Excessive release of inflammatory mediators contributes directly to the pathogenesis of organ injury and death occurring during severe infection complicated by sepsis and septic shock. Nuclear factor kappa B (NF-KB) is a nuclear transcription regulatory protein central to the activation of several different genes encoding proteins associated with the inflammatory response during sepsis. Under normal conditions, NF-KB remains sequestered in an inactive state in the cytoplasm under the control of its cytoplasmic inhibitor (I-(B) proteins. However, differing kinds of stimuli including LPS (the toxic moiety of gram-negative bacteria) and cytokines (e.g. TNF alpha and interleukin-6) cause the phosphorylation, ubiquitinylation, and the subsequent degradation of I-KB proteins in turn resulting in the activation of NF-KB. Then the DNA-binding subunits of NF-KB migrate into the nucleus and activate expression of target genes that code for proteins in the inflammatory and immune responses, such as chemokines, cytokines, inducible nitric oxide synthase (iNOS), and adhesion molecules. Many of these gene products have been closely associated with the pathogenesis of the hemodynamic instability and organ injury occurring during sepsis and septic shock. Therefore, agents designed to inhibit NF-KB may have broad antiinflammmatory effects that could be beneficial during sepsis. However, many of the host mediators associated with the inflammatory response and under the control of NF-KB also contribute to innate immunity and the clearance of bacterial infection. Suppression of NF-KB during sepsis could therefore also worsen underlying infection. ? ? The present protocol has tested the effects of of modulating NF-KB in an LPS challenged mouse sepsis model. Initial studies investigated the effects of parthenolide, a sesquiterpene lactone derived from Asteraceae plants. Parthenolide had been reported to inhibit NF-KB and improve survival when administered up to 3 hours following intravenous LPS stimulation in mice or rats challenged with intraperitoneal or intravenous LPS respectively. However in investigations that have thus far been completed, parthenolide worsened survival with LPS challenge in our mouse model. Furthermore, the effects of parthenolide on NF-KB were time dependent, decreasing these levels early but increasing them later. Similar changes were noted with plasma cytokine levels.? ? We have now extended these studies investigating ethyl pyruvate, a second agent which has been reported to inhibit NF-KB and the inflammatory response and to improve survival in sepsis models including ones employing LPS challenge. Consistent with our findings with parthenolide however, ethyl pyruvate has also been harmful in our most recent studies, and has had similar time dependent effects on inflammatory cytokine and chemokine release. Tissue NF-KB measurements have now been completed and show early decreases and later increases with ethyl pyruvate treatment similar to those observed with parhenolide. ? ? Overall, these studies suggest that the effects of NF-KB inhibition in animal models of sepsis may be variable. Understanding the effects of inhibiting such a central mediator in the inflammatory and host responses during sepsis must be well defined before this is explored in patients. ? ? A manuscript describing experiments with parthenolide has been published. A manuscript describing the effects of ethyl pyruvate has been tentatively accepted for publication pending minimal revisions.
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