Fig. 2

Events occuring over time in the cerebral microvasculature and ischemic brain parenchyma in the setting of ischemic stroke. The temporal sequence of events proceeds in a clockwise rotation. In the steady state, blood components pass by the vascular endothelium with laminar flow and the PMNs are in a resting state. At the time of an ischemic insult, the cerebral microvasculature becomes occluded, and adhesion molecule expression is up-regulated on both the PMNs and the vascular endothelium. Within minutes to hours, PMNs begin to “roll” on the vascular endothelium. This process is dependent on the interaction of sialyl Le^x with P-selectin. Early changes in the cerebral microvessels include the loss of integrin-matrix attachments of endothelial cells and astrocyte end-feet that accompany loss of the basal lamina. Within several hours, high-affinity adhesion of rolling PMNs to the endothelium involves ICAM-1 binding to beta-integrin counterreceptors. Microvascular failure is exacerbated by platelet accumulation, activation, and GP IIb/IIIa upregulation. This leads to platelet crosslinking through fibrinogen and a “no-reflow” state within the microvasculature. E-selectin expression on the endothelium is up-regulated and activated PMN transmigration into the ischemic neurophil occurs through the pourous microvasculature. Within the ischemic parenchyma, the complement cascade is activated and the production of anaphylotoxins such as C5a further exacerbates PMN activating and accumulation. Activated neutrophils secrete cytotoxic factors such as inflammatory mediators (IL-8, LTB4), proteases, and free radicals into the neurophil. The neuronal response includes decreased energy production, increased expression of C1q on its surface, increases in intracellular Na¹, Cl², and Ca^{1 1}.