Blood–brain barrier breakdown and oedema formation in systemic sepsis and human brain tumours

Abstract

Septic encephalopathy (SE) is the commonest form of encephalopathy among patients in intensive care units. SE is associated with breakdown of the blood–brain barrier (BBB) since patients with this condition have high protein levels in their cerebrospinal fluid. Disruption of the BBB and associated oedema is also a common property of brain tumours. Oedema is a significant source of morbidity and mortality in both SE and brain tumours but an understanding of the its pathophysiology is lacking. Perimicrovessel oedema, disruption of associated astrocyte end‐feet and neuronal injury occurs in the brain in a porcine model of acute SE. Expression of the transmembrane protein occludin that is an essential functional component of interendothelial cell tight junctions, is reduced in human cerebral astrocytoma and metastatic adenocarcinoma (MA). This reduction is inversely correlated with the degree of contrast enhancement present on CT and electron microscopy revealed tight junction opening in high grade astrocytoma. Normal astrocytes secrete factors that induce BBB properties in endothelial cells and astroctoma, whereas MA cells secrete VEGF that increases microvessel endothelial permeability. Therefore damage to astrocytes could underlie BBB opening in SE, whilst the neoplastic cells cause a similar effect in astrocytoma and MA. The adrenergic system has been implicated in the inflammatory response to sepsis and it may play a role in the opening of the BBB in SE since the (2 receptor agonist dopexamine inhibits perimicrovessel oedema in septic pigs, whereas the (1 receptor agonist methoxamine causes perimicrovessel oedema formation in controls. However the way in which the adrenergic system is involved in oedema formation remains to be resolved. The amount of oedema fluid present in the brain in SE and tumours must reflect a balance between its production and clearance. The water channel protein aquaporin‐4 (AQP4) is expressed in astrocyte foot processes around microvessels and forming the glial limiting membranes in normal brain. Massive up‐regulation of AQP4 expression occurs in astrocytoma and MA and there is a significant correlation between contrast enhancement on CT and AQP4 expression. This strong correlation suggests that increased AQP4 expression is fundamental to the pathophysiology of brain oedema. However it remains unclear whether the increased AQP4 is functional and if so, whether it 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.