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Title: The role of oxidative and nitrosative stress in the development of circulatory changes in cirrhosis
Author: Marley, Richard Thomas Coles
ISNI:       0000 0004 2669 2199
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2007
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There is abundant evidence that liver disease is associated with both increased production of reactive oxygen species and of nitric oxide. Previous studies of antioxidant therapy in advanced liver disease have, however, shown only minimal effects on disease progression. In this thesis, oxidative stress is shown to be increased in patients with liver disease by quantification of plasma and urinary F2-isoprostanes. The F2-isoprostanes, in addition to being markers of oxidant stress, are also vasoactive compounds. This is confirmed by the demonstration that 8-isoprostaglandin F2a causes intrahepatic vasoconstriction in rat livers, an effect which is markedly enhanced in rats with secondary biliary cirrhosis, when compared to controls. Ethanol is also shown to cause marked vasoconstriction in cirrhotic rats, though this appears to be mediated by endothelins rather than isoprostanes. The effects of antioxidant therapy on both disease progression and haemodynamic parameters were studied. In bile duct ligated rats chronic administration of the antioxidant lipoic acid prevents the development of the hyperdynamic circulation, in association with a reduced level of nitric oxide synthase activity when compared to control rats. There is, however, no effect on either histological or biochemical parameters. The combination of increased nitric oxide production in the presence of reactive oxygen species alters the chemistry and physiology of nitric oxide. Overproduction of a group of long acting nitric oxide carrier molecules, the S-nitrosothiols, would be predicted under such circumstances. In order to examine the biochemistry of S-nitrosothiols the development of a novel assay is described, capable of measuring plasma concentrations of these compounds down to a concentration of 5 nM. Using this assay normal plasma concentrations were shown to be orders of magnitude lower than has been previously suggested. New insights into the chemistry of S-nitrosothiols, in particular their generation by nitric oxide under aerobic conditions, and their degradation by thiols through transnitrosation reactions is described. This development has opened the way to future studies of the role of these compounds in all disease processes including those involving the liver.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available