046

EVIDENCE FOR A ROLE OF CEREBRAL PROINFLAMMATORY CYTOKINES IN THE PATHOGENESIS OF BRAIN EDEMA IN ACUTE LIVER FAILURE

W Jiang, H Qu, P Desjardins, N Chatauret, M Bélanger, RF Butterworth
¹Neuroscience Research Unit, CHUM (Hôpital St-Luc), Montreal, Quebec

Brain edema is a serious cerebral complication of acute liver failure (ALF). The precise pathophysiologic mechanisms responsible have not been fully elucidated but recent A-V difference studies suggest an involvement of proinflammatory cytokines (J. Hepatol, 37, 576, 2002). Direct evidence for brain accumulation of cytokines, as well as their cellular localization is lacking. To address this issue, gene expression analysis was performed using a microarray containing 128 cytokines and genes. A subset of differentially expressed genes, including interleukin-1beta (IL-Ibeta), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) were further assessed by ELISA and real time RT-PCR in both sera and brain extracts from two distinct rodent models of ALF namely the hepatic devascularized rat (portacaval anastomosis followed by hepatic artery ligation) and a newly characterized mouse model with end-stage toxic liver injury due to azoxymethane. Immunohistochemical studies were performed on perfused animals to eliminate circulating cytokines and to confirm the precise cellular localization of the changes in cytokine expression. Mild hypothermia (35°C), a condition shown previously to prevent brain edema and intracranial hypertension in this model of ALF was used to assess its effects on both circulating and brain cytokine levels. TNFalpha and IL-Ibeta mRNA were increased 2 fold (p<0.001) in ALF rat brain compared to sham-operated controls. Comparable increases of both IL-Ibeta and TNFalpha were also found in the brains of azoxymethane mice. Mild hypothermia prevented brain edema in ALF animals accompanied by a normalization of IL-Ibeta mRNA in brain (p<0.001). Hypothermia had no significant effect on brain TNFalpha or on circulating levels of either cytokine. Double labelling studies revealed that increased IL-1beta was uniquely neuronal in localization. Absence of immunolabelling of microglia was confirmed by OX-42 and ED-1 double labelling. These findings demonstrate that (1) ALF results in a selective increase of proinflammatory cytokines in brain (2) Increased brain content of proinflammatory cytokines is independent of etiology of ALF (3) Increased IL-Ibeta is neuronal in localization in ALF and (4) Hypothermia sufficient to prevent brain edema selectively attenuates the increases of IL-Ibeta. Therapeutic approaches aimed at the reduction of brain concentrations of IL-1beta may be beneficial in the prevention of brain edema and its complications in patients with ALF.
Funded by CIHR and CASL

PREVIOUS NEXT