血浆激肽释放酶-激肽系统的活化促进关节炎内皮祖细胞归巢

Plasma kallikrein-kinin system activation regulates the synovial recruitment of endothelial progenitor cells in arthritis

目的:探讨血浆激肽释放酶-激肽系统(KKS)的活化是否促进内皮祖细胞向关节炎滑膜的归巢。方法:从Lewis大鼠骨髓中分离培养内皮祖细胞并经RT-PCR鉴定。腹腔注射肽聚糖-多糖(PG-PS)诱发Lewis大鼠关节炎后,将内皮祖细胞经尾静脉注射入关节炎大鼠,共聚焦显微镜观察内皮祖细胞向炎症滑膜的归巢。关节炎大鼠给予血浆激肽释放酶抑制剂EPI-KAL2抑制KKS系统活化后,检测关节炎大鼠踝关节的直径及内皮祖细胞向炎症滑膜归巢数量的变化。结果:体外培养的内皮祖细胞表达内皮谱系标识分子mRNA,如CD114、CD31、vWF及造血干/祖细胞标记分子Sca-1。内皮祖细胞植入关节炎大鼠后可见其在炎性滑膜的聚集。EPI-KAL2给药后显著抑制植入的内皮祖细胞在关节炎急性期向炎性滑膜的募集,同时明显改善关节炎症。结论:血浆KKS的活化具有促进内皮祖细胞归巢的作用,是该系统介导关节炎发生和发展的新作用。

Objective： To examine whether the activation of plasma kallikrein-kinin system（KKS） regulates synovial recruitment of endothelial progenitor cells（EPCs） in arthritis.Methods： EPCs were isolated from bone marrow of Lewis rats and identified by RT-PCR.Inflammatory arthritis in Lewis rats was induced by intraperitoneal injection of peptidoglycan-polysaccharide（PG-PS）.Recruitment of EPCs in inflamed synovium were evaluated by tail vein injection of EPCs.The role of KKS was examined using a specific inhibitor of plasma kallikrein,EPI-KAL2,the effects were evaluated by measuring the change of joint diameter and mumber of recruitment EPCs.Results： Bone marrow-derived rat EPCs express endothelial cell marker mRNA such as CD144,CD31,vWF,and exclusively expressed hematopoietic progenitor cell markers,Sca-1.In Lewis rats bearing arthritis,EPCs were recruited into inflamed synovium at acute phase.Plasma kallikrein inhibitor EPI-KAL2 significantly suppressed the synovial recruitment of EPCs as well as the joint swelling.Conclusion： Plasma KKS activation mediates EPC homing to inflamed synovium.These observations demonstrate a novel role for plasma KKS activation in arthritis.