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MEK Inhibitors, Novel Anti-Adhesive Molecules, Reduce Sickle Red Blood Cell Adhesion In Vitro and In Vivo, and Vasoocclusion In Vivo

In sickle cell disease, sickle erythrocyte (SSRBC) interacts with endothelial cells, leukocytes, and platelets, and activates coagulation and inflammation, promoting vessel obstruction, which leads to serious life-threatening complications, including acute painful crises and irreversible damage to m...

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Detalles Bibliográficos
Autor principal: Zennadi, Rahima
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203776/
https://www.ncbi.nlm.nih.gov/pubmed/25330306
http://dx.doi.org/10.1371/journal.pone.0110306
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author Zennadi, Rahima
author_facet Zennadi, Rahima
author_sort Zennadi, Rahima
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description In sickle cell disease, sickle erythrocyte (SSRBC) interacts with endothelial cells, leukocytes, and platelets, and activates coagulation and inflammation, promoting vessel obstruction, which leads to serious life-threatening complications, including acute painful crises and irreversible damage to multiple organs. The mitogen-activated protein kinase, ERK1/2, is abnormally activated in SSRBCs. However, the therapeutic potential of SSRBC ERK1/2 inactivation has never been investigated. I tested four different inhibitors of MEK1/2 (MEK), the kinase that activates ERK1/2, in a model of human SSRBC adhesion to TNFα-activated endothelial cells (ECs). SSRBC MEK inhibition abrogated adhesion to non-activated and TNFα-activated ECs to levels below baseline SSRBC adhesion to non-activated ECs in vitro. SSRBC MEK inhibition also prevented SSRBCs from activating naïve neutrophils to adhere to endothelium. To determine the effect of MEK inhibitors on SSRBC adherence in vivo, sham-treated or MEK inhibitor-treated SSRBCs were infused to nude mice previously treated with TNFα. Sham-treated SSRBCs displayed marked adhesion and occlusion of enflamed vessels, both small and large. However, SSRBC treatment with MEK inhibitors ex vivo showed poor SSRBC adhesion to enflamed vessels with no visible vasoocclusion in vivo. In addition, MEK inhibitor treatment of SSRBCs reduced SSRBC organ trapping and increased the number of SSRBCs circulating in bloodstream. Thus, these data suggest that SSRBC ERK1/2 plays potentially a critical role in sickle pathogenesis, and that MEK inhibitors may represent a valuable intervention for acute sickle cell crises.
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spelling pubmed-42037762014-10-27 MEK Inhibitors, Novel Anti-Adhesive Molecules, Reduce Sickle Red Blood Cell Adhesion In Vitro and In Vivo, and Vasoocclusion In Vivo Zennadi, Rahima PLoS One Research Article In sickle cell disease, sickle erythrocyte (SSRBC) interacts with endothelial cells, leukocytes, and platelets, and activates coagulation and inflammation, promoting vessel obstruction, which leads to serious life-threatening complications, including acute painful crises and irreversible damage to multiple organs. The mitogen-activated protein kinase, ERK1/2, is abnormally activated in SSRBCs. However, the therapeutic potential of SSRBC ERK1/2 inactivation has never been investigated. I tested four different inhibitors of MEK1/2 (MEK), the kinase that activates ERK1/2, in a model of human SSRBC adhesion to TNFα-activated endothelial cells (ECs). SSRBC MEK inhibition abrogated adhesion to non-activated and TNFα-activated ECs to levels below baseline SSRBC adhesion to non-activated ECs in vitro. SSRBC MEK inhibition also prevented SSRBCs from activating naïve neutrophils to adhere to endothelium. To determine the effect of MEK inhibitors on SSRBC adherence in vivo, sham-treated or MEK inhibitor-treated SSRBCs were infused to nude mice previously treated with TNFα. Sham-treated SSRBCs displayed marked adhesion and occlusion of enflamed vessels, both small and large. However, SSRBC treatment with MEK inhibitors ex vivo showed poor SSRBC adhesion to enflamed vessels with no visible vasoocclusion in vivo. In addition, MEK inhibitor treatment of SSRBCs reduced SSRBC organ trapping and increased the number of SSRBCs circulating in bloodstream. Thus, these data suggest that SSRBC ERK1/2 plays potentially a critical role in sickle pathogenesis, and that MEK inhibitors may represent a valuable intervention for acute sickle cell crises. Public Library of Science 2014-10-20 /pmc/articles/PMC4203776/ /pubmed/25330306 http://dx.doi.org/10.1371/journal.pone.0110306 Text en © 2014 Rahima Zennadi http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Zennadi, Rahima
MEK Inhibitors, Novel Anti-Adhesive Molecules, Reduce Sickle Red Blood Cell Adhesion In Vitro and In Vivo, and Vasoocclusion In Vivo
title MEK Inhibitors, Novel Anti-Adhesive Molecules, Reduce Sickle Red Blood Cell Adhesion In Vitro and In Vivo, and Vasoocclusion In Vivo
title_full MEK Inhibitors, Novel Anti-Adhesive Molecules, Reduce Sickle Red Blood Cell Adhesion In Vitro and In Vivo, and Vasoocclusion In Vivo
title_fullStr MEK Inhibitors, Novel Anti-Adhesive Molecules, Reduce Sickle Red Blood Cell Adhesion In Vitro and In Vivo, and Vasoocclusion In Vivo
title_full_unstemmed MEK Inhibitors, Novel Anti-Adhesive Molecules, Reduce Sickle Red Blood Cell Adhesion In Vitro and In Vivo, and Vasoocclusion In Vivo
title_short MEK Inhibitors, Novel Anti-Adhesive Molecules, Reduce Sickle Red Blood Cell Adhesion In Vitro and In Vivo, and Vasoocclusion In Vivo
title_sort mek inhibitors, novel anti-adhesive molecules, reduce sickle red blood cell adhesion in vitro and in vivo, and vasoocclusion in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203776/
https://www.ncbi.nlm.nih.gov/pubmed/25330306
http://dx.doi.org/10.1371/journal.pone.0110306
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