The catabolism of protein after injury or infection results in multiple complications which prolong recovery and cause death. Nutrient intake is unable to prevent protein catabolism suggesting other factors are important. Growth hormone (GH) induces circulating insulin-like growth factor-I (IGF-I) synthesis by liver, which stimulates muscle protein synthesis. During sepsis, a 2-4 fold increase in circulating GH is seen with a 50% decrease in plasma IGF-I, a 40% reduction in muscle protein synthesis, and decreased muscle mass. The onset of GH resistance and loss of muscle in sepsis is mediated by the inflammatory cytokines, TNF and IL-I. Treating septic rats with IL-1 or TNF antagonists ameliorates the effects of sepsis on plasma IGF-I levels and muscle catabolism. The liver is the major source of circulating IGF-I, and will be the focus of this project to elucidate the mechanisms responsible for GH resistance. Postreceptor defects in GH signaling represent the predominant mechanism for GH resistance in sepsis. The magnitude of the IGF-I response to GH is determined by three distinct processes: the activation/propagation of JAK/STAT and MAP kinase signaling by GH, the regulation of IGF-I gene expression, and the termination of GH signaling. To investigate the mechanisms responsible for GH resistance, we developed a hepatocyte model of cytokine-mediated GH resistance. This novel hepatocyte model uniquely positions us to delineate the mechanisms responsible for defective GH signaling and IGF-I expression. TNF inhibits both the activation and termination of GH signaling by the JAK/STAT and MAP kinase pathways. IL-1 also inhibits the induction of IGF-I by GH, but the time course differs from TNF, potentially involving different mechanisms. The mechanisms responsible for GH resistance will be determined with in vitro studies involving TNF and IL-1, and in vivo studies in our rat model of sepsis. Our hypothesis is that cytokine-rnediated alterations in GH signaling mediate hepatic GH resistance and muscle catabolism during sepsis.
The specific aims are: (1) to delineate the effects of sepsis, TNF and IL-1 on the activation/propagation of GH signaling; (2) to elucidate the mechanisms by which sepsis, TNF and IL-1 regulate IGF-I gene expression; and (3) to determine the mechanisms by which sepsis, TNF and IL-1 terminate GH signaling. An understanding of how cytokines and growth factors regulate protein catabolism is important for the care of septic patients.
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