The general research plan for this proposal tests the following hypotheses; A major portion of the morbidity and mortality following burn injury result from continued activation of the """"""""Inflammatory Reaction"""""""" in both its stimulatory and """"""""suppressive"""""""" activities at the systemic level. This activity when carried on over extended periods results in """"""""immuno-metabolic"""""""" injury and ineffective defense against bacteria. The major source of the Inflammatory stimulae is a persistent open and bacterially contaminated wound and the ability to understand and modulate this persistent inflammatory reaction will produce substantial decreases in morbidity and mortality. To test these hypotheses, studies are designed to: 1) identify, understand and modulate the mechanisms of activation and control of the Inflammatory Reaction following injury concentrating on mechanisms of induction and action of monokine inflammatory mediators such as Il-1, TNF and related molecules and their interaction with the immunologic components of the inflammatory system such as complement products to effect the clinical course of the burned patient; 2) test the hypothesis that the protein catabolic state characteristic of Burn Injury (particularly hypermetabolism increased amino acid, glucose and energy turnover) is due in major part to alterations in the regulation of the metabolism of dispensable (non-essential) amino acids and potentially their availability for meeting tissue needs to optimize protein balance. In these studies a major effort will be directed towards metabolic modeling techniques to develop new and innovative methodologies which will allow non-invasive study of metabolic events in patients at the organ and cellular level in addition to the """"""""whole body""""""""; 3) develop understanding of the liver and the gut (splanchnic organ system) function following injury and their interactions in the initiation, amplification, and maintenance of the reaction to injury; test the hypothesis that the increased gut permeability to macromolecules (? endotoxin) seem immediately following burn injury produces increase in bacterial translocation through the gut wall and activation of Kupffer cells. These studies will concentrate on the interaction between Kupffer cell and hepatocyte reordering of synthetic activity using a novel in vitro system as well as bacterial translocation and substrate absorption at various levels of the small and large gut.
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