Azithromycin Alters Macrophage Phenotype and Pulmonary Compartmentalization during Lung Infection with Pseudomonas
Azithromycin Alters Macrophage Phenotype and Pulmonary Compartmentalization during Lung Infection with Pseudomonas
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DOI：
10.1128/aac.01424-09
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发表时间：
2010-06-01
影响因子：
4.9
通讯作者：
Murphy, Brian S.
中科院分区：
文献类型：
--
作者：
Feola, David J.;Garvy, Beth A.;Murphy, Brian S.
气道慢性炎症性疾病中铜绿假单胞菌黏液株感染难以根除，可引起过度炎症。巨噬细胞的选择性激活和调节亚群在这一病理生理过程中的作用尚未得到很好的表征。我们之前证明了阿奇霉素在体外诱导可选活化的巨噬细胞样表型。在本研究中，我们检测了阿奇霉素是否影响铜绿假单胞菌感染小鼠肺部巨噬细胞的激活状态和迁移。C57BL/6小鼠每日口服阿奇霉素，气管内感染一株铜绿假单胞菌黏液菌株。观察感染后肺间质和肺泡间室的巨噬细胞活化、免疫细胞浸润和肺部炎症标志物的特性。阿奇霉素处理诱导巨噬细胞选择性活化的标志物，包括甘露糖受体的表面表达、精氨酸酶1的上调和促炎细胞因子的产生减少。此外，阿奇霉素增加了浸润肺泡室的CD11b（+）单核细胞和CD4(+) T细胞的数量。CD11b（+）细胞的主要亚群为Gr-1阳性（Gr-1(+)），表明该细胞亚群已被证明具有免疫调节作用。这些差异对应于中性粒细胞流入肺实质的减少和细支气管周围炎症特征的改变，而生物体的清除率没有任何变化。这些结果表明，阿奇霉素的免疫调节作用与感染期间诱导巨噬细胞的选择性和调节性活化特性以及细胞区室化的改变有关。
Infection with mucoid strains of Pseudomonas aeruginosa in chronic inflammatory diseases of the airway is difficult to eradicate and can cause excessive inflammation. The roles of alternatively activated and regulatory subsets of macrophages in this pathophysiological process are not well characterized. We previously demonstrated that azithromycin induces an alternatively activated macrophage-like phenotype in vitro. In the present study, we tested whether azithromycin affects the macrophage activation status and migration in the lungs of P. aeruginosa-infected mice. C57BL/6 mice received daily doses of oral azithromycin and were infected intratracheally with a mucoid strain of P. aeruginosa. The properties of macrophage activation, immune cell infiltration, and markers of pulmonary inflammation in the lung interstitial and alveolar compartments were evaluated postinfection. Markers of alternative macrophage activation were induced by azithromycin treatment, including the surface expression of the mannose receptor, the upregulation of arginase 1, and a decrease in the production of proinflammatory cytokines. Additionally, azithromycin increased the number of CD11b(+) monocytes and CD4(+) T cells that infiltrated the alveolar compartment. A predominant subset of CD11b(+) cells was Gr-1 positive (Gr-1(+)), indicative of a subset of cells that has been shown to be immunoregulatory. These differences corresponded to decreases in neutrophil influx into the lung parenchyma and alteration of the characteristics of peribronchiolar inflammation without any change in the clearance of the organism. These results suggest that the immunomodulatory effects of azithromycin are associated with the induction of alternative and regulatory macrophage activation characteristics and alteration of cellular compartmentalization during infection.