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The Journal of Neuroscience, October 1, 1999, 19(19):8182-8198
Cellular and Molecular Mechanisms of Glial Scarring and Progressive Cavitation: In Vivo and In Vitro Analysis of Inflammation-Induced Secondary Injury after CNS Trauma
Michael T. Fitch1, Catherine Doller1, Colin K. Combs2, Gary E. Landreth2, and Jerry Silver1 1 Department of Neurosciences and 2 Alzheimer Research Laboratory, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
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 vitro model 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
2-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-
may be therapeutic in preventing progressive cavitation by limiting inflammation and subsequent secondary damage after CNS injury.
Key words: chondroitin sulfate proteoglycan; inflammation; gliosis; microglia; macrophage; astrocyte; injury; trauma; regeneration; necrosis; cavitation; mannose receptor; CR3;
Copyright © 1999 Society for Neuroscience 0270-6474/99/19198182-17$05.00/0
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