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FASEB J. 2016 Mar;30(3):1171-86. doi: 10.1096/fj.15-278481. Epub 2015 Nov 30.

MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease.

Author information

1
*Division of Hematology and Departments of Medicine and Radiation Oncology, Duke University, Durham, North Carolina, USA.
2
*Division of Hematology and Departments of Medicine and Radiation Oncology, Duke University, Durham, North Carolina, USA rahima.zennadi@duke.edu.

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.

KEYWORDS:

MEK inhibitors; adhesion; leukocytes; sickle red cells

PMID:
26631480
DOI:
10.1096/fj.15-278481
[Indexed for MEDLINE]

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