GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice

Jungshan Chang, John T. Patton, Arun Sarkar, Beat Ernst, John L. Magnani, Paul S. Frenette

研究成果: 雜誌貢獻文章同行評審

193 引文 斯高帕斯(Scopus)


Leukocyte adhesion in the microvasculature influences blood rheology and plays a key role in vaso-occlusive manifestations of sickle cell disease. Notably, polymorphonuclear neutrophils (PMNs) can capture circulating sickle red blood cells (sRBCs) in inflamed venules, leading to critical reduction in blood flow and vasoocclusion. Recent studies have suggested that E-selectin expression by endothelial cells plays a key role by sending activating signals that lead to the activation of Mac-1 at the leading edge of PMNs, thereby allowing RBC capture. Thus, the inhibition of E-selectin may represent a valuable target in this disease. Here, we have tested the biologic properties of a novel synthetic pan-selectin inhibitor, GMI-1070, with in vitro assays and in a humanized model of sickle cell vasoocclusion analyzed by intravital microscopy. We have found that GMI-1070 pre-dominantly inhibited E-selectin-mediated adhesion and dramatically inhibited sRBC-leukocyte interactions, leading to improved microcirculatory blood flow and improved survival. These results suggest that GMI-1070 may represent a valuable novel therapeutic intervention for acute sickle cell crises that should be further evaluated in a clinical trial.

頁(從 - 到)1779-1786
出版狀態已發佈 - 9月 9 2010

ASJC Scopus subject areas

  • 生物化學
  • 免疫學
  • 血液學
  • 細胞生物學


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