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Title: A novel anti-inflammatory mechanism identified by an in vivo chemical genetic screen
Author: Robertson, Anne L.
ISNI:       0000 0004 2745 1135
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2013
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Neutrophil clearance is an essential prerequisite for the successful resolution of inflammation. Dysregulation of the mechanisms that regulate inflammation resolution may lead to persistent neutrophilic inflammation and extensive host tissue damage, which contributes to the pathogenesis of chronic inflammatory diseases. Many of these respond poorly to current treatments and uncovering new mechanisms by which inflammation resolution can be accelerated is key for the development of novel, more effective therapies, which specifically target neutrophil clearance. Using a zebrafish model of neutrophilic inflammation, I have designed and optimised a partially automated compound screening assay, with the hypothesis that this would lead to the discovery of novel or previously unsuspected anti-inflammatory compounds that accelerate the resolution of inflammation. This approach enabled the identification of multiple active compounds, acting via distinct anti-inflammatory and pro-resolution mechanisms. By hierarchical cluster analysis, I was able to accurately predict the mechanism of action of one of these compounds, isopimpinellin, which led to the development of a model for analysing PI-3K activity during neutrophil recruitment in vivo. Chemical structure comparison also revealed a potential structure-activity relationship within a subset of the assay positive compounds. The most interesting compound identified, tanshinone IIA, was found to induce apoptosis of human neutrophils in vitro, even in the presence of survival signals, but also drive inflammation resolution in vivo via an additional, novel mechanism. Tanshinone IIA promotes neutrophil clearance from the wound by reverse migration, without increasing neutrophil speed, and dynamic modelling reveals that this occurs as a passive redistribution process rather than active fugetaxis. Importantly, this effect is maintained in the presence of survival signalling. This is the first evidence to demonstrate that it is possible to pharmacologically drive inflammation resolution by promoting neutrophil reverse migration.
Supervisor: Renshaw, Stephen A. ; Whyte, Moira K. B. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available