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

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1779-1786
Number of pages8
JournalBlood
Volume116
Issue number10
DOIs
StatePublished - Sep 9 2010

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Selectins
E-Selectin
Blood Vessels
Blood
Neutrophils
Leukocytes
Erythrocytes
Venules
Rheology
Sickle Cell Anemia
Microvessels
Cell Communication
Adhesion
Endothelial Cells
Clinical Trials
Endothelial cells
Assays
Chemical activation
Cells
GMI-1070

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

Cite this

GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice. / Chang, Jungshan; Patton, John T.; Sarkar, Arun; Ernst, Beat; Magnani, John L.; Frenette, Paul S.

In: Blood, Vol. 116, No. 10, 09.09.2010, p. 1779-1786.

Research output: Contribution to journalArticle

Chang, Jungshan ; Patton, John T. ; Sarkar, Arun ; Ernst, Beat ; Magnani, John L. ; Frenette, Paul S. / GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice. In: Blood. 2010 ; Vol. 116, No. 10. pp. 1779-1786.
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