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Title: The regulation of mesangial cell apoptosis by inflammatory macrophages
Author: Duffield, Jeremy Stuart
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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Mesangial cells (MC) are a major cell-type in the healthy glomerulus. They respond to inflammation by proliferation and laying-down scar tissue. In animal models, deletion of excess MC by a cell death process called apoptosis is crucial for resolution and restoration of the normal tissue. Coincident with the occurrence of MC apoptosis is the presence of inflammatory macrophages (M) in the mesangial areas of the glomerulus. Motivated by a clear role for M in deleting excess cells in developmental remodelling, I sought to determine whether inflammatory M as found in the diseased glomerulus could induce apoptotic death in of cultured MC. By developing an in vitro assay of proliferating MC with M as a model of glomerular inflammation, M, either activated by cytokines, or taken directly from diseased glomeruli, induced apoptotic death of MC. Thus, M were able to control MC populations. Roles for M derived nitric oxide and tumour necrosis factor (TNF) in mediating these effects on MC were clearly shown. Further, when M ingested opsonised particles (to model immune complex activation), hydrogen peroxide release was also found to induce MC apoptosis. Excessive M killing of MC is also deleterious to healing of the glomerulus, since excessive MC loss also leads to scarring. Negative feedback in M killing was sought. Since M ingestion of apoptotic cells leads to transforming growth factor beta release, I hypothesised that once M had induced MC apoptosis and ingested that dead cells, they might deactivate. Co-culture was modified whereby activated M ingested pre-formed apoptotic cells whilst in the process of killing healthy MC. These M were rendered incapable of inducing TNF dependent MC apoptosis, indicating a novel negative feedback loop in the inflammatory response. TNF receptor 1 signalling pathways of apoptosis in MC were investigated. Following stable transfection, an important role for interferon regulatory factor-1 was shown.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available