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PROTEIN MICROARRAY STUDY REVEALS TOXIN-SELECTIVE CYTOKINE PROFILES IN EXPERIMENTAL ACUTE LIVER FAILURE: BENEFICIAL EFFECTS OF MILD HYPOTHERMIA AND N-ACETYLCYSTEINE
C Bémeur, J Vaquero, P Desjardins, RF Butterworth
Neuroscience Research Unit, Hôpital Saint-Luc (CHUM), Montreal
Hepatic encephalopathy and cerebral edema are serious neurological complications of acute liver failure (ALF). The precise pathophysiologic mechanisms responsible for these complications have not been fully established but recent studies suggest the involvement of proinflammatory cytokines. In order to address this issue, protein array technology was used to investigate changes in the expression profile of 62 pro- and anti-inflammatory cytokines and related chemokines and growth factors in mice with ALF due to toxic liver injury. Male C57BL6 mice were treated with azoxymethane (AOM) (100µg/g; i.p.) or acetaminophen (APAP) (300µg/g; i.p.); control mice received an equal volume of saline. At equivalent stages of ALF, determined by measurement of serum transaminases and verified post-mortem by histopathology (hematoxylin-phloxine-saphron staining of paraffin-embedded liver sections), mice were killed and blood drawn for cytokine measurement. AOM-treated comatose mice manifested significant brain edema (measured by a sensitive gravimetric technique) and increased expression of a wide range of cytokines including interferon-gamma (IFN-gamma), interleukins (IL-1beta, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17), tumor necrosis factor-alpha (TNF-alpha) as well as monocyte chemoattractant proteins MCP-1 and MCP-5. Cytokine profiles from APAP-treated mice showed some similarities but also major differences from those associated with AOM-induced ALF (in particular with regard to the interleukins IL-1beta, IL-5 and IL-6). Treatment of AOM mice with mild hypothermia (35°C) or N-Acetylcysteine (NAC) (1,200 mg/kg; i.p.) led to reduced hepatic damage and improvement in neurological function (brain edema prevention). Both hypothermia and NAC led to selective attenuation in expression of IFN-gamma, IL-10, IL-12 and IL-17. Hypothermia caused additional decreases in expression of IL-3, IL-4 and IL-6. These findings demonstrate that 1-) cytokine profiles in ALF due to toxic liver injury are both selective and toxin-dependent; 2-) treatment such as mild hypothermia or NAC have distinct actions on cytokine expression profiles in ALF. These findings suggest that novel treatment strategies using anti-cytokine or immunoneutralization therapy aimed at reduction of hepatic injury or stimulation of hepatic regeneration may need to target cytokines specific to the etiology of the ALF.
Funded by CIHR and CASL, Canada