Following a surgical injury, trauma, burn or bacterial infection, the host undergoes a series of characteristic tissue responses, including anorexia, wasting of skeletal protein and an hepatic """"""""acute-phase"""""""" protein response. Despite considerable evidence that interleukin 1 (IL-1) and cachectin (tumour necrosis factor- alpha), two secretory products of activated blood monocytes and tissue macrophages, play a pivotal role in how the host responds to trauma and infection, there is only scant information regarding the regulation of their biosynthesis in surgery, injury and bacterial infections. Therefore, the in vivo production rate of both IL-1 (alpha and beta) and cachectin will be assessed in hospitalized patients after surgery or thermal injury, and in murine and rat models of trauma, surgical injury and infections. In addition to measuring circulating concentrations, highly specific human and murine cDNA probes for IL-1 (alpha and beta) will be used to assess the quantity of mRNA present in blood monocytes and tissue macrophages from animals subjected to inflammatory stress. To directly determined tissue sources of IL-1 and cachectin production, immunocytochemical techniques will be employed. In addition, despite similarities in the tissue responses to IL-1 and cachectin, little information is currently available about the contribution these two monokines make, singly and together, to the pathophysiologic changes which occur. Therefore, the administration of either neutralizing antibodies to IL-1 (both species) and/or cachectin, or the infusion of recombinant-derived protein, to both healthy and traumatized animals will be performed to assess the quantitative importance these monokines make to either the hepatic acute phase protein, skeletal protein synthesis, or whole body compositional changes which occur. In addition, utilizing a semi-lethal burn and infection model, survival in response to additional IL-1 or cachectin, or to neutralizing antibodies, will be assessed. Such studies will thus provide a more complete understanding of the underlying mechanisms by which IL-1 and cachectin biosynthesis are regulated, as well as their prevalence and importance in clinically-relevant disease. Such investigations will both improve our basic understanding of the metabolic response to surgery and injury as well as provide a theoretical basis for attempts to modify this host response.
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