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Temperature-dependent response in neuronal injury by hypoxia-induced microglia

缺氧诱导小胶质细胞神经元损伤的温度依赖性反应

基本信息

批准号：
20791077
负责人：
MATSUI Tomohiro
金额：
$ 2.75万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2009
项目状态：
已结题

项目摘要

Pro-inflammatory cytokines and NO are considered responsible for exacerbating brain injury. Activated microglia produce these potentially cytotoxic factors during neuron destruction. Therefore, the beneficial effects of therapeutic hypothermia on neuroprotection are considered to be due, in part, to suppression of post-injury inflammatory factors by microglia. In this study, I examined whether altering culture temperature modifies production of cytokines and NO by microglia activated with ATP, a product leaked from injured neurons/cells after brain insults. Compared to normothermia, hypothermia ecreased ATP-induced production of pro-inflammatory cytokines, TNF- α and IL-6, within 6 h of culture. NO production was reduced by hypothermia but augmented by hyperthermia at 6 h. In addition, activation of p38 MAPK was reduced in hypothermia at 1 min, compared to normothermia. In conclusion, hypothermia reduced the rapid activation of p38 MAPK and the following TNF-α, IL-6, and NO production in ATP-activated microglia, suggesting that the reduction of the early-phase inflammatory factors via suppression of p38 MAPK in microglia is one possible neuroprotective mechanism of therapeutic hypothermia. Hyperthermia specifically increased the early-phase NO production in these cells. These temperature-dependent changes in NO production may imply that NO in the early phase is useful as an important clinical marker in hypothermia-related neuronal protection and in hyperthermia-related neuronal injury.

促炎细胞因子和一氧化氮被认为是加重脑损伤的原因。激活的小胶质细胞在神经元破坏过程中产生这些潜在的细胞毒性因子。因此，治疗性低温对神经保护的有益作用被认为部分归因于小胶质细胞对损伤后炎症因子的抑制。在这项研究中，我研究了改变培养温度是否改变了由ATP激活的小胶质细胞产生的细胞因子和NO，ATP是脑损伤后受损神经元/细胞泄漏的产物。与常温相比，低温可在培养6h内减少三磷酸腺苷诱导的促炎细胞因子肿瘤坏死因子-α和IL-6的产生。与常温相比，低温处理6h后NO生成减少，而高温处理后6h，p38MAPK的活性降低。结论：低温可降低小胶质细胞p38MAPK的快速活化及随后的肿瘤坏死因子-α、IL-6和NO的产生，提示通过抑制小胶质细胞内的p38MAPK而减少早期炎症因子的产生可能是低温治疗的神经保护机制之一。高温特别地增加了这些细胞中早期阶段的NO产生。这些NO产生的温度依赖性变化可能暗示，早期的NO在低温相关的神经元保护和高温相关的神经元损伤中作为一个重要的临床标志物是有用的。