The mechanisms whereby injury and infection eventuate in alterations of host metabolic responses and immune dysfunction remain poorly defined. Characteristics of the host response to endotoxin induced injury arise from individual as well as synergistic interactions between endocrine stress hormones and other micromediator systems, such as the cytokines. Such influences result from both clinical management regimens as well as from endogenous counter-regulatory mechanisms which contribute to acute and chronic metabolic expression and immune function. The counter-regulatory response may now be more broadly defined to include additional elements which serve to attenuate the activities of both endotoxin (such as bactericidal/permeability- increasing protein, BPI) and pro-inflammatory cytokine (soluble TNF receptors, sTNF-R) activity. As both BPI and sTNF-Rs exhibit potent neutralizing capacities, the stereotypic pattern of such mediator antagonist generation suggests that the in vivo regulation of such antagonists is influenced, in a manner similar to that for cytokines, by additional elements of the stress response, such as classical endocrine hormones. While the relative contributions of stress hormones and cytokines toward host responses characteristic of endotoxinemia remain ill defined, our recent data suggests that any cytokine induced metabolic and immune dysfunction likely arises from TNF as the most proximal mediator of the cytokine cascade. Hence, the exogenous intervention with BPI and/or sTNF-R during endotoxinemia permits a more precise dissection of endotoxin or TNF specific mechanisms for host responses. This proposal will seek to comprehensively assess the in vivo contributions of both endocrine hormone and endotoxin induced TNF mediation of host energy regulation, substrate turnover (L-[1-13C] leucine, L-[phenyl-2H5] phenylalanine, D-[6,6(2)H2] glucose, D-[1,1,2,3,3-2H5]glycerol)), and immune dysfunction (utilizing in vitro monocyte and neutrophil preparations as well as of tissue TNF-R and BPI expression) under conditions of experimental endotoxinemia in normal male and female subjects. The individual and synergistic influences of antecedent hypercortisolemia and of adrenergic (epinephrine) excess will be assessed before and subsequent to endotoxinemia. In a parallel fashion, TNF specific influences upon these parameters will be determined utilizing exogenous sTNF-R intervention and contrasted to those observations obtained during endotoxin neutralization (BPI). Studies utilizing mediator antagonist interventions against an antecedent background of hormone excess will permit a determination of this influence upon both the basal and LPS stimulated metabolic, immune, and endogenous antagonist responses. These responses will be contrasted to concurrent studies of similar design in endotoxinemic critically ill patients receiving similar mediator specific interventions. The proposed studies will assess differences between normal subjects and patient populations in a manner permitting more precise definition of hormonal and TNF contributions to endotoxin induced metabolic and immune processes.