Whiteley, Graham Stuart Wynward; (1990) The modulation of lipid peroxidation in liver ischaemia. Doctoral thesis (M.S), University of London, Royal Free Hospital School of Medicine.

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Abstract

The Modulation of Lipid Peroxidation in Liver Ischaemia Iatrogenic and pathological organ ischaemia and subsequent reperfusion are common occurrences in surgical practice. The inevitable ischaemia which follows removal of an organ for transplantation and its reperfusion in the recipient, the planned occlusion of blood vessels to control haemorrhage during surgery on the organs supplied by them, or to repair or replace the vessels themselves are examples. Understanding the sequelae of these unphysiological situations, with a view to reducing irreversible damage, is essential. Oxygen derived free radicals have been implicated as agents of damage during both ischaemia and reperfusion. To investigate this hypothesis, the effect of normothermic ischaemia on rat liver has been investigated. Lipid peroxidation, which has been shown to be an indicator of free radical production was measured over three hours normothermic ischaemia. This was assessed by measuring the peroxidation products malondialdehyde and conjugated dienes and the ratio of oxidised to reduced glutathione. Glutathione is an endogenous scavenger of oxygen derived free radicals and exists in both oxidised and reduced forms. Lipid peroxidation results in the oxidation of reduced glutathione. The total glutathione level remains constant as it is not used up in the conversion to the oxidised from the reduced form. Thus both oxidised and reduced forms of glutathione were measured and a ratio of oxidised to reduced glutathione was calculated and used as an estimation of the extent of lipid peroxidation. Any changes in liver metabolism after three hours warm ischaemia in vitro was determined by measuring one element of synthetic ability, urea production. A repeatable pattern of deterioration was established. The production of lipid peroxidation products, malondialdehyde and conjugated dienes increased significantly after periods of 60 minutes ischaemia. The oxidised/reduced glutathione ratio showed highly significant changes after the same period. Taken together these results suggest significant free radical production during this time. Having established that lipid peroxidation due to free radical production increased and rat liver synthetic function decreased, the modulation of this peroxidation by free radical scavenging agents was then studied. The free radical scavenging agents superoxide dismutase, allopurinol, desferrioxamine and mannitol were given to the animals before experimental ischaemia was induced. When these were administered, with the exception of mannitol, significant reduction in the parameters of lipid peroxidation were observed. Different scavengers were found to have effects on different aspects of lipid peroxidation, with superoxide dismutase being effective on all parameters. When the effect of these scavengers on synthetic function was measured, superoxide dismutase partially preserved the synthetic function. The other scavengers had no significant effect. The conclusion of the study is that significant lipid peroxidation, an index of free radical damage, occurs with periods of ischaemia of 60 minutes and above in the intact rat liver and that this peroxidation can, by the administration of superoxide dismutase, allopurinol and desferrioxamine, be reduced. The deterioration of liver function cannot totally be explained by free radical activity since only partial preservation of function was possible with superoxide dismutase. It remains to be shown if the administration of free radical scavenging agents prior to any clinical procedure which leads to hepatic ischaemia, would be beneficial in reducing hepatocellular damage.

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