PATHOGENESIS OF HEPATIC COMA

肝昏迷的发病机制

• 批准号: 3225647
• 负责人: Arthur Joseph Cooper
• 金额: $ 28.85万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3225647
• 关键词: 6 phosphofructokinase; acute disease /disorder; alpha ketoglutarate; aminoacid metabolism; aspartate; astrocytes; bioenergetics; brain metabolism; cellular pathology; chronic disease /disorder; enzyme inhibitors; enzyme mechanism; glutamate dehydrogenase; glutathione; hepatic coma /encephalopathy; hepatotoxin; high performance liquid chromatography; laboratory mouse; laboratory rat; liver failure; liver function; malates; medical complication; neurotransmitter metabolism; nitrogen balance; pathologic process; radiotracer; tissue /cell culture; urea cycle

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.

拟议研究的基本假设是，过量 氨是引起神经系统并发症的主要因素 急性和慢性肝病。 患病的肝脏无法 从门脉循环中去除氨，并且容量有限 肝外组织去除这种氨，导致 氨进入大脑。 我们的假设是增加 氨负荷导致脑能量代谢紊乱 干扰，a) 苹果酸-天冬氨酸穿梭 (MAS) 细胞质和线粒体之间还原当量的转运 b) TCA循环（在α-酮戊二酸脱氢酶水平 复杂，并且可能在其他脱氢酶步骤中）。 延长 接触过量的氨会导致大脑“敏感性”增加 氨、缺氧和其他叠加的代谢应激。 肝病患者大脑中的星形胶质细胞和 遭受实验诱导的代谢损伤的动物。 到 评估氨在肝病发病机制中的作用 脑病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[13N] 亮氨酸、[13N]酪氨酸、[13N-胺'-和[13N-酰胺]谷氨酰胺（13N、 正电子发射器； t 1/2=9.96 分钟）来标记体内星形胶质细胞池， 提供星形胶质细胞谷氨酰胺是神经元前体的证据 GABA 并确定该途径是否在 高氨血症动物； 3）阐明谷胱甘肽的作用 正常和高氨血症大鼠大脑； 4）确定主要来源 大脑中代谢产生的氨（谷氨酰胺酶、谷氨酸 脱氢酶和/或嘌呤核苷酸循环）。 最后，一些 工人们对尿素循环的主要作用这一观点提出了质疑。 是为了去除多余的氮，并表明尿素循环可能 已经进化到调节酸碱水​​平。 提供证据，或 反对这一理论，我们将使用我们最近开发的示踪剂 研究 13N 标记的短期代谢命运的技术 代谢性酸中毒大鼠中的氨、丙氨酸和谷氨酸。 这 肝脏疾病时尿素循环受到损害。 因此，重要的是 了解这个循环的破坏如何影响全身 肝脏疾病中的氮稳态和酸碱平衡。 这是 希望上述研究的结果能够带来 改善肝病患者的治疗方法。