Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke.
OBJECTIVE
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 microg), 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 microg), 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.
Huang
J
J
Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Choudhri
T F
TF
Winfree
C J
CJ
McTaggart
R A
RA
Kiss
S
S
Mocco
J
J
Kim
L J
LJ
Protopsaltis
T S
TS
Zhang
Y
Y
Pinsky
D J
DJ
Connolly
E S
ES
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D012039:Regional Blood Flow / Q000502:physiology; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology; D020521:Stroke / Q000473:pathology / Q000503:physiopathology*; D015854:Up-Regulation
D019040:E-Selectin