GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice.
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 vaso-occlusion. 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 vaso-occlusion analyzed by intravital microscopy. We have found that GMI-1070 predominantly 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.
Departments of Medicine and Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Jungshan
J
Chang
John T
JT
Patton
Arun
A
Sarkar
Beat
B
Ernst
John L
JL
Magnani
Paul S
PS
Frenette
D000208:Acute Disease; D000755:Anemia, Sickle Cell / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D019040:E-Selectin / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006017:Glycolipids / Q000737:chemistry / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D019041:L-Selectin / Q000378:metabolism; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000378:metabolism; D019087:Selectins / Q000378:metabolism*; D014652:Vascular Diseases / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*
D019040:E-Selectin; D006017:Glycolipids; D019007:P-Selectin; D019087:Selectins; D019041:L-Selectin; C553182:rivipansel