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