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- W2275822324 abstract "In sickle cell disease (SCD), treatment of recurrent vasoocclusive episodes, leading to pain crises and organ damage, is still a therapeutic challenge. Vasoocclusion is caused primarily by adherence of homozygous for hemoglobin S (SS) red blood cells (SSRBCs) and leukocytes to the endothelium. We tested the therapeutic benefits of MEK1/2 inhibitors in reversing vasoocclusion in nude and humanized SCD mouse models of acute vasoocclusive episodes using intravital microscopy. Administration of 0.2, 0.3, 1, or 2 mg/kg MEK1/2 inhibitor to TNF-α-pretreated nude mice before human SSRBC infusion inhibited SSRBC adhesion in inflamed vessels, prevented the progression of vasoocclusion, and reduced SSRBC organ sequestration. By use of a more clinically relevant protocol, 0.3 or 1 mg/kg MEK1/2 inhibitor given to TNF-α-pretreated nude mice after human SSRBC infusion and onset of vasoocclusion reversed SSRBC adhesion and vasoocclusion and restored blood flow. In SCD mice, 0.025, 0.05, or 0.1 mg/kg MEK1/2 inhibitor also reversed leukocyte and erythrocyte adhesion after the inflammatory trigger of vasoocclusion and improved microcirculatory blood flow. Cell adhesion was reversed by shedding of endothelial E-selectin, P-selectin, and αvβ3 integrin, and leukocyte CD44 and β2 integrin. Thus, MEK1/2 inhibitors, by targeting the adhesive function of SSRBCs and leukocytes, could represent a valuable therapeutic intervention for acute sickle cell vasoocclusive crises.—Zhao, Y., Schwartz, E. A., Palmer, G. M., Zennadi, R., MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease. FASEB J. 30, 1171–1186 (2016). www.fasebj.org" @default.
- W2275822324 created "2016-06-24" @default.
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- W2275822324 date "2015-11-30" @default.
- W2275822324 modified "2023-10-03" @default.
- W2275822324 title "MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease" @default.
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- W2275822324 doi "https://doi.org/10.1096/fj.15-278481" @default.
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