Holyer, Ian (2011)
Ph.D. thesis, University of Birmingham.
Recent studies have demonstrated a key role for platelets and microthrombi in the pathophysiology of intestinal ischaemia-reperfusion (IR) injury. The research described in this thesis investigates the role of the major platelet glycoprotein receptors in recruiting and activating platelets following intestinal IR injury, namely GPVI, GPIb-IX-V and the integrins IIb3 and 21. Intravital microscopy was utilised to monitor individual platelet adhesion and microthrombus formation in anaesthetised mice undergoing intestinal IR injury \(in\) \(vivo\) using a novel dual labelling methodology. This study focussed on the microcirculation of the mucosal villi as this luminal surface is most susceptible to IR injury. We demonstrate that it was necessary to inhibit both microthrombus formation as well as platelet-leukocyte-endothelial interactions in order to ensure longer lasting improvement in gut microcirculation and histology. This was achieved through a dual therapy that targeted both GPIb and P-selectin. The strongest anti-platelet effect was observed with blocking the IIb3 integrin, but this was also associated with a sustained bleeding from the mucosal surface. Overall, the research within this thesis suggests that therapeutic strategies targeting GPIb and P-selectin may prove beneficial in improving the clinical morbidity associated with gut IR injury.
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