中枢神经系统氯稳态失衡参与肝性脑病的机制研究
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摘要
肝性脑病（hepatic encephalopathy, HE）是由肝功能严重不足引起的神经功能紊乱综合征，是肝病患者最常见的并发症和死亡原因之一。关于其发病机制的学说众多，至今尚未完全阐明，临床上也无特效疗法。
HE的运动障碍和中枢神经系统（central nervous system, CNS）内的基底神经节的精细调控状态密切相关。在基底神经节复杂的网络中，黑质网状部（substantia nigra pars reticulate, SNr）是运动调控环路上的关键一环，主要由γ-氨基丁酸（Gamma-amino butyric acid, GABA）能投射神经元组成。研究表明，GABA与HE的脑细胞功能紊乱密切相关，但其作用机制尚不明确。
氯离子（Cl~-）是细胞内最重要的阴离子。特别在神经系统，神经元内外氯离子浓度保持相对平衡状态，即形成氯离子稳态，是维持神经元和局部环路形态和机能稳定的内环境基础。氯离子稳态失衡可引起GABA能传递的改变，氯离子稳态及其调控因子已经成为多种GABA相关神经病理性疾病的潜在治疗靶点。研究显示CNS内不同部位的氯稳态失衡参与多种神经功能紊乱，然而其在HE中的作用尚不清楚。
Na~+-K~+-2Cl~-共转运体1（Na~+-K~+-Cl~-cotransporter1, NKCC1）和K~+-Cl~-共转运体2（K~+-Cl~-cotransporter2, KCC2）是一组结构相似、功能截然相反的氯离子转运体。NKCC1为氯离子内向转运体，KCC2为氯离子外向转运体，两者共同介导神经元氯离子稳态以实现对GABA效应的调控。研究表明，NKCC1和KCC2在多种GABA相关神经病理性疾病中发生表达或者功能的改变，进而实现对GABA能神经传递的影响作用。然而，这两个转运体在HE发病机制中是否发挥作用尚不明确。
本研究深入探讨HE状态下SNr内的氯离子稳态失衡情况及可能的分子机制，以期从新的角度阐明HE的中枢发病机制、为寻找有效的HE临床治疗手段提供实验室依据。本研究使用谷氨酸脱羧酶（glutamate decarboxylase,GAD）67-绿色荧光蛋白（green fluorescent protein, GFP）转基因小鼠。在该基因敲入小鼠体内，GFP的表达受GAD67启动子序列的调控，因此所有的GABA能神经元均被GFP绿色荧光蛋白所标记，该特点能够很好的解决传统染色方法无法清晰、准确的标记GABA能神经元这一关键问题。目的：
1、以GAD67-GFP转基因小鼠为研究对象，探讨SNr内GABA能神经元氯稳态失衡在急性HE运动缺陷中的作用及可能的作用机制。
2、检测临床上不同类型患者的NKCC1、KCC2的表达水平，同时分析其与患者肝脏功能、神经功能之间的关系。方法：
1、使用硫代乙酰胺（thioacetamide, TAA）腹腔注射建立HE模型，通过血清转氨酶检测、血氨及大脑氨含量的测定、大脑含水量测定、肝脏组织学染色、神经系统功能评分、旷场实验等来验证实验小鼠出现HE及运动迟缓；利用荧光染料孵育脑薄片结合激光共聚焦显微镜观察，检测HE小鼠SNr内GABA能神经元内的氯离子浓度的变化情况；利用实时定量反转录聚合酶链反应（reverse transcriptase polymerase chain reaction, RT-PCR）和Western blot分别在mRNA和蛋白水平检测NKCC1和KCC2的表达变化情况；进行双重免疫染色法，即使用抗GFP抗体检测SNr内GABA能神经元和使用抗酪氨酸羟化酶（tyrosine hydroxylase, TH）抗体检测黑质致密部（substantia nigra pars compacta, SNc）多巴胺神经元，检测KCC2在神经元中亚细胞分布情况；进行神经元尼氏染色评估TAA处理是否会改变SNr内GABA能神经元的数量；通过立体定位手术黑质内注射NKCC1选择性抑制剂布美他尼或KCC2阻断剂己二酸二异辛酯（di-isooctyladinpate, DIOA），评估其对血清转氨酶水平、血氨水平、大脑氨含量、大脑含水量、肝脏组织学染色、运动能力等的影响。
2、利用实时定量RT-PCR检测36名患有Ⅲ-Ⅳ期HE的肝硬化患者、20名未患HE的肝硬化患者及15名健康对照组的NKCC1和KCC2的mRNA水平，使用2CT方法计算表达情况。同时分析KCC2的水平与Child-Pugh评分、MELD评分、Glasgow昏迷评分及血氨水平的相关性。结果：
1、TAA处理导致HE和运动迟缓。氯离子成像结果显示HE小鼠SNr内GABA能神经元内的氯离子浓度升高。HE小鼠KCC2在mRNA及蛋白水平的表达都下降，在神经元细胞膜处的表达下降尤为明显；与此相反，NKCC1的表达没有明显变化。TAA处理并不能改变SNr内GABA能神经元的数目。黑质内注射DIOA使正常小鼠的血清转氨酶水平升高，而黑质内注射布美他尼，虽然能改善HE小鼠的乳酸脱氢酶（lactate dehydrogenase,LDH）水平，但并不能降低天冬氨酸转氨酶（aspartate aminotransferase,AST）、丙氨酸转氨酶（alanine aminotransferase, ALT）水平。黑质内注射DIOA的正常小鼠肝脏组织学染色结果基本正常，黑质内注射布美他尼并不能改善HE小鼠的肝脏坏死和炎性病变。黑质内注射DIOA和布美他尼的HE小鼠在血氨水平、大脑氨含量和大脑含水量等方面，没有明显变化。黑质内注射DIOA可导致运动能力的下降，在HE小鼠可导致运动迟缓进一步加剧；相反，在HE小鼠黑质内注射布美他尼并不能使其运动能力恢复正常。
2、患有HE的肝硬化患者KCC2mRNA的水平与未患HE的肝硬化患者及健康对照组相比明显下降；然而，NKCC1mRNA水平在各组之间无明显差异性。此外，患有HE的肝硬化患者的KCC2mRNA水平与Child-Pugh评分、MELD评分及血氨的水平呈负相关，与Glasgow昏迷评分呈正相关。结论：
1、氯稳态失衡可能是HE导致的运动迟缓的病理生理学基础，恢复氯稳态的相关药物可能成为治疗肝功能衰竭的潜在性选择。
2、KCC2和NKCC1的表达失衡可能成为预测HE的信号。
Hepatic encephalopathy (HE) is defined as a spectrum of neuropsychiatricabnormalities in patients with severe liver dysfunction. It’s one of the mostcommon causes for the complications and deaths of hepatic patients. Thoughthere are many theories explaining its pathogenesis mechanism, it has not yetbeen fully elucidated. There is still no specific therapy.
The dyskinesia of HE is closely related to the precise regulation of the basalganglia in the central nervous system (CNS) and the substantia nigra parsreticulate (SNr) plays the central role in the motion regulation in thecomplicated basal ganglia network. SNr is mainly composed of Gamma-aminobutyric acid (GABA)-containing projection neurons. Previous studies haveshown that GABA is closely related to the cerebral cell’s dysfunction of HE, butits mechanism is not clear.
The chloride ion (Cl~-) is one of the most important intracellular anions. Inthe nervous system, the balance of chloride ion concentration between the insideand the outside of the neural cells, which is called the chloride homeostasis, isthe internal environmental basis in maintaining the shape and function of bothneurons and local loops. The imbalance of chloride ion can result in the changeof GABA transmission, so the chloride homeostasis and its regulatory factorshave become the potential therapeutic target of many GABA-related neuropathicdiseases. Studies revealed that the chloride homeostasis imbalance in manyplaces of the CNS could lead to different kinds of neurological disorders, but itsfunction in HE is still unknown.
Na~+-K~+-Cl~-cotransporter1(NKCC1) and K~+-Cl~-cotransporter2(KCC2)are two chloride ion transporters which are similar in structures but totallyopposite in functions. NKCC1imports Cl into the neurons, while KCC2exports Cl out of neurons. They both play roles in inducing the neuron chloridehomeostasis so that they can work in GABA regulation. Studies showed that theexpressions or the functions of NKCC1and KCC2would change in manyneuropathic diseases and will further affect the neurotransmission of GABA.But whether the two transporters will play roles in the pathogenesis of HE is notyet fully investigated.
This study will explore the roles of chloride homeostasis imbalance in SNrduring HE and its potential molecular mechanism, which may provideexperimental evidence for clarifying the pathogenesis of HE from a new viewand searching effective clinical treatment for HE. In the present study, glutamatedecarboxylase67(GAD67)-green fluorescent protein (GFP) knock-in transgenicmice were used to easily detect GABAergic neurons with GFP fluorescencewithin the SNr, because GFP expression was controlled by the promoter of the major GABA synthesizing enzyme, GAD67.
Aim:
1. We aimed to analyze the involvement and possible mechanisms ofaltered chloride homeostasis of GABAergic neurons within the SNr in the motordeficit in a model of the acute form of HE in acute liver failure usingGAD67-GFP transgenic mice.
2. We aimed to detect the expression of NKCC1and KCC2in differentpathological type patients and analyse the relationship between the levels ofthem and liver or nerve function.
Methods:
1. We set up the HE model by intraperitoneal injection of thioacetamide(TAA). The HE and hypolocomotion of mice were confirmed by serumdetection of hepatic enzymes, blood and brain ammonia estimation, brain watermeasurement, histological staining of liver and neurological evaluations, as wellas open field test. We then incubated the brain slices with the fluorescent dyes incombination with laser confocal microscopy to observe the changes of chlorideion concentration of GABA neurons in the SNr of HE mice. Reversetranscriptase polymerase chain reaction (RT-PCR) and western blot were usedto test the mRNA and protein expressions of NKCC1and KCC2. Doubleimmunofluorescence staining, including detection of the GABA neurons in theSNr by anti-GFP antibody and the dopaminergic neurons in the substantia nigrapars compacta (SNc) by the anti-tyrosine hydroxylase (TH) antibody, was usedto detect the subcellular distribution of KCC2in the neurons. Nissl stain wasdone to evaluate whether the number of GABA neurons in the SNr wouldchange after TAA treatment. We also injected the NKCC1specific inhibitor Bumetanide or KCC2inhibitor di-isooctyladinpate (DIOA) stereotactically tothe substantia nigra to evaluate their effect on serum transaminase, blood andbrain ammonia, brain water content, histological staining of liver and motioncapacity.
2. KCC2and NKCC1mRNA levels were detected by real time reversetranscriptase polymerase chain reaction (RT-PCR) in the plasma of36cirrhosispatients with HE of grade III-IV,20cirrhosis patients without HE and15healthy controls. Calculations of expression were made with the2CTmethod.The relations between the expression of KCC2and Child-Pugh scores, MELDscales, Glasgow coma scores and blood ammonia were also analyzed.
Results:
1. TAA treatment would lead to HE and hypolocomotion. Chlorideimaging indicated an enhanced local intracellular chloride concentration in theGABAergic neurons within the SNr of transgenic mice with HE. In addition, themRNA and protein levels of KCC2were reduced, particularly on neuronal cellmembranes; in contrast, NKCC1did not change significantly. TAA treatmentcould not change the number of GABAergic neurons in the SNr. Injection ofDIOA to the substantia nigra could increase the serum transaminase in thenormal mice. Injection of bumetanide to the substantia nigra could not decreasethe aspartate aminotransferase (AST) and alanine aminotransferase(ALT) in HEmice, though the lactate dehydrogenase (LDH) could be a little better. Livers ofnormal mice received injection of DIOA were histological normal and injectionof bumetanide could not improve the liver necrosis and inflammation of the HEmice. There was no significant difference in the blood and brain ammonia andbrain water content in the HE mice received DIOA or bumetanide injection tothe substantia nigra. The injection of DIOA to the substantia nigra would reduced motor activity in the normal mice and led to deterioratedhypolocomotion in the HE mice. In contrast, the injection of bumetanide to thesubstantia nigra did not normalize motor activity in HE mice.
2. KCC2mRNAs in cirrhosis patients with HE showed significantdecreases when compared with those in cirrhosis patients without HE or healthycontrols. However, NKCC1mRNAs in different groups did not change. Inaddition, for cirrhosis patients with HE, there were significant negativecorrelations between KCC2levels with Child-Pugh scores, MELD scales andthe levels of blood ammonia; there was a significant positive correlationbetween KCC2levels with Glasgow coma scores.
Conclusion:
1. Our data suggest that altered chloride homeostasis might be responsiblefor the pathophysiology of hypolocomotion following HE. Drugs aimed atrestoring normal chloride homeostasis would be a potential treatment for hepaticfailure.
2. Our study suggests that imbalance of KCC2and NKCC1may be a signalto predict HE.
HE的运动障碍和中枢神经系统（central nervous system, CNS）内的基底神经节的精细调控状态密切相关。在基底神经节复杂的网络中，黑质网状部（substantia nigra pars reticulate, SNr）是运动调控环路上的关键一环，主要由γ-氨基丁酸（Gamma-amino butyric acid, GABA）能投射神经元组成。研究表明，GABA与HE的脑细胞功能紊乱密切相关，但其作用机制尚不明确。
氯离子（Cl~-）是细胞内最重要的阴离子。特别在神经系统，神经元内外氯离子浓度保持相对平衡状态，即形成氯离子稳态，是维持神经元和局部环路形态和机能稳定的内环境基础。氯离子稳态失衡可引起GABA能传递的改变，氯离子稳态及其调控因子已经成为多种GABA相关神经病理性疾病的潜在治疗靶点。研究显示CNS内不同部位的氯稳态失衡参与多种神经功能紊乱，然而其在HE中的作用尚不清楚。
Na~+-K~+-2Cl~-共转运体1（Na~+-K~+-Cl~-cotransporter1, NKCC1）和K~+-Cl~-共转运体2（K~+-Cl~-cotransporter2, KCC2）是一组结构相似、功能截然相反的氯离子转运体。NKCC1为氯离子内向转运体，KCC2为氯离子外向转运体，两者共同介导神经元氯离子稳态以实现对GABA效应的调控。研究表明，NKCC1和KCC2在多种GABA相关神经病理性疾病中发生表达或者功能的改变，进而实现对GABA能神经传递的影响作用。然而，这两个转运体在HE发病机制中是否发挥作用尚不明确。
本研究深入探讨HE状态下SNr内的氯离子稳态失衡情况及可能的分子机制，以期从新的角度阐明HE的中枢发病机制、为寻找有效的HE临床治疗手段提供实验室依据。本研究使用谷氨酸脱羧酶（glutamate decarboxylase,GAD）67-绿色荧光蛋白（green fluorescent protein, GFP）转基因小鼠。在该基因敲入小鼠体内，GFP的表达受GAD67启动子序列的调控，因此所有的GABA能神经元均被GFP绿色荧光蛋白所标记，该特点能够很好的解决传统染色方法无法清晰、准确的标记GABA能神经元这一关键问题。目的：
1、以GAD67-GFP转基因小鼠为研究对象，探讨SNr内GABA能神经元氯稳态失衡在急性HE运动缺陷中的作用及可能的作用机制。
2、检测临床上不同类型患者的NKCC1、KCC2的表达水平，同时分析其与患者肝脏功能、神经功能之间的关系。方法：
1、使用硫代乙酰胺（thioacetamide, TAA）腹腔注射建立HE模型，通过血清转氨酶检测、血氨及大脑氨含量的测定、大脑含水量测定、肝脏组织学染色、神经系统功能评分、旷场实验等来验证实验小鼠出现HE及运动迟缓；利用荧光染料孵育脑薄片结合激光共聚焦显微镜观察，检测HE小鼠SNr内GABA能神经元内的氯离子浓度的变化情况；利用实时定量反转录聚合酶链反应（reverse transcriptase polymerase chain reaction, RT-PCR）和Western blot分别在mRNA和蛋白水平检测NKCC1和KCC2的表达变化情况；进行双重免疫染色法，即使用抗GFP抗体检测SNr内GABA能神经元和使用抗酪氨酸羟化酶（tyrosine hydroxylase, TH）抗体检测黑质致密部（substantia nigra pars compacta, SNc）多巴胺神经元，检测KCC2在神经元中亚细胞分布情况；进行神经元尼氏染色评估TAA处理是否会改变SNr内GABA能神经元的数量；通过立体定位手术黑质内注射NKCC1选择性抑制剂布美他尼或KCC2阻断剂己二酸二异辛酯（di-isooctyladinpate, DIOA），评估其对血清转氨酶水平、血氨水平、大脑氨含量、大脑含水量、肝脏组织学染色、运动能力等的影响。
2、利用实时定量RT-PCR检测36名患有Ⅲ-Ⅳ期HE的肝硬化患者、20名未患HE的肝硬化患者及15名健康对照组的NKCC1和KCC2的mRNA水平，使用2CT方法计算表达情况。同时分析KCC2的水平与Child-Pugh评分、MELD评分、Glasgow昏迷评分及血氨水平的相关性。结果：
1、TAA处理导致HE和运动迟缓。氯离子成像结果显示HE小鼠SNr内GABA能神经元内的氯离子浓度升高。HE小鼠KCC2在mRNA及蛋白水平的表达都下降，在神经元细胞膜处的表达下降尤为明显；与此相反，NKCC1的表达没有明显变化。TAA处理并不能改变SNr内GABA能神经元的数目。黑质内注射DIOA使正常小鼠的血清转氨酶水平升高，而黑质内注射布美他尼，虽然能改善HE小鼠的乳酸脱氢酶（lactate dehydrogenase,LDH）水平，但并不能降低天冬氨酸转氨酶（aspartate aminotransferase,AST）、丙氨酸转氨酶（alanine aminotransferase, ALT）水平。黑质内注射DIOA的正常小鼠肝脏组织学染色结果基本正常，黑质内注射布美他尼并不能改善HE小鼠的肝脏坏死和炎性病变。黑质内注射DIOA和布美他尼的HE小鼠在血氨水平、大脑氨含量和大脑含水量等方面，没有明显变化。黑质内注射DIOA可导致运动能力的下降，在HE小鼠可导致运动迟缓进一步加剧；相反，在HE小鼠黑质内注射布美他尼并不能使其运动能力恢复正常。
2、患有HE的肝硬化患者KCC2mRNA的水平与未患HE的肝硬化患者及健康对照组相比明显下降；然而，NKCC1mRNA水平在各组之间无明显差异性。此外，患有HE的肝硬化患者的KCC2mRNA水平与Child-Pugh评分、MELD评分及血氨的水平呈负相关，与Glasgow昏迷评分呈正相关。结论：
1、氯稳态失衡可能是HE导致的运动迟缓的病理生理学基础，恢复氯稳态的相关药物可能成为治疗肝功能衰竭的潜在性选择。
2、KCC2和NKCC1的表达失衡可能成为预测HE的信号。
Hepatic encephalopathy (HE) is defined as a spectrum of neuropsychiatricabnormalities in patients with severe liver dysfunction. It’s one of the mostcommon causes for the complications and deaths of hepatic patients. Thoughthere are many theories explaining its pathogenesis mechanism, it has not yetbeen fully elucidated. There is still no specific therapy.
The dyskinesia of HE is closely related to the precise regulation of the basalganglia in the central nervous system (CNS) and the substantia nigra parsreticulate (SNr) plays the central role in the motion regulation in thecomplicated basal ganglia network. SNr is mainly composed of Gamma-aminobutyric acid (GABA)-containing projection neurons. Previous studies haveshown that GABA is closely related to the cerebral cell’s dysfunction of HE, butits mechanism is not clear.
The chloride ion (Cl~-) is one of the most important intracellular anions. Inthe nervous system, the balance of chloride ion concentration between the insideand the outside of the neural cells, which is called the chloride homeostasis, isthe internal environmental basis in maintaining the shape and function of bothneurons and local loops. The imbalance of chloride ion can result in the changeof GABA transmission, so the chloride homeostasis and its regulatory factorshave become the potential therapeutic target of many GABA-related neuropathicdiseases. Studies revealed that the chloride homeostasis imbalance in manyplaces of the CNS could lead to different kinds of neurological disorders, but itsfunction in HE is still unknown.
Na~+-K~+-Cl~-cotransporter1(NKCC1) and K~+-Cl~-cotransporter2(KCC2)are two chloride ion transporters which are similar in structures but totallyopposite in functions. NKCC1imports Cl into the neurons, while KCC2exports Cl out of neurons. They both play roles in inducing the neuron chloridehomeostasis so that they can work in GABA regulation. Studies showed that theexpressions or the functions of NKCC1and KCC2would change in manyneuropathic diseases and will further affect the neurotransmission of GABA.But whether the two transporters will play roles in the pathogenesis of HE is notyet fully investigated.
This study will explore the roles of chloride homeostasis imbalance in SNrduring HE and its potential molecular mechanism, which may provideexperimental evidence for clarifying the pathogenesis of HE from a new viewand searching effective clinical treatment for HE. In the present study, glutamatedecarboxylase67(GAD67)-green fluorescent protein (GFP) knock-in transgenicmice were used to easily detect GABAergic neurons with GFP fluorescencewithin the SNr, because GFP expression was controlled by the promoter of the major GABA synthesizing enzyme, GAD67.
Aim:
1. We aimed to analyze the involvement and possible mechanisms ofaltered chloride homeostasis of GABAergic neurons within the SNr in the motordeficit in a model of the acute form of HE in acute liver failure usingGAD67-GFP transgenic mice.
2. We aimed to detect the expression of NKCC1and KCC2in differentpathological type patients and analyse the relationship between the levels ofthem and liver or nerve function.
Methods:
1. We set up the HE model by intraperitoneal injection of thioacetamide(TAA). The HE and hypolocomotion of mice were confirmed by serumdetection of hepatic enzymes, blood and brain ammonia estimation, brain watermeasurement, histological staining of liver and neurological evaluations, as wellas open field test. We then incubated the brain slices with the fluorescent dyes incombination with laser confocal microscopy to observe the changes of chlorideion concentration of GABA neurons in the SNr of HE mice. Reversetranscriptase polymerase chain reaction (RT-PCR) and western blot were usedto test the mRNA and protein expressions of NKCC1and KCC2. Doubleimmunofluorescence staining, including detection of the GABA neurons in theSNr by anti-GFP antibody and the dopaminergic neurons in the substantia nigrapars compacta (SNc) by the anti-tyrosine hydroxylase (TH) antibody, was usedto detect the subcellular distribution of KCC2in the neurons. Nissl stain wasdone to evaluate whether the number of GABA neurons in the SNr wouldchange after TAA treatment. We also injected the NKCC1specific inhibitor Bumetanide or KCC2inhibitor di-isooctyladinpate (DIOA) stereotactically tothe substantia nigra to evaluate their effect on serum transaminase, blood andbrain ammonia, brain water content, histological staining of liver and motioncapacity.
2. KCC2and NKCC1mRNA levels were detected by real time reversetranscriptase polymerase chain reaction (RT-PCR) in the plasma of36cirrhosispatients with HE of grade III-IV,20cirrhosis patients without HE and15healthy controls. Calculations of expression were made with the2CTmethod.The relations between the expression of KCC2and Child-Pugh scores, MELDscales, Glasgow coma scores and blood ammonia were also analyzed.
Results:
1. TAA treatment would lead to HE and hypolocomotion. Chlorideimaging indicated an enhanced local intracellular chloride concentration in theGABAergic neurons within the SNr of transgenic mice with HE. In addition, themRNA and protein levels of KCC2were reduced, particularly on neuronal cellmembranes; in contrast, NKCC1did not change significantly. TAA treatmentcould not change the number of GABAergic neurons in the SNr. Injection ofDIOA to the substantia nigra could increase the serum transaminase in thenormal mice. Injection of bumetanide to the substantia nigra could not decreasethe aspartate aminotransferase (AST) and alanine aminotransferase(ALT) in HEmice, though the lactate dehydrogenase (LDH) could be a little better. Livers ofnormal mice received injection of DIOA were histological normal and injectionof bumetanide could not improve the liver necrosis and inflammation of the HEmice. There was no significant difference in the blood and brain ammonia andbrain water content in the HE mice received DIOA or bumetanide injection tothe substantia nigra. The injection of DIOA to the substantia nigra would reduced motor activity in the normal mice and led to deterioratedhypolocomotion in the HE mice. In contrast, the injection of bumetanide to thesubstantia nigra did not normalize motor activity in HE mice.
2. KCC2mRNAs in cirrhosis patients with HE showed significantdecreases when compared with those in cirrhosis patients without HE or healthycontrols. However, NKCC1mRNAs in different groups did not change. Inaddition, for cirrhosis patients with HE, there were significant negativecorrelations between KCC2levels with Child-Pugh scores, MELD scales andthe levels of blood ammonia; there was a significant positive correlationbetween KCC2levels with Glasgow coma scores.
Conclusion:
1. Our data suggest that altered chloride homeostasis might be responsiblefor the pathophysiology of hypolocomotion following HE. Drugs aimed atrestoring normal chloride homeostasis would be a potential treatment for hepaticfailure.
2. Our study suggests that imbalance of KCC2and NKCC1may be a signalto predict HE.
引文
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