Ammonia and proinflammatory cytokines modify expression of genes coding for astrocytic proteins implicated in brain edema in acute liver failure
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There is evidence to suggest that, in acute liver failure (ALF), brain ammonia and proinflammatory cytokines may act synergistically to cause brain edema and its complications (intracranial hypertension, brain herniation). However, the molecular mechanisms involved remain to be established. In order to address this issue, semi-quantitative RT-PCR was used to measure the expression of genes coding for astrocytic proteins with an established role in cell volume regulation in cerebral cortical astrocytes exposed to toxic agents previously identified in experimental and clinical ALF. Such agents include ammonia, the proinflammatory cytokine interleukin-1beta (IL-1β) and combinations of the two. Exposure of cultured astrocytes to recombinant IL-1β (but not ammonia) resulted in increased expression of aquaporin-4 (AQP-4). Both ammonia and proinflammatory mediators led to decreased expression of glial fibrillary acidic protein (GFAP), a cytoskeletal protein, but these effects were not additive. On the other hand, heme oxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS) expression were significantly increased by exposure to both ammonia and proinflammatory mediators and although modest, these effects were additive suggestive of a synergistic mechanism. These findings suggest that worsening of brain edema and its complications in ALF due to proinflammatory mechanisms may result from exacerbation of oxidative stress-related mechanisms rather than upregulation of AQP-4 or decreases in expression of the astrocytic structural protein GFAP.
KeywordsAmmonia Acute liver failure Neuroinflammation Proinflammatory cytokines Brain edema Hepatic encephalopathy Oxidative stress
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