دورية أكاديمية
MEK inhibitors, novel anti-adhesive molecules, reduce sickle red blood cell adhesion in vitro and in vivo, and vasoocclusion in vivo.
| العنوان: | MEK inhibitors, novel anti-adhesive molecules, reduce sickle red blood cell adhesion in vitro and in vivo, and vasoocclusion in vivo. |
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| المؤلفون: | Zennadi, Rahima |
| بيانات النشر: | Public Library of Science (PLoS) |
| سنة النشر: | 2014 |
| المجموعة: | Duke University Libraries: DukeSpace |
| مصطلحات موضوعية: | Adult, Anemia, Sickle Cell, Animals, Cell Adhesion, Disease Models, Animal, Erythrocyte Aggregation, Erythrocytes, Human Umbilical Vein Endothelial Cells, Humans, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Male, Mice, Nude, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Protein Kinase Inhibitors, Vascular Diseases |
| جغرافية الموضوع: | United States |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1932-6203 |
| العلاقة: | PLoS One; http://www.ncbi.nlm.nih.gov/pubmed/25330306Test; PONE-D-14-25200; https://hdl.handle.net/10161/11165Test |
| الإتاحة: | https://hdl.handle.net/10161/11165Test http://www.ncbi.nlm.nih.gov/pubmed/25330306Test |
| رقم الانضمام: | edsbas.2FC848E0 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 19326203 |
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