CCR2 Regulates Inflammatory Cell Accumulation in the Lung and Tissue Injury following Ozone Exposure
CCR2 Regulates Inflammatory Cell Accumulation in the Lung and Tissue Injury following Ozone Exposure
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DOI：
10.1093/toxsci/kfw226
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发表时间：
2017-02-01
影响因子：
3.8
通讯作者：
Laskin, Debra L.
中科院分区：
文献类型：
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作者：
Francis, Mary;Groves, Angela M.;Laskin, Debra L.
臭氧诱导的肺损伤与肺中活化巨噬细胞的积聚有关。趋化因子受体CCR 2介导炎性单核细胞/巨噬细胞向组织损伤部位的迁移。它也是单核细胞从骨髓中排出所必需的。在目前的研究中，我们分析了CCR 2在炎症细胞运输到肺部响应臭氧的作用。用臭氧（0.8 ppm，3 h）处理小鼠导致24 h时肺中促炎性CCR 2（+）巨噬细胞增加，以及24 h和48 h时促炎性CD 11b（+）Ly 6C（Hi）和iNOS（+）巨噬细胞增加。甘露糖受体（+）抗炎巨噬细胞也观察到在肺24和48小时后臭氧。CCR 2的缺失与肺中促炎性巨噬细胞数量的减少以及促炎性细胞因子IL-1 β和TNF α表达的减少相关。在用臭氧处理的CCR 2（-）/（-）小鼠的肺中也观察到抗炎性CD 11b（+）Ly 6C（Lo）巨噬细胞的减少，而甘露糖受体（+）巨噬细胞积累延迟;相反，CX 3CL 1和CX 3CR 1上调。CCR 2（-）/（-）小鼠肺巨噬细胞亚群和炎性基因表达的变化与臭氧毒性和氧化应激的降低相关，通过支气管肺泡灌洗液蛋白含量的降低和血红素加氧酶-1，4-羟基壬烯醛和细胞色素b5的肺表达降低来测量。这些数据表明，CCR 2在臭氧暴露后肺中促炎和抗炎巨噬细胞积聚中发挥作用。臭氧诱导的肺损伤和氧化应激在CCR 2（-）/（-）小鼠中减少的事实表明对促炎性巨噬细胞的作用更显著。
Ozone-induced lung injury is associated with an accumulation of activated macrophages in the lung. Chemokine receptor CCR2 mediates the migration of inflammatory monocytes/acrophages to sites of tissue injury. It is also required for monocyte egress from the bone marrow. In the present studies, we analyzed the role of CCR2 in inflammatory cell trafficking to the lung in response to ozone. Treatment of mice with ozone (0.8 ppm, 3h) resulted in increases in proinflammatory CCR2(+) macrophages in the lung at 24 h, as well as proinflammatory CD11b(+) Ly6C(Hi) and iNOS(+) macrophages at 24 and 48 h. Mannose receptor(+) anti-inflammatory macrophages were also observed in the lung 24 and 48 h post-ozone. Loss of CCR2 was associated with reduced numbers of proinflammatory macrophages in the lung and decreased expression of the proinflammatory cytokines, IL-1 beta and TNF alpha. Decreases in anti-inflammatory CD11b(+) Ly6C(Lo) macrophages were also observed in lungs of CCR2(-)/(-) mice treated with ozone, whereas mannose receptor(+)macrophage accumulation was delayed; conversely, CX3CL1 and CX3CR1 were upregulated. Changes in lung macrophage subpopulations and inflammatory gene expression in CCR2(-)/(-) mice were correlated with reduced ozone toxicity and oxidative stress, as measured by decreases in bronchoalveolar lavage protein content and reduced lung expression of heme-oxygenase-1, 4-hydroxynonenal and cytochrome b5. These data demonstrate that CCR2 plays a role in both pro-and anti-inflammatory macrophage accumulation in the lung following ozone exposure. The fact that ozone-induced lung injury and oxidative stress are reduced in CCR2(-)/(-)mice suggests more prominent effects on proinflammatory macrophages.