ResolvinD1介导的炎症主动消散在术后认知功能障碍中的作用及机制研究

Peripheral surgery-induced neuroinflammation and accumulation of β-amyloid（Aβ）play important roles in pathological progression of postoperative cognitive dysfunction (POCD). Previous studies suggest that inhibition of peripheral inflammation can lead to attenuation of neuroinflammation；and increasing clearance of peripheral Aβ can lead to increase in Aβ efflux and clearance from CNS. Altered resolution of inflammation is reported to be involved in pathogenesis of neuroinflammation related neurodegenerative diseases, which suggests its possible involvement in POCD pathogenesis as well. Resolvin D1(RvD1), a important member of specialized pro-resolving mediators, successfully inhibited peripheral inflammation and neuroinflammation, reduced Aβ accumulation in brain, and controlled disease progression in our POCD mouse model. In this study we will, based on the corresponding animal models, investigate if regulation of RvD1-ALX pathway, by exogenous compounds or cell-specific gene knockout, can promote macrophage/monocyte phagocytosis of apoptotic inflammatory cells and peripheral Aβ, shift them into anti-inflammatory subtype, contribute to resolution of peripheral inflammation, and thereby control the neuroinflammation and activation status of glial cells, eventually ameliorate the cognitive impairment. This study would help us to better understand the pathogenesis and pathological progression of POCD, and thus provide safer and more efficient therapeutic targets and options against POCD.

神经中枢炎症和β淀粉样蛋白（Aβ）的异常聚集被认为是术后认知功能障碍（POCD）重要的病理机制。现有报道和我们的前期研究提示：抑制外周炎症能间接控制中枢炎症，外周Aβ的清除也能促进脑内Aβ的外流和减少。炎症主动消散的异常被证实与中枢炎症相关的神经系统疾病有关，提示能参与POCD的病理过程。申请者发现特异性促炎症消散介质家族中的重要成员resolvin D1（RvD1）能同时抑制外周和中枢炎症、减少脑内Aβ，进而控制POCD的发展。本课题拟基于相应的动物模型，采用外源药物干预和条件性基因敲除等方法，探讨能否通过RvD1-ALX通路干预内源性炎症调节，促进外周单核/巨噬细胞吞噬Aβ和凋亡炎症细胞，缓解外周炎症，进而抑制中枢炎症并调控胶质细胞的激活状态，最终改善认知障碍。本研究将进一步完善POCD的病因和病理机制，特别是与炎症主动消散的内在联系，最终为POCD的治疗提供新的思路。

神经中枢炎症和β淀粉样蛋白（Aβ）的异常聚集被认为是术后认知功能障碍（POCD/PND）等一系列中枢神经系统疾病的重要病理机制。现有报道和我们的前期研究提示：对外周的炎症抑制可以间接控制中枢炎症，而清除外周Aβ能促进脑内Aβ的外流和减少。炎症主动消散机制的异常被证实与中枢炎症的相关神经系统疾病有关，而被提示可能参与POCD/PND等的病理过程。我们发现特异性促炎症消散介质家族中重要的一员ResolvinD1（RvD1）能通过抑制外周炎症而缓解中枢炎症、减少脑内Aβ，而控制POCD/PND等的发展。首先我们通过使用激动剂RvD1，抑制剂BOC-1，干扰RNA等调控RvD1-ALX通路能能够有效地增强外周单核/巨噬细胞胞葬凋亡细胞，吞噬外周Aβ，并向抗炎型极化，促进外周炎症消散，进而间接减少中枢Aβ聚集、抑制中枢炎症进展。同时调控RvD1-ALX通路也能直接作用于中枢小胶质细胞，并加强Aβ吞噬，直接改善中枢炎症消散，进而缓解认知障碍。但是外周用药可以更加便利和有效地同时促进外周和中枢炎症的主动消散，减少外周和中枢的Aβ聚集，从而也验证了Aβ外周储存槽效应。进而，我们通过对原代巨噬细胞、野生型小鼠疾病模型、转基因小鼠APP/PS1和FPR2条件性敲除鼠等，筛选出PPAR-γ/P-STAT6等通路进行干预，在细胞和动物层面通过激动/抑制剂进行调控，反复验证其对巨噬细胞吞噬Aβ的作用，进而影响外周Aβ清除和中枢Aβ聚集，从而减轻中枢炎症及小胶质细胞异常激活，最终对POCD/PND等相关神经病理改变和认知功能障碍的影响。我们还通过对于通路相关蛋白、促炎/抑炎因子、巨噬细胞吞噬能力、Aβ中枢聚集、行为学等方面进行研究，探索了更多的外周和中枢炎症的交互关系，神经炎症的直接、间接抑制和促消散，其他神经胶质细胞可能的参与作用等等，补充和完善了POCD/PND等一系列神经系统病变的病因和病理发展机制，这些结果也能进一步地为临床预防和治疗包括POCD/PND在内的一系列具有类似神经病理变化和认知功能障碍的相关疾病提供了更安全有效的治疗思路和方法。