Head injured patients are hypermetabolic, hypercatabolic, hyperdynamic, and manifest the a cute phase response. They have elevations of classic counter-regulatory hormones (e.g., catecholamines) which play an important role in the metabolic response to brain injury. These patients also have marked elevations in serum and ventricular fluid cytokines interleukin-1, tumor necrosis factor, and interleukin-6 as well as decreased plasma levels of the anabolic hormone insulin-like growth factor-1 (IGF-I). Many of the metabolic effects of cytokines also are clinical consequences of head injury (e.g., fever, neutrophilia, muscle catabolism, and increased hepatic acute phase reactants). We have [postulated that an imbalance between increases in proinflammatory catabolic cytokines and inadequate concentrations of the anabolic hormone IGF-I lead to many of the metabolic consequences of head injury. It is our hypothesis that the liver, the largest reservoir of tissue macrophages in the body, plays an important role in the increased cytokines and cytokine mediated complications/manifestations of head injury. In this study, we will use the electronically controlled pneumatic impactor rat model of brain injury to quantitate the time course and extent of increased cytokine production following head injury, the role of the liver and peripheral blood mononuclear cells in cytokine production, the time course and depression of IGF-I production, and the role of gut-derived endotoxin in stimulating these metabolic events. We next will evaluate the effects of brain injury on the development of liver injury and cholestasis using in vivo, in vitro, and isolated perfused liver models. We will investigate two potentially interactive mechanisms for increased cytokine production after brain injury: 1) increased intestinal permeability to gut-derived toxins which stimulate cytokines, 2) impaired Kupffer cell clearance of toxins which stimulate peripheral mononuclear cell cytokine production. Next, we will determine whether head injury, with increased cytokine activity and impaired RE function, predisposes to lethality in a model of sepsis. Finally, extensive preliminary data from our laboratory indicate that both brain injury and cytokines markedly alter the expression and regulation of hepatic drug metabolizing enzymes. Therefore, we will evaluate the effect of isolated brain injury in the rat on hepatic drug metabolism using molecular biology techniques in vitro as well as in vivo drug metabolism assays. These studies will provide new insights into the role of the liver in the metabolic a abnormalities/complications following head injury. Potential new therapies for these metabolic abnormalities/complications (e.g.,cytokine inhibition and growth factors) are available for testing in our model systems, and they may provide unique management options for head injured patients in the near future.

Project Start
1997-04-01
Project End
1998-03-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Type
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
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