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Title: Propagation of inflammation in burn injury and the role of microvesicles
Author: Katbeh, Umar
ISNI:       0000 0004 7427 6923
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Burn injuries are the fourth most common type of major trauma and responsible for approximately 300,000 deaths worldwide. Most of these deaths are ascribed to the systemic inflammation and multiple organ failure that commonly manifests following burn injury. The ideology that systemic inflammatory response syndrome develops secondary to the action of systemic cytokines has led to clinical trials aimed at intercepting these blood-borne inflammatory mediators before reaching their target sites, these efforts were however in vain. Microvesicles (MVs) are cell-derived signalling particles emerging as important mediators of local and systemic inflammation. Our objective was to investigate the role of microvesicles in the propagation of inflammation following burn injury, focussing on their induction in skin by extracellular ATP signalling. In vitro models of cell injury demonstrated that high temperature causes the release and stabilisation of ATP, in contrast to ATP degradation following mechanically-induced cell lysis. Treatment of skin explants ex vivo with ATP resulted in microvesicle release, which were macrophage-derived, capable of stimulating inflammatory responses in vitro and packaged with pro-IL-1β. Burn injury to skin explants via scalding (steam or immersion) also resulted in the release of microvesicles that were pro-inflammatory in vitro and following intravenous injection into mice, induced leukocyte activation and margination in the vascular beds of the lung and liver. Using a partial-width contact burn injury in skin explants, we were able to demonstrate ATP-purinergic receptor mediated microvesicle release. In conclusion, the results here demonstrate that burn injury can elicit a significant release of microvesicles from skin tissue and that ATP release from injured cells could play a central role in this process. The stabilisation of extracellular ATP by burn injury would produce a unique pathophysiological environment for microvesicle production, which, if released systemically, could play an important and disproportionate role in promoting systemic inflammation following severe burn injury as compared to other SIRS aetiologies.
Supervisor: O'Dea, Kieran ; Takata, Masao Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral