Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Biochem Biophys Res Commun. 2010 Jan 1;391(1):1080-6. doi: 10.1016/j.bbrc.2009.12.025. Epub 2009 Dec 14.
Neutrophils and monocytes are abundantly represented in the synovial fluid and tissue in rheumatoid arthritis patients. We therefore explored the effects of small molecule chemokine receptor antagonists to block migration of these cells in anti-collagen antibody-induced arthritis. Targeting neutrophil migration with the CXCR2/CXCR1 antagonist SCH563705 led to a dose-dependent decrease in clinical disease scores and paw thickness measurements and clearly reduced inflammation and bone and cartilage degradation based on histopathology and paw cytokine analyses. In contrast, targeting monocyte migration with the CCR2 antagonist MK0812 had no effect on arthritis disease severity. The pharmacodynamic activities of both SCH563705 and MK0812 were verified by assessing their effects on the peripheral blood monocyte and neutrophil populations. SCH563705 selectively reduced the peripheral blood neutrophil frequency, and caused an elevation in the CXCR2 ligand CXCL1. MK0812 selectively reduced the peripheral blood monocyte frequency, and caused an elevation in the CCR2 ligand CCL2. The much greater impact of CXCR2/CXCR1 antagonism relative to CCR2 antagonism in this model of arthritis highlights the therapeutic potential for targeting CXCR2/CXCR1 in human arthritides.
中性粒细胞和单核细胞在类风湿关节炎患者的滑液和组织中大量存在。因此，我们研究了小分子趋化因子受体拮抗剂对阻断抗胶原抗体诱导关节炎中这些细胞迁移的影响。用 CXCR2/CXCR1 拮抗剂 SCH563705 靶向中性粒细胞迁移导致临床疾病评分和爪厚度测量的剂量依赖性下降，并基于组织病理学和爪细胞因子分析明显减少炎症和骨与软骨降解。相比之下，用 CCR2 拮抗剂 MK0812 靶向单核细胞迁移对关节炎严重程度没有影响。通过评估 SCH563705 和 MK0812 对外周血单核细胞和中性粒细胞群的影响，验证了它们的药效学活性。SCH563705 选择性降低外周血中性粒细胞频率，并引起 CXCR2 配体 CXCL1 的升高。MK0812 选择性降低外周血单核细胞频率，并引起 CCR2 配体 CCL2 的升高。在这种关节炎模型中，CXCR2/CXCR1 拮抗作用相对于 CCR2 拮抗作用的影响大得多，这突出了在人类关节炎中靶向 CXCR2/CXCR1 的治疗潜力。
