The metabolic response to infection/injury has many components which may be viewed as beneficial from the perspective of the host. These include 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, increased gluconeogenesis, host protein, and mineral redistribution, and acute phase protein synthesis. Substantial evidence has accumulated that most, and probably all of these responses, can be mimicked by the administration of a biologically derived, partially purified protein, interleukin I or LEM. Recombinant interleukin I (IL-I) and tumor necrosis factor (TNF) which are present in LEM can also produce most elements of the response, particularly when co-infused. Furthermore, highly purified soluble and particulate glucan or beta-1, 3-glucopyranose, a biological response modifier, is effective in the treatment of experimental bacterial, viral and neoplastic states and acts by a specific glucan receptor on macrophages. Malnutrition diminishes IL-1 secretion, the injury/infection response, and host resistance while nutritional repletion restores all three. However, TNF is also one of the principal mediators of the lethal effect of endotoxin. Some of the adverse effects of the injury response are mediated by prostanoid metabolism which can be favorably altered by substituting dietary omega 3 fatty acids (eicosapentaenoic and docosahexaenoic) of fish oil for omega 6 fatty acids of vegetable oils. Thus with refeeding to restore immune and metabolic responsiveness, attempts to modulate the injury response may further benefit the host. The scientific design of this proposal provides experiments to 1) document in a mammalian model the metabolic effects of individual recombinant products (IL-1 alpha, IL-6) and highly purified soluble and particulate glucans, and 2) determine the modification of the injury response induced by endotoxin and natural models of injury/infection by fish oil or fish oil structured lipid feeding.
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