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Title: Resolving inflammation after stroke through modulation of Formyl Peptide Receptor 2, the lipoxin receptor
Author: Smith, Helen Katherine
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Stroke kills 15 million people a year and causes disabilities in many more millions who survive. Most strokes are caused by a blood clot, yet only seven percent of patients qualify for early pharmacological clot removal. Damage is frequently exacerbated even as blood reperfuses an ischaemic brain region, through a concomitant inflammatory response to the damaged tissue. Following the continual failure in clinical trials of drugs intended to tackle both initial excitotoxic cell death and pro-inflammatory mechanisms during ischaemia/reperfusion (I/R), this thesis is premised on enhancing 'pro-resolving' anti-inflammatory pathways. Formyl Peptide Receptor 2/the lipoxin receptor (FPR2/ALX; mouse orthologue Fpr2/3) and two of its ligands, Lipoxin A4 (LXA4) and Annexin A1 (AnxA1), are part of an endogenous anti-inflammatory system. They actively resolve inflammation through a reduction in characteristic leukocyte-endothelial (L-E) interactions, while promoting the production of anti-inflammatory cytokines and non-phlogistic phagocytosis of leukocytes already within tissue. Chapters 3-5 of this thesis describe the development of mouse model of global cerebral I/R (5 min ischaemia/40 min or 2 h reperfusion) through which L-E interactions are assessed using intravital microscopy. Substantial reductions in L-E interactions following treatment with FPR2/ALX ligands (AnxA1 N-terminal peptide AnxA1Ac2-26 and LXA4 analogue 15-epi-LXA4) are demonstrated along with variations in cytokine levels (MCP-1, IL-6 and IL-10) after 2 h of reperfusion. The reductions are shown to be variable with respect to the duration of reperfusion, concentration of 15-epi-LXA4 and the time of treatment administration. In addition, the effects are abrogated by co-treatment with FPR antagonists, which independently cause a highly pronounced acute inflammatory response in the model. Chapters 6 and 7 provide further investigation into the role of FPRs in stroke and inflammation, through chemotaxis studies on human monocytes (from stroke patients and healthy controls) and through use of an FPR1-target MRI contrast agent in mice following lipopolysaccaride-induced inflammation. Overall, the data provide evidence that Fpr2/3 ligands are able to reduce inflammation following cerebral I/R, that an FPR2/ALX-targeted drug may therefore be effective in human stroke, and that its optimal use is likely to be administration time, dose and FPR2/ALX ligand-dependent.
Supervisor: Gavins, Felicity Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral