers of their activity, we have investigated the influence of azithromycin and clarithromycin on the inflammatory cascade leading to neutrophil infiltration into lungs after intranasal lipopolysaccharide challenge in mice. Azithromycin and clarithromycin pretreatment reduced total cell and neutrophil numbers in bronchoalveolar lavage fluid and myeloperoxidase concentration in lung tissue. In addition, concentrations of several inflammatory mediators, including CCL2, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha, and sE-selectin in lung homogenates were decreased after macrolide treatment. Inhibition of cytokine production observed in vivo was also corroborated in vitro in lipopolysaccharide-stimulated monocytes/macrophages, but not in an epithelial cell line. In summary, results presented in this article confirm that macrolides can suppress neutrophil-dominated pulmonary inflammation and suggest that the effect is mediated through inhibition of GMCSF and IL-1 beta production by alveolar macrophages. Besides GM-CSF and IL-1 beta, CCL2 and sE-selectin are also identified as potential biomarkers of macrolide anti-inflammatory activity in the lungs.