CEREBRAL PROTECTION IN HOMOZYGOUS NULL ICAM-1 MICE AFTER MIDDLE CEREBRAL-ARTERY OCCLUSION - ROLE OF NEUTROPHIL ADHESION IN THE PATHOGENESISOF STROKE

Acute neutrophil (PMN) recruitment to postischemic cardiac or pulmonar y tissue has deleterious effects in the early reperfusion period, but the mechanisms and effects of neutrophil influx in the pathogenesis of evolving stroke remain controversial. To investigate whether PMNs con tribute to adverse neurologic sequelae and mortality after stroke, and to study the potential role of the leukocyte adhesion molecule interc ellular adhesion molecule-1 (ICAM-1) in the pathogenesis of stroke, we used a murine model of transient focal cerebral ischemia consisting o f intraluminal middle cerebral artery occlusion for 45 min followed by 22 h of reperfusion, PMN accumulation, monitored by deposition of In- 111-labeled PMNs in postischemic cerebral tissue, was increased 2.5-fo ld in the ipsilateral (infarcted) hemisphere compared with the contral ateral (noninfarcted) hemisphere (P < 0.01). Mice immunodepleted of ne utrophils before surgery demonstrated a 3.0-fold reduction in infarct volumes (P < 0.001), based on triphenyltetrazolium chloride staining o f serial cerebral sections, improved ipsilateral cortical cerebral blo od flow (measured by laser Doppler), and reduced neurological deficit compared with controls. In wild-type mice subjected to 45 min of ische mia followed by 22 h of reperfusion, ICAM-1 mRNA was increased in the ipsilateral hemisphere, with immunohistochemistry localizing increased ICAM-1 expression on cerebral microvascular endothelium, The role of ICAM-1 expression in stroke was investigated in homozygous null ICAM-1 mice (ICAM-1 -/-) in comparison with wild-type controls (ICAM-1 +/+). ICAM-1 -/- mice demonstrated a 3.7-fold reduction in infarct volume ( P ( 0.005), a 35% increase in survival (P < 0.05), and reduced neurolo gic deficit compared with ICAM-1 +/+ controls, Cerebral blood flow to the infarcted hemisphere was 3.1-fold greater in ICAM-1 -/- mice compa red with ICAM-1 +/+ controls (P < 0.01), suggesting an important role for ICAM-1 in the genesis of postischemic cerebral no-reflow, Because PMN-depleted and ICAM-1-deficient mice are relatively resistant to cer ebral ischemia-reperfusion injury, these studies suggest an important role for ICAM-1-mediated PMN adhesion in the pathophysiology of evolvi ng stroke.