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Title: Investigation into the role of monocyte tumour necrosis factor-alpha converting enzyme as a regulator of the inflammatory response in sepsis
Author: O'Callaghan, David John Patrick
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Sepsis consists of both the systemic inflammatory response syndrome (SIRS) and the compensatory anti-inflammatory response syndrome (CARS). How these differential response states are regulated is yet to be fully elucidated. Tumour necrosis factor-alpha (TNF) is one of the principal cytokines involved in mediating SIRS. TNF is released from cells by tumour necrosis factor-alpha converting enzyme (TACE), this enzyme is responsible for the ectodomain cleavage of a number of other substrates relevant to inflammation including both TNF receptors and the adhesion molecule L-selectin. How TACE contributes to, and functions in, SIRS and CARS is not yet known. My objective was to investigate TACE activity and associated substrate shedding in monocytes, specifically how the enzyme behaved in the context of in vitro models that I designed to induce states of priming and tolerance. I then obtained in vivo samples from critically ill patients to determine whether there were similarities between the TACE activity profiles found in patient cells, and volunteer cells placed in the in vitro models. My aims were: 1) Determine how TACE activity profiles were altered when sequential inflammatory stimuli were utilised in a two-hit model of sepsis designed to induce states of priming and tolerance and 2) To perform a clinical study to investigate TACE behaviour in the context of critical illness. I successfully refined a method of isolating primary monocytes from healthy volunteers and patients that allowed determination of TACE activity profiles. Furthermore, I demonstrated that the LPS-TACE axis was reset in the context of a two-hit LPS model and in sepsis. I found evidence of differential signalling pathway reprogramming in monocytes taken from patients with infectious and non-infectious SIRS. Finally, I demonstrated that the monocyte TACE response to LPS is dependent on cell contact. These data provide new insights into monocyte inflammatory function during the immune response.
Supervisor: O'Dea, Kieran ; Gordon, Anthony ; Takata, Masao Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available