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Title: An investigation of the transcription factor nuclear factor kappa B in critical illness
Author: Paterson, Ross L.
ISNI:       0000 0001 3476 8753
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2002
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The immuno-inflammatory host response in critically ill patients with sepsis and inflammatory conditions is driven by the expression of compounds acting as, or producing inflammatory mediators, including cytokines, reactive oxygen species and adhesion molecules. Their production is in part controlled by the transcription factor, nuclear factor kB (NFkB).  NFkB is a primary intracellular transcription factor, which transduces extracellular signals to the nucleus and responds to cellular oxidative stress. NFkB activation was assessed in circulating leucocytes from critically ill patients on the intensive care unit.  NFkB was activated in mononuclear and polymorphonuclear leucocytes in all the patients studied, and was significantly greater than in healthy subjects (p=0.01, p=0.001).  NFkB activation in mononuclear leucocytes increased markedly in those patients who died whilst remaining constant in those patients who survived. The effect of administration of the intracellular antioxidant N-acetylcysteine, on NFkB activation and circulating concentrations of cytokines and adhesion molecules was investigated in patients with sepsis.  In patients who survived and received N-acetylocysteine, mononuclear leucocyte NFkB activation decreased significantly (p=0.016). In contrast there was no change in NFkB activation in mononuclear leucocytes from patients who received the placebo infusion. Additionally, circulating concentrations of interleukin (IL)-8 were found to decrease in those surviving patients receiving N-acetylcysteine. The effect of IL-10 on NFkB activation, coupled to 1kBa degradation, in leucocytes and tissues in endotoxaemic rats, was investigated.  NFkB activation was increased with a corresponding reduction in 1kBa concentrations, in liver (p=0.02) and lung (p=0.004) samples from rats receiving combined LPS and IL-10. NFkB activation may have a central role in the mortality and sepsis.  N-acetylcysteine attenuates mononuclear leucocyte NFkB activation and related IL-8 production in human sepsis, whereas, IL-10 administration resulted in paradoxical increases in NFkB activation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Sepsis