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.

No abstract

The effect of 6 weeks dietary lipid manipulation on the acute physiologic response to 7-hour continuous endotoxin infusion in guinea pigs was examined. One diet was enriched with N-3 fatty acids, whereas the other contained N-6 fatty acids, primarily linoleic acid. Animals fed N-6 fatty acids developed significant lactic acidemia, microvascular muscle hypoperfusion, and pulmonary infiltrates in response to endotoxin infusion. N-3 fatty acid-fed animals demonstrated improved lactate levels, microvascular muscle perfusion, and lung morphology compared to N-6 fatty acid-fed animals after endotoxin infusion. There was no significant change in cardiac output, PaO2, or mean arterial blood pressure at the end of the endotoxin infusion in either group. Pretreatment with indomethacin, or BM 13505, a specific thromboxane A2 receptor blocker, ameliorated the development of metabolic acidosis in N-6 fatty acid-fed animals, demonstrating a role for prostanoids in the sequelae of endotoxemia. The ability of dietary pretreatment with N-3 fatty acids to influence favorably the physiologic response to endotoxin represents a novel nutrient-metabolic interaction with potential therapeutic implications.

We evaluated the effect of total parenteral nutrition (TPN) enriched with n-3 fatty acids on the physiologic response to endotoxin in guinea pigs. Animals were randomly assigned to receive TPN differing only in lipid source for 3.5 d. Group 1 received soybean fat emulsion (Intralipid) whereas group 2 received fish (menhaden) oil. During the last 7 h of TPN, animals were further randomized to have either saline or E coli endotoxin added to the infusate. Acid-base status and serum lactate concentrations were determined. Animals infused with soybean fat emulsions and endotoxin developed a significant metabolic acidosis, lactic acidemia, and decrease in mixed venous O2 compared with controls and fish-oil-treated animals (p less than 0.05). The significantly reduced serum lactate and higher mixed venous O2 in fish-oil-infused animals suggests that the underlying mechanism involves improvement in endotoxin-induced tissue hypoperfusion, presumably through alterations in prostaglandin metabolism.