description): Inflammation is characterized by the production of cytokines, adherence of leukocytes to endothelial walls, and alterations in organ function (ie. hepatic glucose metabolism). Prior studies have indicated that expression of phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme for gluconeogenesis, is suppressed during inflammation. Since it is well established that heat shock (HS) pretreatment protects cells from a variety of stresses including LPS-induced inflammation, the hypothesis to be tested in this proposal is that a nonlethal HS pretreatment will stabilize PEPCK expression and consequently preserve hepatic glucose production after administration of LPS. The second aspect of this proposal is to understand the mechanisms of HS protection of hepatic glucose metabolism after LPS.
The specific aims of the proposal include assessment of HS pretreatment during varying concentrations of LPS-induced inflammation by measuring liver steady state mRNA levels and specific activity of PEPCK and glucose production in an isolated perfused liver. Mechanisms underlying how HS pretreatment protects PEPCK gene expression will be elucidated by assessing transcriptional regulation of the gene, degradation of PEPCK message, and translation of PEPCK mRNA. Next studies will ask whether HS protection of PEPCK expression is a function of the presence of HS proteins or a secondary inflammatory response associated with hyperthermia. Finally, the role of extracellular factors that might contribute to PEPCK gene expression will be evaluated: effects of insulin/glucagon balance and the role of cytokines in the regulation of PEPCK in HS pretreatment and after LPS alone.
| Trentzsch, Heiko; Stewart, Dylan; Paidas, Charles N et al. (2003) The combination of polymicrobial sepsis and endotoxin results in an inflammatory process that could not be predicted from the independent insults. J Surg Res 111:203-8 |
| Paidas, Charles N; Mooney, Maria Lourdes; Theodorakis, Nicholas G et al. (2002) Accelerated recovery after endotoxic challenge in heat shock-pretreated mice. Am J Physiol Regul Integr Comp Physiol 282:R1374-81 |
| Stewart, Dylan; Fulton, William B; Wilson, Chad et al. (2002) Genetic contribution to the septic response in a mouse model. Shock 18:342-7 |
