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Title: The effect of sulforaphane on leukocyte-endothelial interactions and platelet activation during inflammation and thrombosis
Author: Gillespie, Scarlett
ISNI:       0000 0004 6059 0989
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Inflammation is thought to play a driving role in an expanding number of vascular and cerebral pathologies. Sulforaphane (SFN) is a naturally occurring isothiocyanate which has previously been shown to harbour anti-inflammatory properties in several immune cell types. In this work, intra vital microscopy was used to visualise the cellular interactions within the cerebral microvasculature stimulated downstream of an inflammatory challenge, namely intraperitoneal injection of LPS (0.1-4mg/kg). This resulted in a time, not dose, dependent stimulation of leukocyte-endothelial interactions; the number of rolling cells significantly increased, cells exhibited a slow rolling velocity and the number of adherent cells significantly increased versus sham or vehicle treated animals. SFN pre-treatment at 50mg/kg 24hr prior to LPS challenge (0.5mg/kg), increased the number of cells rolling through the cerebral microvasculature, significantly increased the speed at which they were rolling versus LPS treated animals and decreased the number of cells that were adherent to the pial vessel walls. These alterations were not associated with alterations in systemic cytokine levels (IL12p70, IL-6, TNFα, IL-10, IFNγ, MCP-1) or nuclear Nrf2 expression within the cerebral cortex. LPS (1µg/ml) increased IL-1β release from isolated human neutrophils which also showed no alteration following SFN incubation (0.1-25µM). Investigation into the effects of SFN revealed that SFN significantly altered the ability of platelets to aggregation in response to several agonists (thrombin, collagen and ADP), and that this response was not associated with the intracellular Ca2+ movement or induction of LDH release. This work highlights the ability of SFN to alter inflammatory cell interactions within the cerebral microvasculature in vivo, and also indicates the inhibitory effect of SFN on isolated platelet function ex vivo.
Supervisor: Gavins, Felicity Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral