Neuronal apoptosis and inflammatory responses in the central nervous system of a rabbit treated with Shiga toxin-2.
Neuronal apoptosis and inflammatory responses in the central nervous system of a rabbit treated with Shiga toxin-2.
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DOI：
10.1186/1742-2094-5-11
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发表时间：
2008-03-21
影响因子：
9.3
通讯作者：
Sato S
中科院分区：
文献类型：
--
作者：
Takahashi K;Funata N;Ikuta F;Sato S
滋贺毒素（Stx）是在由产Stx大肠杆菌（STEC）如血清型O 157：H7引起的感染期间引起出血性结肠炎和溶血性尿毒症综合征（HUS）的主要因子。中枢神经系统（CNS）受累是HUS相关性腹泻死亡率的重要决定因素。已经表明，由Stxs引起的血管内皮损伤在疾病的发展中起着至关重要的作用。目前的研究调查的Stxs的细胞毒性作用和炎症反应之间的关系，在兔脑与Stx 2治疗。在用纯化的Stx 2或PBS（-）处理的兔模型中，我们使用免疫组织化学检查了CNS中Stx受体神经酰胺（Gb 3）/CD 77的表达和小胶质细胞活化。采用真实的实时定量逆转录-聚合酶链反应（RT-PCR）检测促炎细胞因子的表达，末端脱氧核苷酸转移酶（TdT）介导的dUTP缺口末端标记（TUNEL）法检测细胞凋亡。Gb 3/CD 77在内皮细胞中表达，而在神经元和胶质细胞中不表达。在脊髓灰质中，观察到显著水平的Gb 3/CD 77表达。严重的内皮损伤和微血管血栓形成导致广泛的坏死性梗死，从而导致急性神经元损伤。相反，在大脑中，Stx受体的表达要低得多。观察到的神经病理学不太严重。然而，在神经系统症状发作时观察到神经元凋亡，并且在发病后几天的后期阶段，脑中凋亡细胞的数量显著增加。小胶质细胞活化，肿瘤坏死因子（TNF）-α和白细胞介素（IL）-1β mRNA表达上调。脑组织中TNF-α转录物明显过表达。这项研究表明，Stx 2可能不会直接损害神经细胞，而是在脑实质中发生炎症反应，以响应表达Gb 3/CD 77的血管内皮细胞中Stx 2的原发性损伤。这些研究结果表明，神经炎症可能在STEC感染期间的神经退行性过程中发挥关键作用，抗炎干预可能具有治疗潜力。
Shiga toxins (Stxs) are the major agents responsible for hemorrhagic colitis and hemolytic-uremic syndrome (HUS) during infections caused by Stx-producing Escherichia coli (STEC) such as serotype O157:H7. Central nervous system (CNS) involvement is an important determinant of mortality in diarrhea associated-HUS. It has been suggested that vascular endothelial injuries caused by Stxs play a crucial role in the development of the disease. The current study investigates the relationship between the cytotoxic effects of Stxs and inflammatory responses in a rabbit brain treated with Stx2. In a rabbit model treated with purified Stx2 or PBS(-), we examined the expression of the Stx receptor globotriaosylceramide (Gb3)/CD77 in the CNS and microglial activation using immunohistochemistry. The relationship between inflammatory responses and neuronal cell death was analyzed by the following methods: real time quantitative reverse transcriptase (RT)-polymerase chain reaction (PCR) to determine the expression levels of pro-inflammatory cytokines, and the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method to detect apoptotic changes. Gb3/CD77 expression was detected in endothelial cells but not in neurons or glial cells. In the spinal cord gray matter, significant levels of Gb3/CD77 expression were observed. Severe endothelial injury and microvascular thrombosis resulted in extensive necrotic infarction, which led to acute neuronal damage. Conversely, in the brain, Stx receptor expression was much lower. The observed neuropathology was less severe. However, neuronal apoptosis was observed at the onset of neurological symptoms, and the number of apoptotic cells significantly increased in the brain at a later stage, several days after onset. Microglial activation was observed, and tumor necrosis factor (TNF)-α and interleukin (IL)-1β mRNA in the CNS parenchyma was significantly up-regulated. There was significant overexpression of TNF-α transcripts in the brain. This study indicates that Stx2 may not directly damage neural cells, but rather inflammatory responses occur in the brain parenchyma in response to primary injury by Stx2 in vascular endothelial cells expressing Gb3/CD77. These findings suggest that neuroinflammation may play a critical role in neurodegenerative processes during STEC infection and that anti-inflammatory intervention may have therapeutic potential.
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影响因子：
15.9
作者：
Kreutzberg, GW
通讯作者：
Kreutzberg, GW
影响因子：
15.9
作者：
ESOLEN, LM;TAKAHASHI, K;GRIFFIN, DE
通讯作者：
GRIFFIN, DE
影响因子：
3.1
作者：
Isogai, E;Isogai, H;Takeshi, K
通讯作者：
Takeshi, K
DOI：
10.1152/ajpgi.2000.278.5.g811
发表时间：
2000-05-01
影响因子：
4.5
作者：
Jones, NL;Islur, A;Sherman, PM
通讯作者：
Sherman, PM
影响因子：
2.9
作者：
Ling, H;Boodhoo, A;Read, RJ
通讯作者：
Read, RJ