PATHOGENESIS OF HEPATIC COMA

这项研究的基本假设是， 氨是神经系统并发症的主要因素， 急性和慢性肝病。 患病肝脏无法 从门静脉循环中去除氨， 肝外组织清除这种氨，导致增加， 氨进入大脑 我们的假设是 氨负荷导致大脑能量代谢的破坏， 干扰，a）苹果酸-天冬氨酸穿梭（MAS）， 还原当量在细胞质和线粒体之间的转运， 与B）TCA循环（在α-酮戊二酸脱氢酶水平 复杂的，并且可能在其他脱氢酶步骤）。 延长 暴露于过量的氨导致大脑“敏感性”增加 氨，缺氧，和其他叠加的代谢应激。 肝脏疾病患者脑内的星形胶质细胞和正常人脑内的星形胶质细胞 实验诱导的代谢损伤的动物。 到 探讨氨在肝硬化发病中的作用 我们的目标将是多方面的：1）设计抑制剂 天冬氨酸转氨酶（MAS的重要组成部分）， 将穿过血脑屏障，以研究 MAS破坏的代谢后果; 2）使用[13 N] 亮氨酸、[13 N]酪氨酸、[13 N-氨基]-和[13 N-酰胺]谷氨酰胺（13 N， 正电子发射体; t 1/2=9.96 min.）为了在体内标记星形胶质细胞池， 提供证据表明星形胶质细胞谷氨酰胺是神经元 GABA并确定该途径是否在脑中受到干扰 高氨血症动物; 3）阐明谷胱甘肽在高氨血症动物中的作用。 正常和高氨血症大鼠脑; 4）确定主要来源 脑中代谢来源的氨（转氨酶、谷氨酸 脱氢酶和/或嘌呤核苷酸循环）。 最后是一些 研究人员质疑尿素循环的主要作用 是去除过量的氮，并建议尿素循环可以 已经进化到可以调节酸碱水平。 提供证据，或 针对这一理论，我们将使用我们最近开发的示踪剂 研究13 N标记的短时间代谢命运的技术 氨，丙氨酸和谷氨酸在代谢性酸中毒大鼠。 的 尿素循环在肝病中受损。 因此， 为了了解这个循环的中断如何影响全身 肝脏疾病中的氮稳态和酸碱平衡。 是 希望上述研究的结果将导致 改善肝病患者的治疗。

The underlying assumption of the proposed research is that excess ammonia is a major factor in the neurological complications arising from both acute and chronic liver disease. Failure of the diseased liver to remove ammonia from the portal circulation, and limited capacity of extrahepatic tissues to remove this ammonia, leads to an increase in ammonia entering the brain. Our hypothesis is that the increased ammonia load leads to a disruption of cerebral energy metabolism by interfering with, a) the malate-aspartate shuttle (MAS) for the transport of reducing equivalent between cytosol and mitochondria and with b) the TCA cycle (at the level of alpha-ketoglutarate dehydrogenase complex and, possibly, at other dehydrogenase steps). Prolonged exposure to excess ammonia results in increased cerebral "sensitivity" to ammonia, hypoxia, and other superimposed metabolic stresses. Astrocytes in the brains of liver diseased patients and in the brains of animals subjected to experimentally-induced metabolic impairment. To evaluate the role of ammonia in the pathogenesis of hepatic encephalopathy our goals will be multifaceted: 1) to design inhibitors of aspartate aminotransferase (an important component of the MAS) that will cross the blood-brain barrier, in order to investigate the metabolic consequences of disruption of the MAS; 2) to use [13N] leucine, [13N] tyrosine, [13N-amine'- and [13N-amide]glutamine (13N, positron emitter; t 1/2=9.96 min.) to label the astrocytic pool in vivo, to provide evidence that astrocytic glutamine is a precursor of neuronal GABA and to determine whether this pathway is disrupted in the hyperammonemic animal; 3) to elucidate the role of glutathione in the normal and hyperammonemic rat brain; 4) to determine the major source of metabolically-derived ammonia in brain (glutaminase, glutamate dehydrogenase, and/or the purine nucleotide cycle). Finally, some workers have questioned the notion that the major role of the urea cycle is to remove excess nitrogen and have suggested that the urea cycle may have evolved to regulate acid-base levels. To provide evidence for, or against, this theory we will use our recently developed tracer techniques to investigate the short-term metabolic fate of 13N labeled ammonia, alanine and glutamate in the metabolically acidotic rat. The urea cycle is compromised in liver disease. Therefore, it is important to understand how the disruption of this cycle affects both whole-body nitrogen homeostasis and acid-base balance in liver disease. It is hoped that the results of the above mentioned studies will lead to improved therapies in patients with liver disease.