title: MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease.
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.
authors.affiliation: *Division of Hematology and Departments of Medicine and Radiation Oncology, Duke University, Durham, North Carolina, USA.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: *Division of Hematology and Departments of Medicine and Radiation Oncology, Duke University, Durham, North Carolina, USA.
authors.forename: Evan A
authors.initials: EA
authors.lastname: Schwartz
authors.affiliation: *Division of Hematology and Departments of Medicine and Radiation Oncology, Duke University, Durham, North Carolina, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Palmer
authors.affiliation: *Division of Hematology and Departments of Medicine and Radiation Oncology, Duke University, Durham, North Carolina, USA rahima.zennadi@duke.edu.
authors.forename: Rahima
authors.initials: R
authors.lastname: Zennadi
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006451:Hemoglobin, Sickle / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D019007:P-Selectin / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014652:Vascular Diseases / Q000188:drug therapy / Q000378:metabolism
chemical_list: D019040:E-Selectin; D006451:Hemoglobin, Sickle; D018960:Hyaluronan Receptors; D039302:Integrin alphaVbeta3; D019007:P-Selectin; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2
keywords: MEK inhibitors; adhesion; leukocytes; sickle red cells