Increased ammonia accumulation in the brain due to liver dysfunction is a major contributor to the pathogenesis of hepatic encephalopathy (HE). Fatal outcome of rapidly progressing (acute) HE is mainly related to cytotoxic brain edema associated with astrocytic swelling. An increase of brain ammonia in experimental animals or treatment of cultured astrocytes with ammonia generates reactive oxygen and nitrogen species in the target tissues, leading to oxidative/nitrosative stress (ONS). In cultured astrocytes, ammonia-induced ONS is invariably associated with the increase of the astrocytic cell volume. Interrelated mechanisms underlying this response include increased nitric oxide (NO) synthesis which is partly coupled to the activation of NMDA receptors and increased generation of reactive oxygen species by NADPH oxidase. ONS and astrocytic swelling are further augmented by excessive synthesis of glutamine (Gln) which impairs mitochondrial function following its accumulation in there and degradation back to ammonia ("the Trojan horse" hypothesis). Ammonia also induces ONS in other cell types of the CNS: neurons, microglia and the brain capillary endothelial cells (BCEC). ONS in microglia contributes to the central inflammatory response, while its metabolic and pathophysiological consequences in the BCEC evolve to the vasogenic brain edema associated with HE. Ammonia-induced ONS results in the oxidation of mRNA and nitration/nitrosylation of proteins which impact intracellular metabolism and potentiate the neurotoxic effects. Simultaneously, ammonia facilitates the antioxidant response of the brain, by activating astrocytic transport and export of glutathione, in this way increasing the availability of precursors of neuronal glutathione synthesis.

译文

由于肝功能障碍,大脑中氨积累的增加是肝性脑病 (HE) 发病机理的主要原因。快速进展 (急性) HE的致命结果主要与星形细胞肿胀相关的细胞毒性脑水肿有关。实验动物中脑氨的增加或用氨处理培养的星形胶质细胞会在目标组织中产生活性氧和氮,从而导致氧化/亚硝化应激 (ONS)。在培养的星形胶质细胞中,氨诱导的ONS总是与星形细胞体积的增加有关。此响应的相关机制包括增加的一氧化氮 (NO) 合成,这部分与NMDA受体的激活以及NADPH氧化酶增加的活性氧生成有关。谷氨酰胺 (Gln) 的过度合成进一步加剧了ONS和星形细胞的肿胀,谷氨酰胺 (Gln) 在其中积累并降解回氨后会损害线粒体功能 (“特洛伊木马” 假说)。氨还在中枢神经系统的其他细胞类型中诱导ONS: 神经元,小胶质细胞和脑毛细血管内皮细胞 (BCEC)。小胶质细胞中的ONS有助于中枢炎症反应,而其在BCEC中的代谢和病理生理后果则演变为与HE相关的血管源性脑水肿。氨诱导的ONS导致mRNA的氧化和蛋白质的硝化/亚硝基化,从而影响细胞内代谢并增强神经毒性作用。同时,氨通过激活星形细胞的运输和谷胱甘肽的出口来促进大脑的抗氧化反应,从而增加了神经元谷胱甘肽合成前体的可用性。

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