Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke

Background and Purpose-Although the deleterious role of several proinflamma tory mediators, including P-selectin, in reperfused stroke is well establis hed, the role of E-selectin has not been fully characterized. Methods-E-sel ectin mRNA expression was studied at 4, 10, and 24 hours after reperfusion with reverse transcription and polymerase chain reaction in mice (n=18) sub jected to transient intraluminal middle cerebral artery occlusion (MCAO). M ice received intravenous injection with anti-E-selectin monoclonal antibody (10, 35, or 50 mug), nonimmune IgG, or vehicle immediately before MCAO and 90 minutes later (n=85). Others received anti-E-selectin antibody 3 or 6 h ours after MCAO (n=32). Myeloperoxidase activity was measured in sham-opera ted mice and after 10 hours of reperfusion in saline-, nonimmune IgG-, or a nti-E-selectin IgG-treated cohorts (n=17). Serial cerebral blood flow was m easured with laser-Doppler flowmetry, and outcomes were assessed by neurolo gical deficits and infarct volumes with the use of planimetric analysis of triphenyltetrazolium chloride-stained sections. Results-Upregulated E-selec tin expression occurred in the ischemic cerebral vasculature within 4 hours of reperfusion and persisted for 24 hours. Anti-E-selectin antibody increa sed ischemic cortical cerebral blood flow up to 2.6-fold (P<0.05). In addit ion to dose-dependent reductions in neurological deficits (P<0.05), mortali ty, and infarct volumes (P<0.01 for 35 and 50 <mu>g), anti-E-selectin treat ment reduced cerebral neutrophil accumulation (P<0.05) and was neuroprotect ive even if delayed until 3 hours after ischemia (P<0.05). Conclusions-Thes e findings establish a functional role for E-selectin in the pathogenesis o f tissue injury after cerebral ischemia and reperfusion and suggest that E- selectin blockade may be clinically useful in the treatment of reperfused s troke.