Modulation of body and tissue-specific protein turnover proportional to the severity and duration of injury implies a complex level of metabolic control. In addition to immobility and antecedent nutritional status which influence both the capacity for and rate of lean tissue recovery,the neuro-humoral milieu also contributes to the regulation of tissue-specific (skeletal muscle) protein mass and cellular function. Peptide mediators (cytokines) produced either locally at the site of tissue damage and/or appearing systemically may further modulate lean tissue functional and metabolic processes. Following injury, loss of intestinal mucosal barrier function and subsequent portal vein and/or systemic bacterial or endotoxin exposure may further enhance the production of cytokines and stress hormones. Efforts to maintain intestinal integrity by means of enteral nutritional support may then represent a clinically relevant approach to modulating the post- injury response. This proposal will seek to evaluate the individual contributions of stress hormones and endotoxin to body, regional and skeletal protein metabolic and functional homeostasis. Responses observed during acute perturbations induced by endotoxin and/or stress hormone infusions in normal volunteers will be compared to those responses in moderately injured (perioperative) and more severely injured patients(trauma/critical illness). Throughout the above studies, the metabolic and functional responses will be compared between patients receiving a defined enteral formula or parenteral nutrition. Subsequently, we will seek to determine the efficacy of L-glutamine which, as an im- portant intestinal fuel source, may be capable of modulating the stress hormone and cytokine response to endotoxinemia as well as maintaining intestinal mucosal mass. During the above studies, prospective evaluation of energy expenditure, stress hormone and cytokine (cachectin/TNF, lymphotoxin, gamma-interferon, and interleukin 1) responses to controlled stimulae or injury will be performed. In addition, body and regional protein metabolism will be evaluated using stable isotope techniques (L-(1-C13,N15) leu- cine; L-(phenyl-2H5) phenylalanine). Acute skeletal muscle responses will also be assessed by biopsy-determined solute:water ratios, high energy phosphate levels and the relative rate of myosin and Na K ATPase mRNA expression. The latter observations will be correlated to changes in transmembrane potential differences and regional amino acid metabolism to gain further information regarding both the magnitude and timing of these parameters following injury.
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