Blood-brain barrier breakdown in septic encephalopathy and brain tumours

Abstract

Septic encephalopathy is associated with breakdown of the blood-brain barrier and cerebral oedema. These features are also common properties of brain tumours. Perimicrovessel oedema, disruption of associated astrocyte end feet and neuronal injury occur in a porcine model of acute septic encephalopathy. The adrenergic system has been implicated in the inflammatory response to sepsis and may play a role in controlling blood-brain barrier permeability, since the beta2-adrenoceptor agonist dopexamine inhibits perimicrovessel oedema formation whereas the alpha1-adrenoceptor agonist methoxamine provokes it. Electron microscopy revealed tight junction opening in high-grade astrocytoma microvessels. Expression of the tight junction protein occludin is reduced in these microvessels and this reduction is inversely correlated with the degree of cerebral oedema. Normal astrocytes secrete factors that induce barrier properties in endothelial cells, whereas high-grade astrocytomas secrete vascular endothelial growth factor, which stimulates angiogenesis, down regulates occludin and increases endothelial cell permeability. The water channel protein aquaporin-4 is normally expressed in astrocyte foot processes around cerebral microvessels. Its expression is massively up-regulated in high-grade astrocytoma and around metastatic adenocarcinoma. There is a significant correlation between aquaporin-4 expression and the degree of cerebral oedema, but it is not clear whether increased aquaporin-4 expression enhances oedema formation or clearance. These results suggest that the pathophysiology of brain oedema is multifactorial, but that there may be common processes operating regardless of the aetiology.

Fig. 1

Electron micrographs of porcine frontal cortex showing: (A) A normal microvessel from a sham-operated control pig, with negligible perimicrovessel oedema. Magnification = 3500×. (B) A microvessel from a pig 8 h after the induction of caecal peritonitis, with severe perimicrovessel oedema. Magnification = 4400×. (C) A microvessel from a pig treated with the β₂-adrenoceptor agonist dopexamine, 8 h after the induction of caecal peritonitis. Less oedema is present than in (B). Magnification = 3500×. ecn = endothelial cell nucleus, rbc = red blood cell.

Fig. 2

Photomicrographs of cerebral microvessels in longitudinal section from: (A) non-neoplastic human brain showing a tight junction (arrow) immunolabelled with the monoclonal occludin antibody MOC37 (Saitou et al. 1997); (B) occludin immunonegative grade IV astrocytoma. The sections are counterstained with cresyl violet. Scale bars = 10 μm.

Fig. 3

Fig. 3 (A) Photomicrograph of a cerebral microvessel from histologically normal human cerebral cortex, showing aquaporin-4 immunolabelled (AB3068, Chemicon) astrocyte end feet surrounding the endothelial cell walls. (B) A photomicrograph showing up-regulation of aquaporin-4 immunoreactivity in astrocyes from a grade IV astrocytoma. Scale bars = 10 μm.