To improve our alone, could not be explained by a hemodynamic effect of these cytokines. Rather, this finding indicated that muscle proteolysis is enhanced by TNF and synergistically augmented by the addition of IL 1. Compatible with these data was the finding that more prolonged infusions of recombinant TNF/cachectin and the combination with IL 1 increased urinary nitrogen excretion. Changes in I'4Clleucine dilution in the liver were less pronounced than those in skeletal muscle and consistent with net anabolic effect of TNF on liver protein. We conclude that rats exposed systemically to sublethal doses of TNF respond with increasing muscle and decreasing liver proteolysis, similar to that observed in inflammation and in cancer.

Improved survival to endotoxin has been demonstrated in rats pretreated with cyclooxygenase inhibitors or made essential fatty acid deficient, implying that excessive omega 6 fatty acids, possibly through their eicosanoid products, contribute to mortality. Following endotoxin administration, we also have shown improvement in survival with oral diets supplemented with fish oil. This study sought to explore whether parenteral fish oil ameliorates the adverse impact of endotoxin. Male Hartley-strain guinea pigs were obtained at a body weight of 500 g and fed a normal laboratory diet. Central venous lines through which the animals received either a 10% safflower oil emulsion (n = 11) or a 10% fish oil emulsion (n = 11) during two, 24-hr periods separated by two days were inserted. Two days after the second infusion, endotoxin (0.35 mg/100 g b.w.), was given intraperitoneally, and survival was noted. The animals received a total of 25.4 g of IV fat per kg b.w., including 5.3 g of eicosapentaenoic acid per kg b.w., for the fish oil group. From six hr after endotoxin through four days, there was better survival in the fish oil group (p less than .006). Final mortality showed 7/11 fish-fed vs 2/11 safflower-fed animals surviving. We conclude that the administration of parenteral fish oil, even for a brief time, can have a profound effect on subsequent survival to endotoxin.

Over the past several decades, research on the role of mediators in inflammation, immunity, repair processes, cell growth, and substrate metabolism have centered around the use of purified products of stimulated macrophages. With the current availability of recombinant mediators, the participation of individual monokines in cellular metabolism has been more clearly defined. Interactions among various mediators have been demonstrated, but their exact role in metabolism is currently under intense study. With the use of recombinant monokines, formal evidence for their participation in the acute phase response has been developed. Their use has also assisted in the reinterpretation of data gathered in older studies using purified preparations, which were almost certainly contaminated with several monokines. In this review we will try to give the reader insight into recent advances in the understanding of the role of cellular mediators in relation to nutrition and intermediary metabolism. With a clearer knowledge of the role of cellular mediators in the pathophysiology of disease, it may be possible to develop rationales for their therapeutic use as modulators of substrate metabolism during critical illness.