Cellular and molecular mechanisms of glial scarring and progressive cavitation: In vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma

Post-traumatic cystic cavitation, in which the size and severity of a CNS i njury progress from a small area of direct trauma to a greatly enlarged sec ondary injury surrounded by glial scar tissue, is a poorly understood compl ication of damage to the brain and spinal cord. Using minimally invasive te chniques to avoid primary physical injury, this study demonstrates in vivo that inflammatory processes alone initiate a cascade of secondary tissue da mage, progressive cavitation, and glial scarring in the CNS. An in vitro mo del allowed us to test the hypothesis that specific molecules that stimulat e macrophage inflammatory activation are an important step in initiating se condary neuropathology. Time-lapse video analyses of inflammation-induced c avitation in our in vitro model revealed that this process occurs primarily via a previously undescribed cellular mechanism involving dramatic astrocy te morphological changes and rapid migration. The physical process of cavit ation leads to astrocyte abandonment of neuronal processes, neurite stretch ing, and secondary injury. The macrophage mannose receptor and the compleme nt receptor type 3 beta 2-integrin are implicated in the cascade that induc es cavity and scar formation. We also demonstrate that anti-inflammatory ag ents modulating transcription via the nuclear hormone receptor peroxisome p roliferator-activated receptor-gamma may be therapeutic in preventing progr essive cavitation by limiting inflammation and subsequent secondary damage after CNS injury.