A growing body of evidence, primarily from animal models of
cerebral ischemia and preliminary human studies, indicates that inflammatory mechanisms contribute to secondary neuronal injury after acute
cerebral ischemia.
Ischemia followed by reperfusion rapidly leads to the expression of inflammatory
cytokines, particularly
tumor necrosis factor-alpha and
interleukin-1beta, which stimulate a complex cascade of events involving local endothelial cells, neurons, astrocytes, and perivascular cells. A secondary response includes the release of other
cytokines, an increase in components of the coagulation system, an upregulation of
cell adhesion molecule expression, and changes in the expression of components of the immune response. The net effect of these events is transformation of the local endothelium to a prothrombotic/proinflammatory state and induction of leukocyte migration to the site of injury. A number of studies have shown that leukocyte migration occurs within hours of reperfusion. Leukocytes accumulate in the injured region, where they cause tissue injury by several mechanisms, including occlusion of microvasculature, generation of
oxygen free radicals, release of cytotoxic
enzymes, alteration of vasomotor reactivity, and increase in
cytokine and
chemoattractant release.
Monoclonal antibodies against
leukocyte adhesion molecules have been shown to reduce
infarct volume in animal models of
ischemia-reperfusion. However, this treatment failed to show benefit in the
Enlimomab Acute Stroke Trial. A number of factors may complicate the use of antibody directed adhesion molecule blockade in
acute stroke and will be discussed in this article. Overall, an increased understanding of inflammatory and immunologic mechanisms still offers great potential for reducing
acute stroke injury.