The interrelated metabolic/immunologic manifestations caused by major thermal injury initiate a state resulting in malfunction in major organs as well as altering would healing. Understanding of the interrelationships of the various activated mediator cascades is approached utilizing standardized burn wound models (mice, rats, rabbits and guinea pigs), isolated organs, cell cultures and molecular preparations to dissect the sequence that initiates and perpetuates the hyperdynamic - oxidative stress state characteristic of major thermal trauma. The response of each organ system and its contributions is to be evaluated. The role of activated adherent leukocytes in blood flow and intravascular clotting, endothelial adhesion and subsequent intracellular toxic products released in the heart, intestine and wounds will be evaluated. Products of the tissue macrophage response and its interaction with parenchymal cells in the liver will be examined in relation to protein synthesis and mRNA expression to better define or identify secretory products that may affect other major organs (lungs). The role of splanchnic released mediators associated with decrease gut barrier function will be defined and related to their effect on other organ responses. The role of the wound will be defined by examining wound fluids, for compositional changes related proteinase, adhesive proteins and growth factor activity which are related to the wound healing sequence. The project integration of the animal models will permit evaluation of the spectrum from intact animal to the cell and molecular level. MRI spectrometry will determine the bioenergetics of ion transfer and acid base balance of vital organs; organ function in isolated heart preparations (Langendorf), isolated myocyte and parenchymal liver cell perturbations; and subcellular relations of protein synthesis to mRNA regulation. The results of these experiments are expected to define a variety of specific pharmacologic approaches that interrupt pathophysiologic mediator interactions at pre determined pos-burn intervals. The large volume of clinical material available assures the completion of these evaluations.
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