Postischemic Cerebrovascular E-Selectin Expression Mediates Tissue Injury in Murine Stroke

Abstract

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 (nϭ18) subjected to transient intraluminal middle cerebral artery occlusion (MCAO).Mice received intravenous injection with anti-E-selectin monoclonal antibody (10, 35, or 50 g), nonimmune IgG, or vehicle immediately before MCAO and 90 minutes later (nϭ85). Others received anti-E-selectin antibody 3 or 6 hours after MCAO (nϭ32). 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 (nϭ17). 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 (PϽ0.05). In addition to dose-dependent reductions in neurological deficits (PϽ0.05), mortality, and infarct volumes (PϽ0.01 for 35 and 50 g), anti-E-selectin treatment reduced cerebral neutrophil accumulation (PϽ0.05) and was neuroprotective even if delayed until 3 hours after ischemia (PϽ0.05). 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. (Stroke. 2000;31:3047-3053.)

CD40/CD40 Ligand Signaling in Mouse Cerebral Microvasculature After Focal Ischemia/Reperfusion

“…The magnitude of infarct volume reduction (30% to 40%), though substantial and statistically significant, did not approach the more dramatic (53% to 89%) attenuations in infarct volume previously reported in rodents that were either genetically deficient in specific adhesion molecules or in WT animals that received adhesion molecule-blocking monoclonal antibodies. 8,9,41,42 This is somewhat surprising in view of our observation that CD40 Ϫ/Ϫ and CD40L Ϫ/Ϫ mice were associated with nearly complete inhibition of MCAO-induced leukocyte recruitment. Although the different protective responses noted between the adhesion molecule ablation studies and our CD40/ CD40L experiments may be attributed to differences in species (rats versus mice) studied as well as the magnitude (global versus focal ischemia) and duration (30 versus 60 minutes) of the ischemic insult, it is also possible that CD40/CD40L may play a more important role in mediating the early events that occur after acute ischemic stroke.…”

Inflammatory mechanisms involved in brain injury following cardiac arrest and cardiopulmonary resuscitation

“…In the ischemic brain, the high level of pro-inflammatory cytokines induces the cerebral endothelial cells to express CAMs that mediate the recruitment of leukocytes to the injured region. Three well-known CAMs, ICAM-1, and P-and E-selectin, are highly expressed at ischemic areas and promote the firm adhesion and migration of neutrophils into damage brain tissues, thereby contributing to neuroinflammation-mediated neurological injury (91)(92)(93). In response to I/R injury, P-selectin can be detected as early as 15 min after reperfusion, while E-selectin expression is observed from 2 h after ischemia.…”

Platelet C4d Is Associated With Acute Ischemic Stroke and Stroke Severity

“…Previous studies further support this hypothesis. For example, during the ischemia and reperfusion injury observed in acute stroke, endothelial activation occurs through the upregulation of adhesion molecules such as E-selectin and P-selectin, 10,18 which can be upregulated by activated complement, thereby promoting platelet plugging. Furthermore, strong expression of P-selectin has been observed after ischemic stroke in wild-type mice but not in complement deficient (C3)-mice.…”