Striking randomly, traumatic brain injury (TBI) is a """"""""silent epidemic"""""""" which affects two to four million persons each year. The consequences of TBI in these patients, having a mean age of 29.5 years, pose a tremendous loss to family and society in terms of potential productive years of life. Unfortunately, no effective therapies for human head injury are available. The injury to the CNS can be categorized as either primary or secondary. Primary injury results from immediately physical damage as a consequence of trauma and is difficult, it not impossible, to prevent. Secondary injuries are delayed pathological events occurring within minutes, hours, or days after the primary trauma and lead to further damage of the nervous system. Inflammatory responses are major components of secondary injury and are thought to be key contributors to TBI pathophysiology. Prostaglandins, potent mediators of inflammation, are produced via the action of cyclooxygenase-1 and 2 [Cox-1 and COX-2, also known as PGH synthase 1 and 2]. Cox-1 is constitutively expressed in most tissue and is responsible for the physiological production of prostaglandins. In contrast, COX-2 is inducible and is responsible for the elevated production of prostaglandins. A considerable amount of evidence from several experimental systems indicates that COX-2 plays a critical role in inflammation. However, the mechanism(s) of inflammatory responses following TBI has not been elucidated. Our preliminary studies indicate that enhanced Cox-2 expression is associated with experimental TBI. Based on these and other findings, the proposal has three specific aims: (1) to test the hypothesis that induction of Cox-2 contributes to TBI pathophysiology, (2) to test the hypothesis that TBI-induced activation of NFkappaB [nuclear factor kappa B], ATF [activating transcription factor], and/or C/EBP [CCAAT/enhancer binding protein] lead to Cox-2 induction; and (3) to test the hypothesis that the anti- inflammatory agents methylprednisolone and IL-10 attenuate Cox-2 expression. The experiments outlined in this proposal will provide a unique opportunity to both unravel the cellular and molecular mechanisms of TBI- induced inflammation and provide the foundation for therapeutic strategies which will be invaluable in the treatment of TBI.
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