Cellular and molecular mechanisms of glial scarring and progressive cavitation: In vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma
Mt. Fitch et al., Cellular and molecular mechanisms of glial scarring and progressive cavitation: In vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma, J NEUROSC, 19(19), 1999, pp. 8182-8198
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.