LOSS OF THE TIGHT JUNCTION PROTEINS OCCLUDIN AND ZONULA OCCLUDENS-1 FROM CEREBRAL VASCULAR ENDOTHELIUM DURING NEUTROPHIL-INDUCED BLOOD-BRAIN-BARRIER BREAKDOWN IN-VIVO

The tight junctions found between cerebral vascular endothelial cells form the basis of the blood-brain barrier. Breakdown of the blood-brai n barrier is a feature of a variety of CNS pathologies that are charac terized by extensive leucocyte recruitment, such as multiple sclerosis and stroke. The molecular mechanisms associated with opening of the b lood-brain barrier and leucocyte recruitment in vivo are currently poo rly understood. We have used an in vivo rat model to investigate the m olecular response of the CNS endothelium to neutrophil adhesion and mi gration. Injection of interleukin-1 beta into the striatum of juvenile brains results in a neutrophil-dependent increase in vessel permeabil ity at 4 h. Only a subset of blood vessels were associated with neutro phil recruitment. These particular Vessels displayed an increase in ph osphotyrosine staining, loss of the tight junctional proteins, occludi n and zonula occludens-1, and apparent redistribution of the adherens junction protein vinculin. Examination of these vessels under the elec tron microscope indicated that the cell-cell adhesions in such vessels are morphologically different from normal junctions. This study provi des the first direct evidence ill vivo that leucocyte recruitment can trigger signal transduction cascades leading to junctional disorganiza tion and blood-brain barrier breakdown. Our results have established a n endothelial cell molecular profile associated with leucocyte-induced blood-brain barrier breakdown in vivo, and the relevance of different in vitro cell culture models may now be viewed more objectively. (C) 1998 IBRO. Published by Elsevier Science Ltd.