Characterisation of Inflammatory Responses in Two Models of Experimental Ischaemia

Marks, Louise (2001) Characterisation of Inflammatory Responses in Two Models of Experimental Ischaemia. PhD thesis, University of Glasgow.

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Abstract

Stroke is one of the leading causes of death and disability throughout the world with limited effective therapies currently available. It is therefore an important and deserving area for experimental research. The mechanisms underlying the damage associated with stroke are very complex and include excitotoxicity and oxidative stress as well as a number of inflammatory mediated mechanisms which ultimately leads to both necrotic and apoptotic cell death. An inflammatory response can occur within minutes of an ischaemic insult and has been well documented. The response is proposed to involve resident inflammatory cells of the brain such as microglia and circulating inflammatory cells such as macrophages and neutrophils. Although numbers of inflammatory cells have been reported to increase under ischaemic conditions, opinion remains divided as to what the exact role of these cells are in ischaemic damage and whether these roles are beneficial or detrimental. This thesis examined the role of the circulating inflammatory cell the neutrophil, the brain's resident inflammatory cell the microglia and the inflammatory mediators IL-1beta, rat neutrophil collagenase (MMP-8) and gelatinase B (MMP-9) in experimental models of middle cerebral artery occlusion in the rat to gain a better understanding of their roles in ischaemic damage The role of the neutrophil in inflammatory mediated ischaemic damage was examined in two models of focal ischaemia- 1) the intraluminal thread model of transient middle cerebral artery occlusion (2 hours occlusion + 2 or 22 hours reperfusion ) and 2) the diathermy model of permanent middle cerebral artery occlusion (4-72 hours). This study found no evidence for significant neutrophil accumulation in the parenchyma or adherence to cerebral blood vessels in acute focal cerebral ischaemia using scanning electron microscopy and light microscopy in either Sprague Dawley rats (intraluminal thread) or Spontaneously Hypertensive Stroke Prone Rats (SHRSP) (diathermy model) up to 72 hours post ischaemia. It has been reported that neutrophil accumulation following ischaemia can result in the impairment of blood flow and damage via the release of cytotoxic substances. Some groups have reported significant neutrophil accumulation in models of experimental ischaemia and have demonstrated significant reductions in ischaemic damage upon administration of antibodies designed to prevent neutrophil adhesion to the endothelium of blood vessels. However in accordance with the findings of this study, some groups have also failed to show significant neutrophil accumulation in the same models of experimental ischaemia, suggesting that they may not be major contributors to acute ischaemic damage. In addition to neutrophil accumulation, this thesis also considered the possible pathogenic role of microglia in ischaemic damage. Microglial activation was examined in the diathermy model of permanent middle cerebral artery occlusion in the SHRSP and their normotensive reference strain the Wistar Kyoto (WKY) Quantitative analysis of the microglial response to focal cerebral ischaemia in the SHRSP and WKY revealed three major points: 1) SHRSP displayed increases in the numbers of activated microglia associated with the site of injury compared to the WKY reference strain between 4 and 72 hours. These differences were most significant at 24 hours post ischaemia and within the peri-infarct zone. At 24 hours the infarct is still evolving and so the presence of activated microglia in the peri- infarct region may suggest a role for the cells in the expansion of the infarct; 2) activated microglia were found to express MMP-8 and MMP-9, known contributors to the pathology of a number of inflammatory conditions and 3) under normal, non- ischaemic conditions, SHRSP also displayed a greater density of microglia, especially in the white matter tracts compared to WKY rats. This is an important study as it is the first to measure the evolution of the infarct in the SHRSP and investigate the inflammatory response over 72 hours. The greater degree of microglial activation in the SHRSP may be representative of the enhanced inflammatory response to ischaemia previously reported in this strain with the increased microglial activation possibly contributing to the genetically determined stroke sensitivity of the SHRSP. Microglia are known to become activated in conditions of ischaemia and have been reported to either contribute to ischaemic damage via the release of cytotoxic substances or to promote recovery and prevent further damage by inducing re-growth and repair via phagocytosis and the release of growth factors. Therefore, the findings of this study are important both in terms of improving our understanding of genetically determined stroke sensitivity and of the role of inflammatory cells in focal cerebral ischaemia, two research areas associated with many unresolved questions and opposing views. In addition to the role of inflammatory cells in ischaemic damage, this thesis also examined other possible contributors to inflammatory mediated ischaemic damage.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Mhairi Macrae
Keywords: Neurosciences
Date of Award: 2001
Depositing User: Enlighten Team
Unique ID: glathesis:2001-76263
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Dec 2019 09:15
Last Modified: 19 Dec 2019 09:15
URI: http://theses.gla.ac.uk/id/eprint/76263

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