Traumatic brain injury (TBI) initiates a cascade of inflammatory processes that can serve to exacerbate the initial injury. Recent experimental data indicate that post-traumatic temperature manipulations significantly influence the inflammatory responses, including the accumulation of polymorphonuclear leukocytes (PMNL) and inducible nitric oxide synthase activity. The proposed studies will build on these previous results and investigate the cellular, biochemical, and molecular mechanisms underlying the temperature-sensitive inflammatory events seen after TBI.
Three specific aims are proposed that focus on specific questions regarding this investigative issue. In the first specific aim, experiments will focus on inducers of post-traumatic inflammation, with emphasis on inflammatory cytokines. These investigations will determine the importance of injury severity on the cytokine response to TBI as well as determining for the first time the effects of post-traumatic temperature manipulations of these inflammatory inducers. In the second aim, we will investigate the primary actions of these inflammatory molecules on stress signals, including p38 mitogen-activated protein kinase, the transcriptional factor, NF-kB, as well as the expression of endothelial adhesion molecules (ICAM-1, P-selectin). These studies are felt to be important because they will determine whether post-traumatic hypothermia in contrast to affecting the production and release of the pro-inflammatory cytokines, have a primary effect on secondary signaling pathways. In the final aim, we will determine the differential effects of hypothermia on selective aspects of the inflammatory cascade. For this aim, transgenic and knockout mice will be investigated under normothermic and hypothermic conditions. These studies will target injury processes investigated in Aims I and II and assess both the acute and more chronic structural and functional consequences of specific injury processes in hypothermia protection. Established quantitative methods of ELISA's, histophatological analysis, in situ hybridization, molecular techniques, as well as a large battery of behavioral tasks in rats and mice, will be used to complement the overall proposal. This new approach to trauma research should provide important data concerning interactions between inflammatory processes and temperature.
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