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ALTERATIONS IN EXPRESSION OF VASCULAR ENDOTHELIAL GENES IN BRAINS OF RATS WITH ACUTE LIVER FAILURE: EFFECT OF MILD HYPOTHERMIA

K Sawara^1,2, C Bémeur¹, P Desjardins¹, W Jiang¹, M Bélanger¹, A Kato², K Suzuki², RF Butterworth¹
¹Neuroscience Research Unit, CHUM (Hôpital St-Luc), Montreal, Quebec; ²First Department of Internal Medicine, Iwate Medical University, Morioka, Japan

There is no convincing histopathologic evidence for physical rupture of the blood-brain barrier (BBB) in patients or animal models of acute liver failure (ALF) (J Hepatol 27, 231, 1997), however, morphologic and functional changes in cerebrovascular endothelial cells including cell swelling, vesicular enlargement and vacuolation as well as increased BBB permeability have been described. The relationship of these changes to the severity of encephalopathy and brain edema in ALF have not been established. To address this issue, expression of a series of essential vascular endothelial marker genes was measured by reverse transcription-polymerase chain reaction in cerebral cortex of rats with ALF resulting from hepatic devascularization (portacaval anastomosis followed 24h later by hepatic artery ligation) compared to appropriate sham-operated controls. Expression of P-glycoprotein (P-gp), endothelin-1 (ET-1), von Willebrand factor (vWf), occludin (Occ), caveolin (Cav), endothelial nitric oxide synthase (eNOS), the endothelial cell glucose transporter (GLUT-1), metallothionein-I and -II (MT-I+II) and cellular adhesion molecules (VCAM, ICAM, E-selectin) were measured at various times during the development of cerebral edema and encephalopathy. The effects of mild hypothermia (35°C) sufficient to prevent cerebral edema on the expression of these vascular endothelial genes were also studied. Expression levels of MT-I, MT-II, GLUT-1, NOS-3 and E-selectin mRNAs were selectively increased 2-3 fold (p<0.05) at edematous stages of encephalopathy in normothermic ALF rats. Mild hypothermia prevented brain edema and led to a selective attenuation of the increased expression of eNOS, GLUT-1 and E-selectin mRNAs (p<0.05). Expression of the endothelial marker genes P-gp, ET-1, Cav, and ICAM mRNAs were unchanged. Expression of vWf, Occ and VCAM mRNAs were decreased 1.5-2.0 fold (p<0.01) at coma stages of encephalopathy and were not normalized by hypothermia. These results demonstrate that (1) ALF is associated with alterations in the expression of specific vascular endothelial markers (2) the beneficial effects of hypothermia in ALF include the prevention of increased expression of eNOS, GLUT-1 and E-selectin and suggest that endothelial cell-derived nitric oxide rather than that derived from inducible NOS is implicated in the pathogenesis of the cerebral consequences of ALF.
Funded by CIHR

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