applcant's abstract) The central hypothesis to be tested is that in sepsis, the IGF system is regulated by the endogenous production of various inflammatory cytokines and glucocorticoids; and that changes in the various components of this system are capable of impairing muscle protein balance. This hypothesis was derived as the result of studies from the applicant's laboratory indicating that trauma, infection and endotoxin, or exogenous administration of either TNFa or IL-1B, are capable of modulating the various elements of the IGF system in the circulation and in muscle.
The specific aims are: 1) to determine the roles of TNF, IL-1 and glucocorticoids in mediating the sepsis-induced changes in the growth hormone(GH)-IGF axis in vivo. 2) to determine the potency of TNFa, IL-1a, IL- 1B and IL-6 on gene expression and secretion of IGF-1 and IGFBP-1 in cultured rat hepatocytes, Kupffer cells and hepatic endothelial cells. 3) to determine the mechanism for impairment of the GH-induced changes in IGF-1 production during sepsis by a) quantifying GH responsiveness in the whole animal, b) GH stimulation of IGF-1 production by the in situ perfused liver and c) GH receptor binding and mRNA in liver and muscle. 4) to determine the ability of cytokines, glucocorticoids and IGFBPs to antagonize the anabolic actions of IGF-1 on skeletal muscle protein metabolism. These experiments will be conducted on cultured L6 myotubes, and protein synthesis, breakdown and amino acid transport will be quantitated.
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