Maresin1调节小胶质细胞极化改善脓毒症相关脑病的研究

During sepsis, the central nervous system (CNS) is one of the first organs affected, and this is clinically manifested as sepsis-associatedencephalopathy (SAE). It is associated with increased mortality and long-term cognitive impairments. The pathogenesis of SAE remains unclear and an effective treatment is lacking. Activated miroglia are considered to play a pivotal role in sepsis leading to cognitive dysfunction. Microglia have at least two polarized activation states: M1 polarization and M2 polarization. Inhibiting M1 polarization or inducing M2 polarization are involved in anti-inflammation and pro-resolving, which can mitigate the brain injury. Maresins are newly described macrophage-derived mediators during inflammation resolution. Maresin 1 was found to possess potent anti-inflammatory and pro-resolving properties through multiple mechanisms. Therefore, we hypothesize that Maresin1 can improve SAE by modulating microglia polarization. In this study, we will test this hypothese and explore the molecular mechanisms.

脓毒症相关脑病（sepsis-associate encephalopathy, SAE）是脓毒症的严重并发症，出现脑病的脓毒症病人病死率显著增加，幸存者也常遗留神经功能缺损。SAE发病机制尚不明确，且缺乏针对性的治疗措施，有研究认为小胶质细胞激活是脓毒症引起脑功能障碍的关键机制。小胶质细胞存在两种极化的激活状态，M1极化和M2极化，抑制M1极化和诱导M2极化都可以降低炎症反应强度，促进炎症消退和组织修复，减轻神经损伤。Maresin1（MaR1）是由巨噬细胞合成的促炎症消退介质，可以从多个环节减轻炎症反应强度，促进炎症消退。我们提出假设，MaR1可以调节小胶质细胞M1/M2极化，从而减轻神经系统炎症反应，改善SAE。本项目拟于大鼠脓毒症模型和小胶质细胞上，观察MaR1的内源性表达并研究外源性给予MaR1能否调节小胶质细胞极化，减轻中枢神经系统炎症反应，改善SAE，并探讨其可能机制。

脓毒症及其相关并发症是ICU病人的主要致死原因之一。ICU脓毒症患者中 8%-70%会出现脓毒症相关脑病，重度脑病的病人病死率显著升高，幸存者也常遗留神经功能缺损。近年来，一类特殊的促消退介质受到了高度关注，他们抑制炎症反应强度，促进炎症消退，是炎症反应的“刹车信号”，各种离体和在体炎症模型中发挥了强大的抗炎和促消退作用。本研究基于以上临床问题，研究促炎症消退介质对脓毒症引起的中枢神经系统炎症反应及脓毒症相关脑病的保护作用及其相关机制的研究。.研究结果显示：（1）LPS腹腔注射可以导致中枢神经系统炎症反应介质升高和行为学改变，成功构建脓毒症相关脑病模型；（2）促炎症消退介质消退素D1可以显著减轻LPS引起的中枢神经系统炎症（大脑皮质和海马）反应，抑制小胶质细胞M1活化，并且对LPS导致的行为学改变（freezing time延长）有改善作用。但对M2活化无明显影响。（3）较大剂量的消退素D1可以减少LPS引起的IκB-α降解， 减少p65亚基表达和DNA结合活性，抑制M1活化相关信号通路的激活。（4）促炎症消退介质Maresin1可以抑制脓毒症小鼠中枢神经系统炎症介质表达，抑制小胶质细胞M1活化；促进脓毒症小鼠中枢神经系统小胶质细胞M2活化标志物表达，促进M2活化。.目前的研究结果表明，促炎症消退介质可以抑制脓毒症小鼠中枢神经系统炎症反应，促进中枢神经系统小胶质细胞M2活化，从而达到抗炎和促炎症消退的作用，改善脓毒症小鼠导致的行为学改变，为研究脓毒症脑病的可能治疗方向提供理论依据。