There is evidence to suggest that integrity of the neurovascular unit may be compromised in
acute liver failure (ALF). In order to address this issue from a molecular standpoint, expression of an array of genes coding for key cerebrovascular endothelial cell and
tight junction proteins were measured by reverse transcription-polymerase chain reaction in cerebral cortex of rats with ischemic
liver failure resulting from hepatic devascularization (
portacaval anastomosis followed 24h later by hepatic artery
ligation) compared to appropriate
sham-operated controls. Expression of
P-glycoprotein,
endothelin-1,
von Willebrand factor,
caveolin-1,
occludin, and the
endothelial nitric oxide synthase isoform (eNOS) were measured in brain extracts from rats with ALF at
coma/
edema stages of
encephalopathy. The effects of mild
hypothermia (35 degrees C) sufficient to prevent
cerebral edema in ALF animals on the expression of these genes were also studied.
Brain edema and
hepatic coma in normothermic ALF rats was accompanied by selective increases in expression of eNOS. Expression of
occludin and
von Willebrand factor mRNAs were decreased at
coma/
edema stages of
encephalopathy in ALF rats whereas, expression of other cerebrovascular endothelial cell markers
endothelin-1,
P-glycoprotein, and
caveolin-1 were unaffected. Mild
hypothermia led to normalization of brain water content and of eNOS
mRNA. However, the correlation between increased eNOS expression and
encephalopathy/
edema grade was poor suggesting the existence of additional mechanisms. These findings underscore the multifactorial nature of
brain edema/
encephalopathy mechanisms in ALF and question the role of BBB breakdown as a major pathogenetic factor.