DEEP HYPOTHERMIA THERAPY ATTENUATES LPS-INDUCED MICROGLIA NEUROINFLAMMATION VIA THE STAT3 PATHWAY
DEEP HYPOTHERMIA THERAPY ATTENUATES LPS-INDUCED MICROGLIA NEUROINFLAMMATION VIA THE STAT3 PATHWAY
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DOI：
10.1016/j.neuroscience.2017.06.055
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发表时间：
2017-09-01
期刊：
影响因子：
3.3
通讯作者：
Schmitt, K. R. L.
中科院分区：
文献类型：
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作者：
Tong, G.;Krauss, A.;Schmitt, K. R. L.
深低温治疗（HT）是在涉及体外循环和深低温心脏骤停的复杂小儿心脏手术中用于神经保护的标准方法。然而，该手术可引起全身炎症反应综合征（SIRS），这是小儿心脏手术相关的最严重副作用之一。迄今为止，深层HT诱导的细胞炎症机制仍有待阐明。因此，我们研究了深HT（17 ℃）和复温对脂多糖（LPS）刺激的BV-2小鼠小胶质细胞炎症反应的影响。此外，我们还研究了Stattic（一种信号转导和转录激活因子3（STAT 3）激活抑制剂）作为物理冷却的替代方法来减弱LPS诱导的炎症反应的应用。深HT没有细胞毒性作用，但衰减小胶质细胞迁移。hcBa降解被深度HT延迟，导致pNF-κ B p65迁移到细胞核中的减弱，促炎性IL-6、TNF-α和MCP-1表达和分泌显著降低，以及抗炎性IL-10和SOCS 3表达降低。此外，pStat 3在深低温条件下显著下调，也与IL-6和TNF-α表达的显著降低相对应。与HT的作用类似，在常温条件下应用Stattic导致IL-6和TNF-α表达显著降低。此外，炎症反应的衰减导致小胶质细胞和神经元的直接共培养中的细胞凋亡减少。HT降低LPS刺激的BV-2小胶质细胞的炎症反应，暗示治疗性脑缺血诱导的神经保护的可能机制。在未来，减弱磷酸化STAT 3通路可能会导致开发具有更大临床疗效的神经保护剂。(C)2017年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Deep hypothermia therapy (HT) is a standard method for neuroprotection during complex pediatric cardiac surgery involving extracorporeal circulation and deep hypothermic cardiac arrest. The procedure, however, can provoke systemic inflammatory response syndrome (SIRS), one of the most severe side effects associated with pediatric cardiac surgery. To date, the cellular inflammatory mechanisms induced by deep HT remain to be elucidated. Therefore, we investigated the effects of deep HT (17 degrees C) and rewarming on the inflammatory response in lipopolysaccharide (LPS) stimulated BV-2 murine microglia. Additionally, we also investigated the application of Stattic, a signal transducer and activator of transcription 3 (STAT3) activation inhibitor, as an alternative to physical cooling to attenuate the LPS-induced inflammatory response. Deep HT had no cytotoxic effect but attenuated microglia migration. hcBa degradation was delayed by deep HT resulting in the attenuation of pNF-kappa B p65 migration into the nucleus and significant decreases in pro-inflammatory IL-6, TNF-alpha, and MCP-1 expressions and secretions, as well as decreased anti-inflammatory IL-10 and SOCS3 expressions. Additionally, pStat3 was significantly down regulated under deep hypothermic conditions, also corresponding with the significant reduction in IL-6 and TNF-alpha expressions. Similar to the effects of HT, the application of Stattic under normothermic conditions resulted in significantly reduced IL-6 and TNF-alpha expressions. Moreover, attenuation of the inflammatory response resulted in decreased apoptosis in a direct co culture of microglia and neurons. HT reduces the inflammatory response in LPS-stimulated BV-2 microglial cells, alluding to a possible mechanism of therapeutic hypothermia-induced neuroprotection. In the future, attenuating the phospho-STAT3 pathway may lead to the development of a neuroprotectant with greater clinical efficacy. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.