Gomides Lindisley Ferreira, Marques Pedro Elias, Faleiros Bruno Engler, Pereira Rafaela Vaz, Amaral Sylvia Stella, Lage Thais Reis, Resende Gustavo Henrique Souza, Guidine Patricia Alves Maia, Foureaux Giselle, Ribeiro Fabíola Mara, Martins Fabiana Paiva, Fontes Marco Antônio Peliky, Ferreira Anderson José, Russo Remo Castro, Teixeira Mauro Martins, Moraes Márcio Flávio, Teixeira Antonio Lúcio, Menezes Gustavo Batista
Lindisley Ferreira Gomides, Pedro Elias Marques, Rafaela Vaz Pereira, Sylvia Stella Amaral, Thais Reis Lage, Gustavo Batista Menezes, Laboratório de Imunobiofotônica, Department of Morphology, ICB, UFMG, Belo Horizonte 31270-901, Brazil.
World J Hepatol. 2014 Apr 27;6(4):243-50. doi: 10.4254/wjh.v6.i4.243.
To propose an alternative model of hepatic encephalopathy (HE) in mice, resembling the human features of the disease.
Mice received two consecutive intraperitoneal injections of thioacetamide (TAA) at low dosage (300 mg/kg). Liver injury was assessed by serum transaminase levels (ALT) and liver histology (hematoxylin and eosin). Neutrophil infiltration was estimated by confocal liver intravital microscopy. Coagulopathy was evaluated using prolonged prothrombin and partial thromboplastin time. Hemodynamic parameters were measured through tail cuff. Ammonia levels were quantified in serum and brain samples. Electroencephalography (EEG) and psychomotor activity score were performed to show brain function. Brain edema was evaluated using magnetic resonance imaging.
Mice submitted to the TAA regime developed massive liver injury, as shown by elevation of serum ALT levels and a high degree of liver necrosis. An intense hepatic neutrophil accumulation occurred in response to TAA-induced liver injury. This led to mice mortality and weight loss, which was associated with severe coagulopathy. Furthermore, TAA-treated mice presented with increased serum and cerebral levels of ammonia, in parallel with alterations in EEG spectrum and discrete brain edema, as shown by magnetic resonance imaging. In agreement with this, neuropsychomotor abnormalities ensued 36 h after TAA, fulfilling several HE features observed in humans. In this context of liver injury and neurological dysfunction, we observed lung inflammation and alterations in blood pressure and heart rate that were indicative of multiple organ dysfunction syndrome.
In summary, we describe a new murine model of hepatic encephalopathy comprising multiple features of the disease in humans, which may provide new insights for treatment.
提出一种类似于人类肝性脑病（HE）特征的小鼠肝性脑病替代模型。
小鼠连续两次腹腔注射低剂量（300mg/kg）硫代乙酰胺（TAA）。通过血清转氨酶水平（ALT）和肝脏组织学（苏木精和伊红染色）评估肝损伤。通过共聚焦肝脏活体显微镜估计中性粒细胞浸润。使用凝血酶原时间和部分凝血活酶时间延长来评估凝血障碍。通过尾套法测量血流动力学参数。对血清和脑样本中的氨水平进行定量。进行脑电图（EEG）和精神运动活动评分以显示脑功能。使用磁共振成像评估脑水肿。
接受TAA方案的小鼠出现大量肝损伤，血清ALT水平升高和高度肝坏死表明了这一点。TAA诱导的肝损伤导致肝脏中大量中性粒细胞积聚。这导致小鼠死亡和体重减轻，这与严重的凝血障碍有关。此外，TAA处理的小鼠血清和脑内氨水平升高，同时EEG频谱改变和磁共振成像显示有离散的脑水肿。与此一致的是，TAA处理36小时后出现神经精神运动异常，符合在人类中观察到的几种HE特征。在这种肝损伤和神经功能障碍的背景下，我们观察到肺部炎症以及血压和心率改变，这表明存在多器官功能障碍综合征。
总之，我们描述了一种新的肝性脑病小鼠模型，其具有人类疾病的多种特征，这可能为治疗提供新的见解。
