抑制补体C3/C3aR信号可改善新生大鼠脑生发基质出血后脑积水  

Inhibition of complement C3/C3aR alleviates hydrocephalus following germinal matrix hemorrhage in neonatal rats

作　　者：耿军军 唐俊 王莉莉 谭强 张建波 张波[1] 王玲 魏林节 陈志 朱刚 GENG Junjun;TANG Jun;WANG Lili;TAN Qiang;ZHANG Jianbo;ZHANG Bo;WANG Ling;WEI Linjie;CHEN Zhi;ZHU Gang(Department of Neurosurgery,First Affiliated Hospital,Army Medical University(Third Military Medical University),Chongqing,400038;Department of Emergency,First Affiliated Hospital,Air Force Medical University,Xi’an,Shaanxi Province,710032,China)

机构地区：[1]陆军军医大学(第三军医大学)附属第一医院神经外科,重庆400038 [2]空军军医大学附属第一医院急诊科,西安710032

出　　处：《第三军医大学学报》2019年第22期2137-2145,共9页Journal of Third Military Medical University

基　　金：国家自然科学基金青年科学基金(81601356)、面上项目(81571116);军事医学科技创新计划(SWH2017YBXM-19)~~

摘　　要：目的研究补体C3/C3aR信号介导的小胶质细胞-星型胶质细胞交互作用对新生大鼠脑生发基质出血(germinal matrix hemorrhage,GMH)后脑积水的影响。方法检测胶原酶(Ⅶ-S型)诱导新生大鼠GMH后脑室周围C3和C3aR的表达。给予GMH大鼠C3aR拮抗剂(complement C3 receptor antagonist,C3aRA)处理,观察C3aRA对大鼠脑积水(MRI检查)、学习记忆功能(水迷宫实验)和炎症反应(IL-1β、IL-6、TNF-α、TGF-β1和水通道蛋白4)的影响。结果 GMH后脑室周围补体C3和C3aR表达上调,炎症因子IL-1β、IL-6、TNF-α、TGF-β1表达增加,星形胶质细胞表面的水通道蛋白4异位表达且表达增加,脑室扩张,脑皮质和海马受压,大鼠学习记忆功能下降。阻断C3/C3aR信号后,相应C3、C3aR表达减低,炎症因子分泌减少,脑室扩张程度及皮层/海马受压减轻,大鼠神经功能明显改善。结论 GMH后星形胶质细胞上调并释放C3, C3与小胶质细胞表面的C3aR结合促进炎症反应,加重脑积水。星形胶质细胞表面水通道蛋白4的异位表达可能对GMH后脑积水产生起重要作用。Objective To investigate the effect of astrocyte-microglia crosstalk mediated by complement C3/C3 aR signaling on hydrocephalus after germinal matrix hemorrhage(GMH) in newborn rats. Methods GMH was induced in post-natal day 7 SD rats by collagenase Ⅶ-S injection into the ganglionic eminence. We detected the changes in the expression of periventricular C3 and C3 aR over time after GMH, and observed the effect of intraperitoneal injection of C3 aRA(a selective C3 aR antagonist) on hydrocephalus using magnetic resonance imaging(MRI). The learning and memory functions of the rats were tested after the treatment using Morris water maze test, and the expression of interleukin-1β(IL-1β), IL-6, tumor necrosis factor-α(TNF-α), transforming growth factor-β1(TGF-β1) and aquaporin 4 in the brain tissues were detected using Western blotting at different time points after GMH. Results The neonatal rats with GMH showed significantly up-regulated expression of C3 and C3 aR around the cerebral ventricles and increased expression of IL-1β, IL-6, TNF-α and TGF-β1 in the brain, presenting also with obvious lateral ventricle dilation, compression of the cortex and hippocampus, and impairment of the learning and memory functions. Treatment of the rats with C3 aRA obviously decreased C3 and C3 aR expression, alleviated hydrocephalus, improved the neurological deficits, and reduced the expression of the inflammatory factors in the brain. GMH caused obvious ectopic expression of aquaporins 4 and increased its expression level on the astrocytes, and C3 aRA treatment significantly improved the abnormal expression of aquaporins 4. Conclusion GMH causes the astrocytes to up-regulate and release C3, which binds to C3 aR on the microglia to promote inflammation and aggravate hydrocephalus. The ectopic expression of aquaporin 4 in astrocytes may play an important role in the occurrence of hydrocephalus following GMH.

关 键 词：生发基质出血 脑积水 C3/C3aR信号 星形胶质细胞 小胶质细胞 水通道蛋白4 大鼠 新生 

分 类 号：R-322[医药卫生] R392.32