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Title: Vascular cell activation : mechanisms and consequences in human disease
Author: Diamond, Pauline
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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Local vascular cell activation occurs at sites of injury/inflammation. This results in the elaboration of cytokines, chemokines and, ultimately, the infiltration of interstitial tissues by peripheral blood leukocytes. Such vascular cell activation, while essential in host defence, has pathological consequences in a variety of human diseases. The immunopathology of these processes in the development of atherosclerosis, vasculitis, thrombosis, vasoconstriction and allograft rejection and their phenotypic expression is discussed in detail. The growing evidence linking systemic hypertension with the development of atherosclerosis, and glomerular hypertension/glomerulosclerosis is also reviewed. Evidence has been provided that mechanical strain acting on the vessel/glomerulus may be a trigger for antigen-independent vascular cell activation in these diseases. In the current study in vitro experiments were designed to focus specifically on the putative modulation of immune mediator expression by mechanical strain. Results demonstrate that mechanical strain can be either a proinflammatory or prosclerotic stimulus depending on the cell type used and provide further insights into the molecular mechanisms underlying the pathogenesis of these conditions. Finally, observations in both acute and chronic vascular disease suggest the existence of endogenous regulatory systems that act to restore homeostatic vascular tone, thrombogenicity and adhesiveness for leukocytes to normal. In this dynamic process a number of anti-inflammatory molecules are elaborated. Experiments focused on the actions of lipoxins, a group of rapidly-acting anti-inflammatory eicosanoids - specifically the signal transduction events triggered by the activation of lipoxin receptors in endothelial and mesangial cells. The suppressors of cytokine signalling (SOCS) proteins are a recently identified family of proteins which inhibit cytokine-activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) cascade. Experiments were undertaken to elucidate the role of SOCS in renal inflammation. In addition, the profile of SOCS expression, along with that of related immune mediators, was examined in a model of alloantigen-driven inflammation - experimental cardiac transplant rejection. SOCS expression was confirmed in both these models, implicating these endogenous inhibitors in the modulation of cytokine bioactivity in inflammation and host defence.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available