期刊
TRANSLATIONAL RESEARCH
卷 249, 期 -, 页码 1-12出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.trsl.2022.06.018
关键词
-
资金
- NIH [5R01HL114567]
- Hematology Research Training Grant from NIH [T32HL007062]
This study found that both the lectin pathway (LP) and the alternative pathway (AP) play a role in promoting inflammation and vaso-occlusion in sickle cell disease (SCD). Inhibiting complement activation via LP or AP may inhibit inflammation and prevent vaso-occlusive crisis (VOC) in SCD patients.
Patients with sickle cell disease (SCD) have ongoing hemolysis that promotes endothe-lial injury, complement activation, inflammation, vaso-occlusion, ischemia-reperfusion pathophysiology, and pain. Complement activation markers are increased in SCD in steady-state and further increased during vaso-occlusive crisis (VOC). However, the mechanisms driving complement activation in SCD have not been completely eluci-dated. Ischemia-reperfusion and heme released from hemoglobin during hemolysis, events that characterize SCD pathophysiology, can activate the lectin pathway (LP) and alternative pathway (AP), respectively. Here we evaluated the role of LP and AP in Townes sickle (SS) mice using inhibitory monoclonal antibodies (mAb) to mannose binding lectin (MBL)-associated serine protease (MASP)-2 or MASP-3, respectively. Townes SS mice were pretreated with MASP-2 mAb, MASP-3 mAb, isotype control mAb, or PBS before they were challenged with hypoxia-reoxygenation or hemoglobin. Pretreatment of SS mice with MASP-2 or MASP-3 mAb, markedly reduced Bb fragments, C4d and C5a in plasma and complement deposition in the liver, kidneys, and lungs collected 4 hours after challenge compared to control mAb-treated mice. Consistent with complement inhibition, hepatic inflammation markers NF -KB phospho-p65, VCAM-1, ICAM-1, and E-selectin were significantly reduced in SS mice pretreated with MASP-2 or MASP-3 mAb. Importantly, MASP-2 or MASP-3 mAb pretreatment signifi-cantly inhibited microvascular stasis (vaso-occlusion) induced by hypoxia-reoxygen-ation or hemoglobin. These studies suggest that the LP and the AP are both playing a role in promoting inflammation and vaso-occlusion in SCD. Inhibiting complement activation via the LP or the AP might inhibit inflammation and prevent VOC in SCD patients. (Translational Research 2022; 249:1-12)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据