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An activating role for neutrophil serine proteases in rapidly progressive glomerulonephritis

Bevins, Anne (2011)
Ph.D. thesis, University of Birmingham.

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Abstract

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.

Type of Work:Ph.D. thesis.
Supervisor(s):Savage, Caroline and Rainger, Gerald
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Immunity and Infection
Subjects:RA Public aspects of medicine
Institution:University of Birmingham
ID Code:2932
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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