Cellular and Molecular Mechanisms of Glial Scarring and Progressive Cavitation: In Vivo and In VitroAnalysis of Inflammation-Induced Secondary Injury after CNS Trauma
Cellular and Molecular Mechanisms of Glial Scarring and Progressive Cavitation: In Vivo and In VitroAnalysis of Inflammation-Induced Secondary Injury after CNS Trauma
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DOI：
10.1523/jneurosci.19-19-08182.1999
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发表时间：
1999-10
期刊：
影响因子：
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通讯作者：
M. Fitch;C. Doller;C. Combs;G. Landreth;J. Silver
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文献类型：
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作者：
M. Fitch;C. Doller;C. Combs;G. Landreth;J. Silver
创伤后囊性空洞，其中CNS损伤的大小和严重程度从小面积的直接创伤发展为被胶质瘢痕组织包围的极大扩大的继发性损伤，是脑和脊髓损伤的一种知之甚少的并发症。使用微创技术，以避免原发性物理损伤，这项研究表明，在体内，炎症过程单独启动级联的继发性组织损伤，进行性空化，神经胶质瘢痕形成的中枢神经系统。体外模型使我们能够测试这一假设，即刺激巨噬细胞炎症激活的特定分子是引发继发性神经病理学的重要步骤。在我们的体外模型中，对炎症诱导的空化进行的延时视频分析显示，这一过程主要是通过以前未描述的细胞机制发生的，该机制涉及星形胶质细胞的形态学变化和快速迁移。空化的物理过程导致星形胶质细胞放弃神经元突起、神经突伸展和继发性损伤。巨噬细胞甘露糖受体和补体受体3型β 2-整联蛋白参与诱导空洞和瘢痕形成的级联反应。我们还证明，通过核激素受体过氧化物酶体增殖物激活受体-γ调节转录的抗炎剂可能通过限制炎症和CNS损伤后的继发性损伤来预防进行性空化。
Post-traumatic cystic cavitation, in which the size and severity of a CNS injury progress from a small area of direct trauma to a greatly enlarged secondary injury surrounded by glial scar tissue, is a poorly understood complication of damage to the brain and spinal cord. Using minimally invasive techniques to avoid primary physical injury, this study demonstrates in vivo that inflammatory processes alone initiate a cascade of secondary tissue damage, progressive cavitation, and glial scarring in the CNS. An in vitromodel allowed us to test the hypothesis that specific molecules that stimulate macrophage inflammatory activation are an important step in initiating secondary neuropathology. Time-lapse video analyses of inflammation-induced cavitation in our in vitro model revealed that this process occurs primarily via a previously undescribed cellular mechanism involving dramatic astrocyte morphological changes and rapid migration. The physical process of cavitation leads to astrocyte abandonment of neuronal processes, neurite stretching, and secondary injury. The macrophage mannose receptor and the complement receptor type 3 β2-integrin are implicated in the cascade that induces cavity and scar formation. We also demonstrate that anti-inflammatory agents modulating transcription via the nuclear hormone receptor peroxisome proliferator–activated receptor-γ may be therapeutic in preventing progressive cavitation by limiting inflammation and subsequent secondary damage after CNS injury.