Bevins, Anne (2011)
Ph.D. thesis, University of Birmingham.
ANCA-systemic vasculitic glomerulonephritides (ASV) is associated with inflammation and injury to the vascular endothelial cells. Using two different endothelial cells, human umbilical cord endothelial cells (HUVEC) and a conditionally immortalised glomerular endothelial cell line (GEnC), we investigated the role of Proteinase 3 (PR3) and human leukocyte elastase (HLE) on endothelial activation and injury. Short treatments of endothelial cells with PR3 and HLE had no effect on mitochondrial activity; endothelial detachment or intracellular ADP/ATP levels, whilst 24hour treatments induced endothelial cell apoptosis and maximal von Willebrand factor (vWf) release. Short serine protease treatments resulted in dose-dependant release of vWf from endothelial cells, which along with increased release of chemokine ligand 8 (CXCL8) and expression of P-Selectin. PR3 and HLE treatment increased neutrophil adhesion to the endothelium through interactions between P-Selectin and its ligand, P-Selectin glycoprotein ligand-1 (PSGL-1), on neutrophils, and could be inhibited by blocking antibodies directed at PSGL-1. PR3 and HLE cleaved CXCL8 for support of inflammation, perhaps inducing activation of leukocyte integrins to increase adhesion. The inhibition of CXCL8 receptors, CXCR1 and CXCR2, on neutrophils decreased the level of neutrophil adhesion. Together these results suggest a short-term activatory role for the serine proteases on the vascular endothelium.
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