Cain, DJ;
(2017)
Perioperative neutrophil immune function.
Doctoral thesis , UCL (University College London).
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Abstract
Within the UK severe sepsis is responsible for 29% of intensive care admissions and carries a mortality of 44.7%. Decades of research have failed to deliver a single clinically successful immune modulating therapeutic agent. These failings may be explained by fundamental methodological challenges of sepsis laboratory investigations, namely diagnostic uncertainty, an indeterminate onset and the identification of an immunologically similar control population. The underlying hypothesis for this thesis is that the translational investigation of surgical patients may overcome many of these methodological challenges, since surgical trauma generates a homogenous inflammatory insult at a planned time to a carefully phenotyped human population. The biological basis for modelling sepsis with traumatic injury is discussed. Firstly, I reviewed the current literature to demonstrate the methodological advantages of studying surgical patients as a surrogate for sepsis. Next, I performed an observational study of neutrophil immune function following major elective surgery which identified a reduced neutrophil respiratory burst and changes in cell surface immune receptor expression. This impairment of activated neutrophil immune function was associated with resting neutrophil mitochondrial dysfunction, namely a raised mitochondrial membrane potential and increased production of reactive oxygen species. Using two different models of mitochondrial dysfunction I demonstrated that neutrophil respiratory burst may be regulated by altered mitochondrial functionality. Finally, I provide evidence that the cytoplasmic target for this mitochondrial signal is the enzyme pyruvate kinase M2, which through oxidative inhibition reduces the production of the respiratory burst substrate NADPH by limiting flow of glucose through the hexose monophosphate shunt. In summary, major elective surgery provides a translational model of human sepsis. Using this model, I demonstrate impairment of the neutrophil respiratory burst, and provide evidence that this is mediated through neutrophil mitochondrial dysfunction which promotes oxidative inhibition of the glycolytic regulatory enzyme pyruvate kinase.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Perioperative neutrophil immune function |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1568022 |
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