Ravi Arjun K, Plumb Jonathan, Gaskell Rosemary, Mason Sarah, Broome Caroline S, Booth George, Catley Matthew, Vestbo Jørgen, Singh Dave
NIHR Respiratory and Allergy Clinical Research Facility, Manchester Academic Health Science Centre, University Hospital South Manchester NHS Foundation Trust, University of Manchester, Manchester, UK.
The Medicines Evaluation Unit, Wythenshawe Hospital, The Langley Building, Southmoor Road, Wythenshawe, Greater Manchester, M23 9QZ, UK.
Respir Res. 2017 May 11;18(1):90. doi: 10.1186/s12931-017-0569-y.
Increased lung macrophage numbers in COPD may arise from upregulation of blood monocyte recruitment into the lungs. CCR5 is a monocyte chemokine receptor regulated by interleukin-6 (IL-6); the concentration of CCR5 ligands are known to be elevated in COPD lungs. The objective of this study was to investigate mechanisms of monocyte recruitment to the lung in COPD, including the role of CCR5 signalling.
Ninety one COPD patients, 29 smokers (S) and 37 non-smokers (NS) underwent sputum induction, plasma sampling (to measure IL-6 and soluble IL-6 receptor [sIL-6R] by immunoassay), monocyte characterization (by flow cytometry) and monocyte isolation for cell migration and quantitative polymerase chain reaction studies. Lung tissue was used for immunohistochemistry.
Plasma IL-6 and sIL-6R levels were increased in COPD. Greater proportions of COPD CD14CD16 monocytes expressed CCR5 compared to controls. Monocyte stimulation with IL-6 and sIL-6R increased CCR5 gene expression. COPD monocytes demonstrated impaired migration towards sputum supernatant compared to NS (% migration, 4.4 vs 11.5, respectively; p < 0.05). Pulmonary microvessels showed reduced monocyte recruitment (% marginated cells) in COPD compared to NS, (9.3% vs 83.1%, respectively). The proportion of replicating Ki67 alveolar macrophages was reduced in COPD compared to NS. All alveolar macrophages from COPD and S expressed the anti-apoptosis marker BCL2; this protein was not present in non-smokers or COPD ex-smokers.
COPD monocytes show decreased migratory ability despite increased CCR5 expression. Increased COPD lung macrophage numbers may be due to delayed apoptosis.
慢性阻塞性肺疾病（COPD）中肺巨噬细胞数量增加可能源于血液单核细胞向肺内募集的上调。CCR5是一种受白细胞介素-6（IL-6）调节的单核细胞趋化因子受体；已知COPD肺中CCR5配体的浓度升高。本研究的目的是探讨COPD中单核细胞向肺内募集的机制，包括CCR5信号传导的作用。
91例COPD患者、29例吸烟者（S）和37例非吸烟者（NS）进行痰液诱导、血浆采样（通过免疫测定法测量IL-6和可溶性IL-6受体[sIL-6R]）、单核细胞特征分析（通过流式细胞术）以及单核细胞分离以进行细胞迁移和定量聚合酶链反应研究。肺组织用于免疫组织化学分析。
COPD患者血浆IL-6和sIL-6R水平升高。与对照组相比，COPD患者中更大比例的CD14CD16单核细胞表达CCR5。用IL-6和sIL-6R刺激单核细胞可增加CCR5基因表达。与NS组相比，COPD患者的单核细胞向痰液上清液的迁移能力受损（迁移百分比分别为4.4%和11.5%；p<0.05）。与NS组相比，COPD患者肺微血管中的单核细胞募集减少（边缘细胞百分比分别为9.3%和83.1%）。与NS组相比，COPD患者中增殖的Ki67肺泡巨噬细胞比例降低。COPD组和S组的所有肺泡巨噬细胞均表达抗凋亡标志物BCL2；该蛋白在非吸烟者或COPD戒烟者中不存在。
尽管CCR5表达增加，但COPD单核细胞的迁移能力下降。COPD肺巨噬细胞数量增加可能是由于凋亡延迟。
