非细菌性内毒素动物模型中系统性炎症对神经炎症影响的证据
Evidence of the impact of systemic inflammation on neuroinflammation from a non-bacterial endotoxin animal model
背景与目的：
系统性炎症会诱发神经炎症和细胞变化，如tau蛋白磷酸化作用，损害认知功能，包括学习和记忆。这项研究使用了一个单一的模型，用剖腹手术来表示这些变化以及它们在此阶段对抗炎治疗的反应。
1
方法：
一项分为两部分的实验中，野生型 C57BL/6N 小鼠（雄性，3个月大，25 ±2克）分别接受了七氟醚麻醉或剖腹手术。在术后的第（POD）1、3和14天中评估了认知能力、系统和神经炎症反应以及tau蛋白磷酸化。然后评估了围手术期布洛芬干预（60 mg/kg）对这些变化的影响。
结果：
在剖腹手术组中，小鼠到术后第14天表现出记忆障碍，在肝脏、额叶皮质（IL-1β、IL-6和 TNF-α）和海马体(IL-1β 和 IL-8)中有大量的炎性细胞因子。在术后第14天，尽管大多数循环和细胞因子水平恢复正常，但在额叶皮质和海马体仍然活跃着大量的星形胶质细胞和小胶质细胞，以及这两个脑区异常的tau蛋白磷酸化。围手术期使用布洛芬提高了认知能力，减弱了系统性炎症和神经胶质的活化，抑制了额叶皮质和海马区异常的tau蛋白磷酸化。
结论：我们的研究结果表明（1）认知功能障碍与不平衡的促炎和抗炎反应、tau蛋白病变和胶质细胞增多有关;（2）在剖腹手术后，认知功能障碍、胶质细胞增多和tau蛋白病变的持续时间远远超过术后的时间;（3）抗炎药可以迅速降低大脑的炎症反应，并对神经病变进行负面调节，以提高认知能力。这些发现可能对治疗的持续时间有影响，这些治疗策略旨在改善手术后的认知功能障碍。
Abstract
Background: Systemic inflammation induces neuroinflammation and cellular changes such as tau phosphorylation to impair cognitive function, including learning and memory. This study uses a single model, laparotomy without any pathogen, to characterize these changes and their responses to anti-inflammatory treatment in the intermediate term. Methods: In a two-part experiment, wild-type C57BL/6N mice (male, 3 month old, 25 2 g) were subjected to sevoflurane anesthesia alone or to a laparotomy. Cognitive performance, systemic and neuroinflammatory responses, and tau phosphorylation were evaluated on postoperative days (POD) 1, 3, and 14. The effect of perioperative ibuprofen intervention (60 mg/kg) on these changes was then assessed. Results: Mice in the laparotomy group displayed memory impairment up to POD 14 with initial high levels of inflammatory cytokines in the liver, frontal cortex (IL-1β, IL-6, and TNF-α), and hippocampus (IL-1β and IL-8). On POD 14, although most circulating and resident cytokine levels returned to normal, a significant number of microglia and astrocytes remained activated in the frontal cortex and microglia in the hippocampus, as well as abnormal tau phosphorylation in these two brain regions. Perioperative ibuprofen improved cognitive performance, attenuated systemic inflammation and glial activation, and suppressed the abnormal tau phosphorylation both in the frontal cortex and hippocampus. Conclusions: Our results suggest that (1) cognitive dysfunction is associated with an unbalanced pro-inflammatory and anti-inflammatory response, tauopathy, and gliosis; (2) cognitive dysfunction, gliosis, and tauopathy following laparotomy can persist well beyond the immediate postoperative period; and (3) anti-inflammatory drugs can act rapidly to attenuate inflammatory responses in the brain and negatively modulate neuropathological changes to improve cognition. These findings may have implications for the duration of therapeutic strategies aimed at curtaining cognitive dysfunction following surgery.
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