犬尿氨酸介导单核/巨噬细胞中枢浸润致术后认知功能障碍

术后认知功能障碍（POCD）可增加围术期发病率和死亡率，然而其发病机制不清。我们前期研究发现，老年小鼠麻醉和手术后肠道菌群失调是术后认知功能下降的关键。但其机制不明。预实验结果发现，肠道菌群失调致色氨酸代谢异常，血中犬尿氨酸（KYN）水平升高，老年小鼠麻醉和手术后中枢单核/巨噬细胞浸润明显增多，且星形胶质细胞分泌趋化因子CCL2增多。由此提出假说，麻醉和手术造成老年小鼠肠道菌群失调致色氨酸代谢异常，血中KYN升高，KYN进入中枢后致星形胶质细胞表达CCL2增加，KYN还可以促进外周单核/巨噬细胞对CCL2反应性增加，外周单核/巨噬细胞浸润中枢，加重中枢炎症，最终导致POCD。本研究拟采用野生型老年小鼠和相应的模式动物，建立经典胫骨骨折内固定模型，应用流式细胞术，质谱串联色谱蛋白质分析等经典手段证明上述假说。为临床上干预色氨酸代谢途径或者单核/巨噬细胞防治POCD，提高病人生活质量提供依据。

Postoperative cognitive impairment (POCD) can increase the incidence and mortality in perioperative period, but its pathogenesis is unclear. Our previous study found that postoperative intestinal flora imbalance induced by anesthesia and surgery is the key factor of postoperative cognitive decline in elderly mice. However, the mechanism is unclear. The results of pre experiment showed that after anesthesia and surgery, the imbalance of intestinal flora caused tryptophan metabolism abnormality; and KYN level in plasma increased. What’s more, monocyte / macrophage’s infiltration in central nerves system increased significantly after anesthesia and operation in aged mice, and chemokine CCL2 secreted by astrocytes increased. Therefore, it is hypothesized that anesthesia and surgery can cause intestinal flora imbalance in elderly mice, resulting in abnormal tryptophan metabolism, which increased KYN in blood, and increased CCL2 expression in astrocytes after KYN entering the center. KYN can also promote the response of peripheral monocytes / macrophages to CCL2, and increase the infiltration of peripheral monocytes / macrophages into the center, and aggravate central inflammation, and eventually lead to POCD. In this study, we used wild-type old mice and corresponding model animals to establish a classical tibial fracture internal fixation model. Flow cytometry, mass spectrometry and protein analysis were used to verify the above hypothesis. To provide the basis for clinical intervention in tryptophan metabolism pathway or monocyte / macrophage prevention and treatment of POCD, and improve the quality of life of patients.