The concept of “the inflamed brain” in acute liver failure: mechanisms and new therapeutic opportunities

被引:0
作者
Roger F. Butterworth
机构
[1] University of Montreal,Department of Medicine
来源
Metabolic Brain Disease | 2016年 / 31卷
关键词
Neuroinflammation; Encephalopathy; Acute liver failure; Ammonia; Proinflammatory cytokines; Microglia; Minocycline;
D O I
暂无
中图分类号
学科分类号
摘要
The presence and severity of a systemic inflammatory response is a major predictor of brain edema and encephalopathy in acute liver failure (ALF) and polymorphisms of the gene coding for the proinflammatory cytokine TNF-alpha are known to influence the clinical outcome in ALF. Recent reports provide robust evidence for a role of neuroinflammation(inflammation of the brain per se) in ALF with the cardinal features of neuroinflammation including activation of microglial cells and increased production in situ of pro-inflammatory cytokines such as TNF-alpha and interleukins IL-1beta and IL-6. Multiple liver-brain signalling pathways have been proposed to explain the phenomenon of neuroinflammation in liver failure and these include direct effects of systemically-derived cytokines, recruitment of monocytes relating to microglial activation as well as effects of liver failure-derived toxins and altered permeability of the blood-brain barrier. Synergistic mechanisms involving ammonia and cytokines have been proposed. Currently-available strategies aimed at lowering of blood ammonia such as lactulose, probiotics and rifaximin have the potential to dampen systemic inflammation as does the anti-oxidant N-acetyl cysteine, mild hypothermia and albumin dialysis. Experimental studies demonstrate that deletion of genes coding for TNF-alpha or IL-1 leads to attenuation of the CNS consequences of ALF and administration of the TNF-alpha receptor antagonist etanercept has comparable beneficial effects in experimental ALF. Together, these findings confirm a major role for central neuroinflammatory mechanisms in general and mechanisms involving TNF-alpha in particular in the pathogenesis of the cerebral consequences of ALF and open the door to novel therapeutic interventions in this often fatal disorder.
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页码:1283 / 1287
页数:4
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