PROTEIN SYNTHESIS IN LIVER DURING SEPSIS

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The metabolic responses to sepsis are varied, involving changes in protein, carbohydrate, fat, trace metal and amino metabolism. A generally emerging concept is that the interaction between muscle and liver may be summarized by increased flow of amino acids from peripherylean body mass/muscle to the liver. Although increased protein synthesis in liver during sepsis has been reported, other studies have not confirmed these findings. Also, mediator(s) and mechanism(s) of altered protein synthesis in liver during spesis are not fully known. The objectives of the proposed studies are to: (1) determine changes in hepatic protein synthesis in vivo and in perfused rat liver during sepsis; (2) test the hypothesis that increased hepatic protein synthesis is induced by interleukin-1 (IL-1), tumor necrosis factor (TNF), or other monokines; (3) determine the role of the catabolic hormones corticosterone, glucagon and epinephrine for accelerated hepatic protein synthesis; and (4) test the hypothesis that hepatic protein synthesis in spetic rats can be stimulated by the administration of different substrates, among them amino acid solutions of different compositions. Sepsis is induced in rats by cecal ligation and puncture (CLP); control animals are sham-operated. At various time-points after CLP or sham-operation, total hepatic protein synthesis is measured in vivo with a flooding dose technique, using 14C-leucine as precusor amino acid. In other animals the production of the secreted proteins albumin, transferrin, complement component C3, and alpha 1-acid glycoprotein is measured in perfused isolated liver using a recirculating system and immunoprecipitation of radiolabeled specific proteins. In still other studies, total and secreted hepatic protein synthesis will be determined following intraperitoneal administration of activated rat macrophage supernatant, recombinant IL-1 alpha or recombinant TNF. Since it has been suggested that some of the effects of IL-1 are secondary to glucocorticoids, hepatic protein synthesis will also be measured following administration of IL-1 to adrenalectomized rats. In another set of experiments, the catabolic hormones will be simultaneously infused in rats and hepatic protein synthesis will be meaured. Finally, the effects of an 18-20 h or 46-48 h infusion of amin acid solutions of various and novel compositions on protein synthesis in liver during sepsis will be determined. In the same of experiments, the effect in perfused liver of septic rats, will be determined.