(Stroke. 2000;31:3047.)
© 2000 American Heart Association, Inc.
Original Contributions |
Postischemic Cerebrovascular E-Selectin Expression Mediates Tissue Injury in Murine Stroke
From the Departments of Neurological Surgery and Medicine (D.J.P.), Columbia University College of Physicians and Surgeons, New York, NY.
Correspondence to E. Sander Connolly, Jr, MD, Department of Neurological Surgery, Columbia University College of Physicians and Surgeons, 710 W 168th St, Box 72, New York, NY 10032. E-mail esc5{at}columbia.edu
Background and Purpose—Although the deleterious role of several proinflammatory mediators, including P-selectin, in reperfused stroke is well established, the role of E-selectin has not been fully characterized.
Methods—E-selectin mRNA expression was studied at 4, 10, and 24 hours after reperfusion with reverse transcription and polymerase chain reaction in mice (n=18) subjected to transient intraluminal middle cerebral artery occlusion (MCAO). Mice received intravenous injection with anti–E-selectin monoclonal antibody (10, 35, or 50 µg), nonimmune IgG, or vehicle immediately before MCAO and 90 minutes later (n=85). Others received anti–E-selectin antibody 3 or 6 hours after MCAO (n=32). Myeloperoxidase activity was measured in sham-operated mice and after 10 hours of reperfusion in saline-, nonimmune IgG–, or anti–E-selectin IgG–treated cohorts (n=17). Serial cerebral blood flow was measured with laser-Doppler flowmetry, and outcomes were assessed by neurological deficits and infarct volumes with the use of planimetric analysis of triphenyltetrazolium chloride–stained sections.
Results—Upregulated E-selectin expression occurred in the ischemic cerebral vasculature within 4 hours of reperfusion and persisted for 24 hours. Anti–E-selectin antibody increased ischemic cortical cerebral blood flow up to 2.6-fold (P<0.05). In addition to dose-dependent reductions in neurological deficits (P<0.05), mortality, and infarct volumes (P<0.01 for 35 and 50 µg), anti–E-selectin treatment reduced cerebral neutrophil accumulation (P<0.05) and was neuroprotective even if delayed until 3 hours after ischemia (P<0.05).
Conclusions—These findings establish a functional role for E-selectin in the pathogenesis of tissue injury after cerebral ischemia and reperfusion and suggest that E-selectin blockade may be clinically useful in the treatment of reperfused stroke.
Editorial Comment
Cardiovascular Sciences DuPont Pharmaceuticals Co. Wilmington, Delaware
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