The metabolic response to injury is characterized by hypermetabolism and accelerated net breakdown of body mass, particularly body fat and skeletal muscle. While these responses may have adaptive value and beneficial components, this hypercatabolic process may be deleterious if ongoing and prolonged. We hypothesize that the metabolic response to injury can be altered in such a manner as to decrease morbidity, shorten length of convalescence, and reduce mortality. Because such modulation can only be accomplished following a thorough understanding of the mediators of the response, we will study the effects of endotoxin and determine how the signals generated following administration of this substance are modulated by glucocorticoids. The effects of endotoxin will be determined in normal human subjects. We will examine gene expression and the elaboration of various cytokines, lipid mediators and enzymes that elicit responses in the host following endotoxin administration, and examine modification of these responses by pretreatment with glucocorticoids. Endotoxin may gain entry into the body from the intestinal lumen because of a breakdown in intestinal barrier function. We will determine whether endotoxin is transported across the epithelium more readily in TPN-fed rats than chow-fed rats or glutamine-supplemented TPN- fed rats. Endotoxin (ET) will be injected into ligated loops in vivo and localized within the gut mucosa by means of immunocytochemistry using a monoclonal antibody. Results will be assessed by electron microscopy. The presence of ET in portal plasma will be detected by immuno-dot-blot autoradiography. In in vitro studies, gut mucosa from TPN and chow-fed rats will be mounted in Ussing Chambers. Tissues will be studied morphologically and using immunocytochemistry, and serosal fluid will be monitored for relative amounts of endotoxin transported. Similar techniques will be used to study the transfer of ET across the human intestine. Critically ill patients generate toxic oxygen metabolites and these compounds may cause cell injury if disposal systems of these products are not adequate. In contrast to standard parenteral solutions, glutamine- containing solutions are able to maintain hepatic glutathione stores following oxidative stress and reduce morbidity. Further studies are planned to examine these mechanisms in animals and patients.
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