The role of the complement cascade in endotoxin-induced septic encephalopathy
The role of the complement cascade in endotoxin-induced septic encephalopathy
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DOI：
10.1038/labinvest.3700686
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发表时间：
2007-12-01
影响因子：
5
通讯作者：
Alexander, Jessy J.
中科院分区：
文献类型：
--
作者：
Jacob, Alexander;Hensley, Lauren K.;Alexander, Jessy J.
补体系统通常可以消灭细菌并具有保护作用。然而，在脓毒症等炎症环境中，该级联的过度激活或不充分激活可能会通过神经胶质细胞的激活、促炎细胞因子的分泌和其他有毒产物的产生而产生有害影响。本研究的目的是通过向过度表达强效补体抑制剂 CR1 相关 y (Crry-tg) 的小鼠被动注射内毒素/脂多糖 (LPS) 来研究补体级联在脓毒症脑病中的作用。内毒素血症小鼠大脑中神经胶质增生增加。与此同时，这些大脑中 GFAP、CD45 和促炎分子、TLR4、TNF-α 和 NO 的 mRNA 表达显着增加。与这些炎症介质的能力一致，根据 LPS 处理的 DNA 碎片和 TUNEL 染色测定，细胞凋亡增加，这是通过 Akt 途径发生的。此外，大脑中的水含量增加，类似于脓毒症中观察到的脑水肿。相对于野生型小鼠，补体抑制小鼠的炎症反应减弱，水肿减少，细胞凋亡减少。因此，我们首次证明补体级联似乎是在内毒素血症环境中引起脑病理学的关键因素之一，因此是可行的治疗靶点。
The complement system normally eliminates bacteria and has a protective effect. However, in an inflammatory setting such as sepsis, an exaggerated or insufficient activation of this cascade can have deleterious effect through the activation of glial cells, secretion of proinflammatory cytokines and generation of other toxic products. The aim of the present study was to investigate the role of the complement cascade in septic encephalopathy, through the passive injection of endotoxin/lipopolysaccharide (LPS) into mice overexpressing the potent complement inhibitor, CR1-related y (Crry-tg). Increased gliosis occurred in brains of endotoxemic mice. Concomitant with this, there was a significant rise in mRNA expression of GFAP, CD45 and proinflammatory molecules, TLR4, TNF-alpha and NO, in these brains. Consistent with the capacity of these inflammatory mediators, there was increased apoptosis as determined by DNA fragmentation and TUNEL staining on LPS treatment, which occurred through the Akt pathway. In addition, there was increased water content in brain, similar to cerebral edema observed in sepsis. Relative to wild-type mice, complement-inhibited mice had an attenuated inflammatory response, decreased edema and reduced apoptosis. Therefore, we demonstrate for the first time that the complement cascade appears to be one of the key players that cause brain pathology in an endotoxemic setting and therefore is a viable therapeutic target.