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Title: The regulation of neutrophil priming and activation
Author: Kitchen, Elizabeth
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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The potential for neutrophils to recover from a primed state, i.e. to "de-prime", remains largely unexplored. However, the priming of neutrophils under non-physiological conditions, using hypotonic buffers, has been shown to reverse upon the restoration of isotonicity. Having confirmed this finding, I demonstrated that the priming of human neutrophils with PAF, a well-established, rapid-acting, receptor-mediated priming agent, was transient with complete reversal to an un-primed state within 2 hours. Furthermore, de-primed neutrophils retained their capacity to be re-primed when subsequently challenged with either PAF or TNFα. The recovery of neutrophils to an un-primed state was confirmed by the assessment of superoxide anion release, cell polarization, and CD11b/CD18 function, and was shown to reflect neither a reduction in neutrophil viability or cell responsiveness, nor the metabolism of PAF. These observations implied that neutrophil priming to a receptor-mediated agent was fully reversible. Transient neutrophil priming was also observed with inositol hexakisphosphate (InsP6), a ubiquitous inositol polyphosphate whose minimal priming effects were found to occur independently of specific InsP6 receptors on the surface of human neutrophils. In contrast, the receptor-mediated priming effects of TNFα were both slower to evolve and more sustained than those of either PAF or InsP6. However, the primed responses elicited by PAF or TNFα could be manipulated by specific receptor blockade. Thus, the recognition of a novel process whereby neutrophils have the potential to de-prime may represent a physiological and potentially targetable mechanism, upstream of the final activation pathway, to counteract the pro-inflammatory activity of neutrophils in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available