Role of interleukin-1beta in postoperative cognitive dysfunction.
Role of interleukin-1beta in postoperative cognitive dysfunction.
复制标题
白介素-1β在术后认知功能障碍中的作用。
DOI：
10.1002/ana.22082
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发表时间：
2010-09
影响因子：
11.2
通讯作者：
Maze M
中科院分区：
文献类型：
--
作者：
Cibelli M;Fidalgo AR;Terrando N;Ma D;Monaco C;Feldmann M;Takata M;Lever IJ;Nanchahal J;Fanselow MS;Maze M
虽然术后认知功能障碍(POCD)经常使大手术后的康复复杂化，但其发病机制仍不清楚。在骨科手术的小鼠模型中，我们探索了全身炎症是否对手术创伤的反应，触发了海马区炎症和随后的记忆障碍。C57BL/6J、缺失IL-1受体、IL-1R−/−基因敲除小鼠和野生型小鼠在全身麻醉下进行胫骨手术。通过恐惧条件反射测试对不同的动物队列进行记忆功能测试，或在不同时间实施安乐死，以评估全身和海马区细胞因子以及小胶质细胞的激活水平；还评估了旨在阻断炎症(特定和非特定)的干预措施的效果。手术导致了海马区依赖的记忆障碍，这与血浆细胞因子的增加以及反应性小胶质细胞增生和海马区IL-1β的转录和表达有关。米诺环素对天然免疫的非特异性抑制可防止手术引起的改变。在用IL-1受体拮抗剂预先处理的小鼠和IL-1Rβ小鼠中，对IL-1−/−的功能抑制都可以减轻手术和记忆障碍的神经炎性效应。外周手术诱导的先天性免疫反应在海马区触发了IL-1β介导的炎症过程，这是记忆障碍的基础。这可能是阻断术后认知功能障碍发病机制的一个可行靶点。
Although postoperative cognitive dysfunction (POCD) often complicates recovery from major surgery, the pathogenic mechanisms remain unknown. We explored whether systemic inflammation, in response to surgical trauma, triggers hippocampal inflammation and subsequent memory impairment, in a mouse model of orthopedic surgery. C57BL/6J, knock out (lacking interleukin [IL]-1 receptor, IL-1R−/−) and wild type mice underwent surgery of the tibia under general anesthesia. Separate cohorts of animals were tested for memory function with fear conditioning tests, or euthanized at different times to assess levels of systemic and hippocampal cytokines and microglial activation; the effects of interventions, designed to interrupt inflammation (specifically and nonspecifically), were also assessed. Surgery caused hippocampal-dependent memory impairment that was associated with increased plasma cytokines, as well as reactive microgliosis and IL-1β transcription and expression in the hippocampus. Nonspecific attenuation of innate immunity with minocycline prevented surgery-induced changes. Functional inhibition of IL-1β, both in mice pretreated with IL-1 receptor antagonist and in IL-1R−/− mice, mitigated the neuroinflammatory effects of surgery and memory dysfunction. A peripheral surgery-induced innate immune response triggers an IL-1β-mediated inflammatory process in the hippocampus that underlies memory impairment. This may represent a viable target to interrupt the pathogenesis of postoperative cognitive dysfunction.