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The role of extra and intra vascular cells and their molecules in modulating glomerular inflammation during health and disease

Kuravi, Sahithi Jyothsna (2012)
Ph.D. thesis, University of Birmingham.

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Abstract

Endothelium forms an interface between vasculature and cellular sub endothelial environment responding to the changes in the immediate environment in health and disease. During vasculitic glomerulonephritis (VGN), autoantibodies raised against neutrophil serine proteases (SP) activate the neutrophils resulting in the release of neutrophilic products onto the endothelial surface changing its ability to support neutrophil recruitment and leading to its damage. We have hypothesized that endothelial functions are modulated by intra and extracellular environments of the vasculature and that the glomerular epithelial cells (podocytes) regulate glomerular endothelial cell (GEnC) functions.
This work investigated the effects of SP (Proteinase-3 (PR3) and human neutrophil elastase (HNE)) in mediating neutrophil recruitment on EnC prior to the development of injury in a concentration and time dependent fashion. Most of the effects were inhibitable by the presence of α1-antitrypsin (α1-AT). Further, using an in vitro static co-culture system, this work demonstrates an endogenous mechanism by which podocytes modulate endothelial response to inflammatory stimuli in the glomerulus under healthy and disease conditions.
Overall, these studies elucidate that GEnC presents an adhesive phenotype attracting neutrophils under the influence of inflammatory cytokines. During disease conditions as in VGN, exposure of endothelium to SPs results in a pre-activation stage leading to damage with high and/or prolonged exposures. Podocytes modulate glomerular endothelial responses to cytokine stimulation in health and disease. Thus, endothelial functions are tightly regulated by interacting cells and their molecules and could be an important phenomenon in the disease process of VGN where neutrophil recruitment plays a central pathogenic role.

Type of Work:Ph.D. thesis.
Supervisor(s):Savage, Caroline and Rainger, Ed and Tull, Samantha
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Department of Immunity and Infection
Keywords:Inflammation, Antineutrophil cytoplasmic autoantibodies, podocytes, glomerular endothelial cells, neutrophils, Interleukin-6
Subjects:QR Microbiology
R Medicine (General)
Institution:University of Birmingham
ID Code:3363
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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