Despite the use of effective antibiotics in combination with cardiopulmonary support, the mortality rate from sepsis and septic shock for the last three decades has remained high (29%)(1). Furthermore, the incidence of sepsis and septic shock appear to be increasing (2). New therapeutic approaches with wide clinical applicability are needed to lower the high mortality rate of this syndrome. 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 (3). 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-(B. 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 sysnthase (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 is testing 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. Work has shown that parthenolide specifically inhibits NF-kB activation by preventing degradation of I-kBand I- kB. 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. The mechanisms underlying this effect are under investigation.
| Jaswal, Dharmvir S; Leung, Janice M; Sun, Junfeng et al. (2014) Tidal volume and plateau pressure use for acute lung injury from 2000 to present: a systematic literature review. Crit Care Med 42:2278-89 |
| Li, Xuemei; Su, Junwu; Cui, Xizhong et al. (2009) Can we predict the effects of NF-kappaB inhibition in sepsis? Studies with parthenolide and ethyl pyruvate. Expert Opin Investig Drugs 18:1047-60 |
| Li, Xuemei; Cui, Xizhong; Li, Yan et al. (2006) Parthenolide has limited effects on nuclear factor-kappa beta increases and worsens survival in lipopolysaccharide-challenged C57BL/6J mice. Cytokine 33:299-308 |
| Cui, Xizhong; Li, Yan; Moayeri, Mahtab et al. (2005) Late treatment with a protective antigen-directed monoclonal antibody improves hemodynamic function and survival in a lethal toxin-infused rat model of anthrax sepsis. J Infect Dis 191:422-34 |
