Azithromycin blocks neutrophil recruitment in Pseudomonas endobronchial infection
Azithromycin blocks neutrophil recruitment in Pseudomonas endobronchial infection
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DOI：
10.1164/rccm.200402-200oc
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发表时间：
2004-12-15
影响因子：
24.7
通讯作者：
Standiford, TJ
中科院分区：
文献类型：
--
作者：
Tsai, WC;Rodriguez, ML;Standiford, TJ
大环内酯类药物通过调节免疫应答对宿主发挥作用。在这项研究中，我们评估了阿奇霉素在粘液型铜绿假单胞菌支气管内感染的小鼠模型中的治疗效果。用大环内酯阿奇霉素处理的小鼠气道中假单胞菌的清除率与用假单胞菌珠攻击的未处理小鼠没有不同。然而，与未处理的小鼠相比，阿奇霉素处理的小鼠对假单胞菌珠的肺细胞浸润显示出显著的减少。与未治疗的小鼠相比，阿奇霉素治疗的小鼠的肺肿瘤坏死因子-a和角化细胞衍生的趋化因子水平显著降低，这一效应与此相关。此外，在体外研究时，小鼠和人中性粒细胞对趋化因子依赖性和非依赖性趋化因子的反应显著降低。趋化性的抑制与阿奇霉素介导的细胞外信号调节激酶-1和-2活化的抑制相关。这项研究表明，阿奇霉素治疗在体内导致气道特异性炎症显着减少，这部分是通过抑制中性粒细胞招募到肺通过减少促炎细胞因子的表达和抑制中性粒细胞迁移通过细胞外信号调节激酶-1和-2信号转导途径。
Macrolides exert their effects on the host by modulation of immune responses. In this study, we assessed the therapeutic efficacy of azithromycin in a murine model of mucoid Pseudomonas aeruginosa endobronchial infection. The clearance of Pseudomonas from the airway of mice treated with the macrolide azithromycin was not different than untreated mice challenged with Pseudomonas beads. However, the azithromycin-treated mice showed a remarkable reduction in lung cellular infiltrate in response to Pseudomonas beads, as compared with untreated mice. This effect was associated with significant decreases in lung levels of tumor necrosis factor-a and keratinocyte-derived chemokine in azithromycin-treated mice compared with untreated mice. Furthermore, there was a significant reduction in the response of both mouse and human neutrophils to chemokine-dependent and -independent chemoattractants when studied in vitro. Inhibition of chemotaxis correlated with azithromycin-mediated inhibition of extracellular signal-regulated kinase-1 and -2 activation. This study indicates that the azithromycin treatment in vivo results in significant reduction in airway-specific inflammation, which occurs in part by inhibition of neutrophil recruitment to the lung through reduction in proinflammatory cytokine expression and inhibition of neutrophil migration via the extracellular signal-regulated kinase-1 and -2 signal transduction pathway.