Lesion-associated accumulation of uPAR/CD87-expressing infiltrating granulocytes, activated microglial cells/macrophages and upregulation by endothelial cells following TBI and FCI in humans

Urokinase-type plasminogen activator receptor (uPAR/CD87) together with its ligand, urokinase-type plasminogen activator (uPA), constitutes a proteoly tic system associated with tissue remodelling and leucocyte infiltration. u PAR is a member of the glycosyl phosphatidyl inositol (GPI) anchored protei n family. The functional role of uPAR comprises fibrinolysis by conversion of plasminogen to plasmin. In addition, uPAR promotes cell adhesion, migrat ion, proliferation, re-organization of the actin cytoskeleton, and angiogen esis. Furthermore, uPAR is involved in prevention of scar formation and is chemoattractant to macrophages and leucocytes. In order to investigate the pathophysiological role of uPAR following human CNS injury we examined necr otic brain lesions resulting from traumatic brain injury (TBI; n = 28) and focal cerebral infarctions (FCI; n = 17) by immunohistochemistry. Numbers o f uPAR(+) cells and uPAR(+) blood vessels were counted. Following brain dam age, uPAR(+) cells increased significantly within 12 h, reached a maximum a fter 3-4 days and remained elevated until later stages. uPAR was expressed by infiltrating granulocytes, activated microglia/macrophages and endotheli al cells. Numbers of uPAR(+) vessels increased in parallel subsiding earlie r following FCI than post TBI. The restricted, lesion-associated accumulati on of uPAR(+) cells in the brain parenchyma and upregulated expression by e ndothelial cells suggests a crucial role for the influx of inflammatory cel ls and blood-brain barrier (BBB) disturbance. Through a failure in BBB func tion, uPAR participates in formation of brain oedema and thus contributes t o secondary brain damage. In conclusion, the study defines the localization , kinetic course and cellular source of uPAR as a potential pharmacological target following human TBI and FCI.