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Title: The Impact of Systemic Infection Upon Acute CNS Inflammatory Responses
Author: Davis, Andrew E. M.
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2007
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Systemic infection often accompanies or precedes acute brain injury, but it is unclear how systemic responses contribute to clinical outcome. Herein, acute CNS injury in the rat has been modelled using the microinjection of interleukin-l beta (IL-I~) into the brain, or by controlled compression injury to the spinal cord. The impact of systemic bacterial or viral infection upon the pathogenesis of the inflammatory response in these models was studied. Pre-conditioning with intravenous lipopolysaccharide (LPS), mimicking early immune responses to bacterial infection, dose-dependently reduced both the leukocytosis, and the number of leukocytes recruited to the brain parenchyma in response to IL-I ~ challenge. This effect was not mimicked by systemic challenge with IL-I~, suggesting LPS-specific mechanisms were operating. In addition, LPS challenge in a dorsal air pouch did not mirror the actions of LPS administered intravenously, suggesting focal immune responses were not sufficient to stimulate protective signalling pathways. Interestingly, a post-challenge with LPS similarly inhibited the leukocytosis, and leukocyte recruitment to the IL-I ~-challenged brain and compression-injured spinal cord, an effect that was found to be partially mediated by the action of endogenous glucocorticoids. In marked contrast, the protection afforded by LPS was not conserved in a viral infection model. Systemic administration of a luciferase-expressing adenovirus (AdLuc) significantly increased the leukocytosis and numbers of leukocytes recruited to the IL-I ~-challenged brain. This was particularly evident in the contralateral hemisphere, which in our injury model is largely devoid of leukocyte recruitment. Furthermore, viral challenge increased the recruitment of leukocytes to the liver, a factor of potential significance to multi organ dysfunction, which is often concomitant with CNS injury. It can be concluded from this thesis that systemic infection can have dramatic effects upon leukocyte recruitment to sites of injury and disease in the CNS, and that the outcome is specific to the nature of the pathogen.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available