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Title: Microvesicles as mediators of inflammation in severe burn injury
Author: Porter, John Robert Stephen
ISNI:       0000 0004 6059 2116
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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The host response to a severe burn injury is characterised by exaggerated systemic inflammation. Early clinical manifestations include shock, respiratory failure, renal failure and immunosuppression. The signalling pathways that propagate the inflammatory response are unclear but have traditionally been thought to involve overspill of proinflammatory cytokines. The importance of microvesicles, sub-cellular membrane-bound particles, is increasingly being recognised in the context of intercellular communication. Although circulating microvesicles are elevated in proinflammatory states such as sepsis, their relevance to the post-burn inflammatory response has not previously been evaluated. We hypothesised that circulating microvesicles play a crucial role in propagating the post-burn inflammatory response. Our overall aims were to 1) optimise protocols for the processing and analysis of plasma samples for microvesicle content; 2) characterise the circulating microvesicle profile associated with severe burn injury; 3) develop in vitro techniques to assess microvesicle production and function. The major findings of this work were that microvesicles derived from leukocytes, neutrophils, monocytes and endothelial cells were significantly elevated within 24 hours of burn injury. Microvesicle levels fell rapidly and were significantly decreased by day two post-injury. Total leukocyte- and neutrophil-derived microvesicles were significantly higher in non-survivors of burn injury as compared to survivors. In vitro studies demonstrated that neutrophil microvesicle release could be elicited by incubation with opsonised heat-killed cells. Pilot analysis of burn patient samples, using an endothelial co-culture assay, suggested that microvesicles may regulate the innate immune response to burn injury. These findings indicated that circulating microvesicles are an important component of the post-burn inflammatory response. Their precise activity is likely to be subtype-specific but the association of neutrophil-derived microvesicles with patient outcome alludes to a key role in burn pathophysiology.
Supervisor: O'Dea, Kieran ; Singh, Suveer ; Takata, Masao Sponsor: Chelsea & Westminster Healthcare
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral