Alterations of the blood-brain barrier during inflammation

Abstract

Mechanisms for loss of blood-brain barrier (BBB) function were studied in experimental autoimmune encephalomyelitis (EAE) in the Lewis rat and in the rabbit visual system. In EAE, horseradish peroxidase (HRP) was used as an intravascular tracer. Quantitative morphometry of transcytotic endothelial vesicles in capillaries demonstrated a 5.2-fold increase over the normal values at the peak of clinical index, which then resided to twice normal levels during the recovery period. A concomitant decrease in endothelial mitochondrial area was observed. Electron micrographs showed the localization of HRP in transcytotic vesicles, multivesicular bodies and canalicular structures. Rats perfusion-fixed prior to HRP infusion showed interendothelial tracer leakage through junctions in the vicinity inflammatory cells adherent to venules. These results show different mechanisms of tracer leakage in capillaries and venules. In other experiments, rats sensitized to develop EAE were treated with prazosin, an a{dollar}\sb{lcub}1{rcub}{dollar}-adrenoreceptor antagonist. This treatment reduced the severity of clinical signs and the extent of vesicular transport. The data from prazosin treated EAE rats also suggests that a minimum level of mitochondrial content is necessary for endothelial cells to function as a barrier. Prazosin treatment may affect the permeability of pericytes allowing for accumulation of tracer in these cells. The amounts of leakage and of inflammation were also reduced after prazosin treatment. In order to study the direct effects inflammatory factors on barrier endothelial cells, intraocular injection of cytokines in the rabbit eye was used. The results showed that the cytokines interleukin-1 and tumor necrosis factor induced changes in the blood-retina barrier endothelial cells that were similar to those seen in endothelial cells during EAF. The data presented suggests that inflammatory cells can induce BBB changes through the release of cytokines. Inflammatory cells may also act directly on the venular bed by increasing the permeability of tight junctions. These findings are important in understanding the behavior of the BBB during inflammation.