Monocytic microparticles as mediators of the vascular inflammatory response

Abstract

Unregulated inflammation is broadly often held accountable for the devastating effects of sepsis and septic shock. This crude description does not allow for the full appreciation of the complexity of events that precede what is finally observed as the symptoms of septic shock. Current important players which are well understood and well described that are responsible for microvasculature dysfunction include monocytes and endothelial cells. However, the contribution of a new class of inflammatory mediators, namely plasma membrane microparticles, remains to be fully understood. This study aimed to better evaluate the production, cell-interactions and effects of microparticles derived from monocytes. The knockdown effect of ATP-binding cassettes on monocytic-microparticle release upon endotoxin stimulation was investigated. Tracing the path of monocytic-microparticles, from binding to endothelial processing, revealed not only a separation of microparticle membrane from cytosolic cargo but also endothelial trafficking and compartmentalisation. Such vesicles also imparted profound effects on endothelial cells, both phenotypically and functionally The data within this thesis suggest and provide a basis for future investigation and a new target for therapeutic manipulation. It also offers a small insight into the fine but complicated mechanisms of microparticle production and communication that may occur in the early stages of sepsis.