The role of inflammation in secondary pathology following central nervous system injury

Injury to the adult mammalian central nervous system leads to a complex series of cellular and molecular reactions as damaged tissue attempts to repair, reorganize, and restore normal physiological functions. For over a century, scientists have conducted experiments investigating the wound healing responses of the brain and spinal cord in an effort to understand why the central nervous system does not repair itself efficiently after traumatic injury. The experiments presented in this thesis demonstrate that inflammation plays a key role in the secondary pathological changes which are seen in the central nervous system following trauma. The results illustrate the upregulation of extracellular matrix molecules in the presence of post-traumatic inflammatory infiltrates, and document the association of inhibitory proteoglycans with the borders of enlarging cavities in the brain and spinal cord. Utilizing 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 central nervous system. An in vitro model is described which shows that macrophage inflammatory activation initiates secondary neuropathology. A novel mechanism of inflammation-induced cavitation is described using time-lapse video analysis which shows astrocyte morphological changes and migration that lead to astrocyte abandonment of neuronal processes, neurite stretching, and secondary injury. The macrophage mannose receptor and the CR3 beta2-integrin are implicated in the cascade which induces cavity and scar formation. Finally, a potential new anti-inflammatory therapeutic treatment has been proposed to minimize post-traumatic inflammatory damage utilizing agonists to the PPAR-gamma nuclear hormone receptor. These studies demonstrate the destructive effects of persistent inflammation in the development of secondary pathology within the central nervous system, and provide encouraging results that suggest that modulation of the acute inflammatory response may be an important therapeutic target for preventing detrimental responses to injury in the central nervous system.