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Tumor Necrosis Factor &agr; Expression and Protein Levels after Fluid Percussion Injury in Rats: The Effect of Injury Severity and Brain Temperature

OBJECTIVE:Tumor necrosis factor &agr; (TNF&agr;) is elevated in some models of traumatic brain injury (TBI). However, it is unclear how TNF&agr; messenger ribonucleic acid (mRNA) expression and protein levels are affected by injury severity and posttraumatic temperature modification. This study determined the regional and temporal profile of TNF&agr; levels after moderate and severe TBI and assessed the effects of posttraumatic hypothermia or hyperthermia on this proinflammatory cytokine. METHODS:Adult male Sprague-Dawley rats were subjected to sham procedures (no injury), moderate fluid-percussion TBI (1.8–2.2 atm), or severe fluid-percussion TBI (2.4–2.6 atm). After 1 to 72 hours of survival, animals were killed, and brain samples, cerebrospinal fluid, and serum were harvested for enzyme-linked immunosorbent assay quantification of TNF&agr; levels. In a subsequent study, a 3-hour period of post-traumatic hypothermia (33°C) or hyperthermia (39.5°C) was applied, followed by immediate killing and cytokine assay. Another group was subjected to moderate TBI (1.8–2.2 atm), followed by killing at 15 minutes or at 1, 3, or 24 hours for TNF&agr; reverse transcriptase-polymerase chain reaction analysis. RESULTS:A significant increase in TNF&agr; mRNA and protein levels in cellular lysates of injured cortex and ipsilateral hippocampus was noted by 1 hour after TBI; it was sustained to 3 hours, followed by a rapid decline. Increased injury severity was associated with increased protein levels at remote injury sites and in the injured cerebral cortex at 72 hours. Posttraumatic hypothermia significantly reduced TNF&agr; mRNA expression in the hippocampus compared with that in normothermic rats. In contrast, no temperature effects on TNF&agr; protein levels were documented. CONCLUSION:Rapid and marked increase in TNF&agr; mRNA expression and protein levels follows moderate and severe TBI. Injury severity and posttraumatic temperature play a modest but significant role on TNF&agr; expression and protein levels. These findings suggest that the effects of posttraumatic temperature on histopathological and behavioral outcome primarily may involve secondary mediators that do not operate directly through their effect on TNF&agr;.