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Title: Characterisation and modulation of the intracellular inflammatory signalling pathways activated during surgery with cardiopulmonary bypass
Author: Nguyen, Bao-Anh Vu
ISNI:       0000 0004 5918 4406
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Surgery with cardiopulmonary bypass (CPB) is associated with post-operative complications due to systemic inflammation. However, the intracellular signalling pathways that promote inflammation in cardiac surgery with CPB are uncertain. The studies presented in this thesis were designed to illuminate these molecular mechanisms, thereby informing the development of novel anti-inflammatory strategies. This was addressed through a clinical trial to determine the effects of CPB on inflammatory signalling in leukocytes (Chapter 4). In this study, the induction of reactive oxygen species (ROS) and the activation of NF-κB and p38 MAP kinase within leukocytes was compared in patients exposed to miniaturised CPB (mCPB; an optimised form of CPB designed to attenuate systemic inflammatory activation) or conventional CPB (cCPB). Twenty-six patients undergoing surgical revascularisation for advanced coronary artery disease were randomised to undergo surgery with either cCPB or mCPB. Blood samples were collected pre-operatively and at various times after the initiation of CPB and analysed by intracellular staining and flow cytometry for intracellular markers of activation. p38 MAP kinase phosphorylation in granulocytes was enhanced in patients receiving cCPB compared to mCPB (p < 0.05). Levels of ROS in lymphocytes were elevated in cCPB compared to mCPB (p < 0.01) whereas ROS levels in granulocytes and monocytes were similar between groups. NF-κB phosphorylation in leukocyte sub-sets, leukocyte tissue migration as well as conventional markers of inflammation were comparable between the investigative groups. A porcine model was also established to study the signalling pathways that promote systemic inflammation in response to cardiac surgery with CPB under well-controlled experimental conditions. The influence of sulforaphane, an anti-inflammatory compound derived from green vegetables, on inflammation and injury in response to CPB was also studied. It was observed that pre-treatment of animals with sulforaphane reduced p38 MAP kinase (p < 0.05) and NF-κB (p < 0.05) phosphorylation in leukocytes exposed to CPB and protected porcine kidneys from exhibiting histological features of early injury. A small clinical study demonstrated biologically significant levels of sulforaphane could be determined in plasma, with lower levels of p38 MAP kinase (p < 0.01) and attenuated ROS (p < 0.01) in the early stages following consumption. In conclusion, systemic inflammatory responses following CPB were associated with activation of p38 MAP kinase and NF-κB pathways in circulating leukocytes in both porcine and clinical studies. Inflammatory responses to CPB can be reduced by miniaturisation of the CPB circuit and pharmacologically using sulforaphane.
Supervisor: Haskard, Dorian ; Evans, Paul Sponsor: Heart Research UK ; British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available