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dc.contributor.authorPaul-Clark, Mark John
dc.description.abstractNitric oxide (NO) is a signalling molecule formed when L-arginine is converted to L-citrulline by the enzyme NO synthase (NOS. NOS exists as three isoforms, ecNOS is constitutively expressed in endothelial cells and nNOS in neuronal cells, while a third isoform (iNOS) is induced in response to inflammatory stimuli and is capable of sustained production of high levels of NO. NO produced in response to an inflammatory insult, has been shown by use of NOS inhibitors to be detrimental during inflammation by producing the potent oxidising agent peroxynitrite. However, iNOS knockout animals generally produce a similar inflammatory profile to wild type controls. Hence, there is a discrepancy between the effects of phamacological inhibition and gene deletion of iNOS in vivo. Therefore, the aim of this thesis is to use a number of approaches to modulate NO production in acute and chronic inflammatory models and to assess the effects on the NOS pathway and other markers of the inflammatory response. In this thesis, it was established that iNOS protein expression and nitrite formation was significantly elevated after injection of the inflammatory stimulus in the carrageenin-induced pleurisy (RCIP), bovine serum albumin (BSA)-induced pleurisy and methylated BSA-induced pleurisy in the rat, and a murine models of croton oil-induced chronic granulomatous tissue of the air pouch (MCGTAP). The majority of immunostaining was associated with migrating inflammatory cells. NO production was modulated in acute and chronic models of inflammation using NOS inhibitors and NSAIDs. Local injection of NOS inhibitors in the RCIP model caused an increase in pro-inflammatory mediators, including superoxide, histamine and PMN chemoattractants that resulted in an exacerbation of inflammation. This was a result of inhibition of both eNOS and NOS at the inflammatory site. In contrast, systemic inhibition of NOS reduced both inflammatory cell influx and exudation into the pleural cavity. A similar inhibitory ABSTRACT result was obtained after NOS inhibition in the MCGTAP model. This antiinflammatory effect was supported by experiments in mice whose iNOS gene had been genetically deleted. Interestingly, oral aspirin administration significantly elevated nitrite formation in both the RCIP and MCGTAP with a concomitant decrease in inflammation. Further analysis demonstrated that aspirin was able to elevate NO production in lipopolysaccharide induced J774 macrophages and A23187 stimulated EA. hy926 endothelial cells, suggesting that both cell types may be involved in the pharmacological actions of aspirin. In conclusion, NO is a multi-functional free-radical which had advantageous effects in the acute resolving model and detrimental effects in chronic inflammation. Therefore, depending on the levels and micro-environment in which it is produced NO can be either good or baden_US
dc.publisherQueen Mary University of London
dc.subjectElectronic Engineeringen_US
dc.titleNitric oxide in acute and chronic inflammation.en_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author

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    Theses Awarded by Queen Mary University of London

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