The metabolic response to infection/injury has many components which may be viewed as beneficial from the perspective of the host. These involve the development of specific immune responses at the site of tissue damage, limitation of the magnitude of normal tissue injury, and promotion of wound healing but also include a wide range of putatively beneficial metabolic responses such as fever, host protein and mineral redistribution, whole body protein turnover and energy expenditure, and acute phase protein synthesis. Substantial evidence has accumulated that most, and probably all, of these response can be mimicked by the administration of a biologically derived, partially purified protein, interleukin 1 or LEM. Murine and human recombinant interleukin 1 and human tumor necrosis factor, both of the latter being present in LEM, are now available for testing and preliminary work suggests that both proteins are involved in the LEM response. However, tumor necrosis factor is also one of the principal mediators of the lethal effect of endotoxin. In the anterior hypotholamus and in skeletal muscle LEM induces the synthesis of prostoglandin E2 which mediates fever and skeletal protein catabolism, which inhibition of prostaglandin synthesis by ibuprofen attenuates. An alternative means to affect prostanoid metabolism and the metabolic response to infection/injury is to alter the substrate pool of the more usual omega 6 fatty acids (linoleic and arachidonic) found in vegetable oils to omega 3 fatty acids (eicosopentaenoic and docosahexaenoic) found in certain fish oils. The scientific design of this proposal provides experiments to 1) document in a mammalian model the metabolic effects of individual recombinant products that are components of LEM, 2) determine if the individual responses to human and mouse recombinant interleukin 1 and tumor necrosis factor, and the overall LEM response can be altered by dietary lipid manipulation and 3) investigate the effect of natural models of injury/infection on the LEM response and its potential alteration by dietary lipids. The significance of this application stems not only from its potential to increase our knowledge of the basic biology of the metabolic response to injury and infection, but also the potential practical application of this information to the treatment of protein malnourished patients undergoing surgical injury or susceptible to bacterial infections.
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