NF-kappa B in Murine Sepsis

严重感染并发脓毒症和感染性休克时，炎症介质的过度释放直接导致器官损伤和死亡。核因子κ B （NF-kB）是一种核转录调节蛋白，在脓毒症期间与炎症反应相关的几种不同基因编码蛋白的激活中起核心作用。在正常情况下，NF-kB在其细胞质抑制剂(I-(B)蛋白的控制下，以无活性状态被隔离在细胞质中。然而，不同种类的刺激，包括脂多糖（革兰氏阴性菌的有毒部分）和细胞因子（如TNF α和白细胞介素-6）引起磷酸化、泛素化和随后的I-kB蛋白降解，进而导致NF-kB的激活。然后NF-kB的dna结合亚基迁移到细胞核中，激活靶基因的表达，这些基因编码炎症和免疫反应中的蛋白质，如趋化因子、细胞因子、诱导型一氧化氮合酶（iNOS）和粘附分子。这些基因产物中有许多与脓毒症和感染性休克时血流动力学不稳定和器官损伤的发病机制密切相关。因此，设计抑制NF-kB的药物可能具有广泛的抗炎作用，在败血症期间可能是有益的。然而，在NF-kB的控制下，许多与炎症反应相关的宿主介质也有助于先天免疫和细菌感染的清除。因此，败血症期间NF-kB的抑制也可能加重潜在感染。

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 tests the effects of agents designed to modulate NF-kB in a murine model of sepsis. The first agent under investigation is parthenolide. Parthenolide is a sesquiterpene lactone derived from Asteraceae plants. Parthenolide has been reported to 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 the investigations that have thus far been completed in a fluid supported mouse model under this protocol, inhibition of NF-KB with parthenolide has been harmful with LPS challenge. These results emphasize the potential protective effect NF-KB has in host defense against microbial toxins. Work in this project is now centered on investigating tissue expression of NF-kB over the time following LPS challenge. Thus far, studies in the lung have shown that NF-kB expression is related to the dose of LPS challenge. Furthermore, parthenolide?s effects on NF-kB expression appear to be time dependent. Although levels are decreased early, they are increased late after LPS challenge with parthenolide. These changes are now being investigated in other tissues. In addition, the relationship between these changes in tissue NF-kB expression are being correlated to changes in plasma cytokine levels.