Alterations in expression of genes coding for proteins of the neurovascular unit in ischemic liver failure.
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.
First Department of Internal Medicine, Iwate Medical University, Morioka, Japan.
Kei
K
Sawara
Paul
P
Desjardins
Nicolas
N
Chatauret
Akinobu
A
Kato
Kazuyuki
K
Suzuki
Roger F
RF
Butterworth
D000818:Animals; D001923:Brain Chemistry / Q000502:physiology; D001929:Brain Edema / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology*; D007035:Hypothermia / Q000378:metabolism; D007511:Ischemia / Q000235:genetics* / Q000473:pathology; D008099:Liver / Q000098:blood supply* / Q000294:innervation*; D008102:Liver Circulation / Q000235:genetics* / Q000502:physiology; D017093:Liver Failure / Q000235:genetics* / Q000473:pathology; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014867:Water / Q000378:metabolism
D012333:RNA, Messenger; D014867:Water; D019001:Nitric Oxide Synthase