Abstract
Patients with sickle cell disease (SCD) have ongoing hemolysis that promotes endothelial 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 elucidated. 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-ĸB 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 significantly inhibited microvascular stasis (vaso-occlusion) induced by hypoxia-reoxygenation 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.
Original language | English (US) |
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Pages (from-to) | 1-12 |
Number of pages | 12 |
Journal | Translational Research |
Volume | 249 |
DOIs | |
State | Published - Nov 2022 |
Bibliographical note
Funding Information:We would like to thank Dr. Joan Beckman for helpful comments. All authors have read the journal's authorship agreement and the manuscript has been reviewed by and approved by all authors. Research funding from NIH: 5R01HL114567. ZKI was supported by the Hematology Research Training Grant from NIH: T32HL007062, Conflicts of interest: JDB and GMV receive research funding from CSL-Behring and Mitobridge/Astellas and have applied for funding from Omeros. In addition, JDB and GMV are consultants to Mitobridge/Astellas. TD and JC are employees of Omeros. JDB, GMV, TD, and JC have a pending patent application for the use of anti-MASP monoclonal antibodies in sickle cell disease.
Funding Information:
Research funding from NIH : 5R01HL114567 . ZKI was supported by the Hematology Research Training Grant from NIH: T32HL007062
Publisher Copyright:
© 2022 The Author(s)
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