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Human phospholipase A2 and its relationship to the biochemistry of disease states

Langton, Simon R. (1992) Human phospholipase A2 and its relationship to the biochemistry of disease states. PhD thesis, Murdoch University.

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The thesis has produced 9 publications, two in Australian and seven in International journals. A further article has been subitted and a review by invitation on "PLA2 and Cardiovascular Disease" is in preparation for an international journal; 5 oral presentations have been given at three National and two International meetings. The subject of the thesis is phospholipase A2 (PLA2) and its immediate metabolic products (lysolecithin and fatty acids), and their influence on specific conditions or diseases in human medicine.

During this study several assays were used for the measurement of the enzyme. They were radiometric, bioassay, and fluorimetric methods for measuring the catalytic activity of PLA2. One assay was developed for measuring the concentration of specific PLA2 protein immunologically. This immunoassay involved the preparation of pure human PLA2 and the production of monoclonal and polyclonal antibodies to the purified human enzyme. These were produced and used to measure PLA2 in blood in several clinical conditions. The levels of reaction products of PLA2, lysolecithin, fatty acids and in one instance Lyso-platelet activating factor (LysoPAF) were also measured. A novel method was developed for measuring lysolecithin, a parameter which provides an indirect measure of the in-vivo activity of PLA2.

The magnitude and changes in value of the PLA2 enzyme and lysolecithin were measured in several clinical studies on patients with defined diseases such as pancreatitis, myocardial infarction and gastritis. They were also measured in relation to aspects of diseases resulting from ischaemia and blood transfusions. The effect of plasma proteins, in particular albumin on the PLA2 results in acute pancreatitis and the relationship between PLA2, amylase and lipase was examined. An investigation of autoimmune response to PLA2 in the pancreatitis patients was also undertaken. The effect of PLA2 from Helicobacter pylori, a recently discovered gastric bacterium was investigated in respect of its acknowledged association with peptic ulcers, involvement of PLA2 in inflammatory diseases is well established and an hypothesis was developed for its involvement in gastric ulceration.

PLA2 was also investigated in experimental, surgical and spontaneous cardiac ischaemia (infarction). The objective was to examine the mechanisms by which ischaemic changes can affect patient wellbeing. PLA2 was also investigated briefly in pulmonary diseases such as sudden infant death syndrome (SIDS) and adult respiratory distress syndrome (ARDS) to see if PLA2 was involved and if parallels could be drawn between these pulmonary problems.

Finally the changes in PLA2 and its metabolites in stored blood, blood transfusions and during vascular and cardiac bypass surgery were examined. The implications and potential problems arising from the biochemical changes in both homologous and heterologous blood transfusions, were investigated.

The overall conclusions indicate that PLA2 is an enzyme that can damage tissues in several ways and small increases in its activity in the circulation are enough to precipitate systemic problems. The use of PLA2 inhibitors was investigated briefly and it is clear that this is one direction in which further research into PLA2 will proceed. There is a need for an effective PLA2 inhibitor that has few side effects and can be used for reducing PLA2 activity in a wide variety of clinical conditions and in inflammatory It is conceivable that anti-PLA2 compounds may be given prophylactically to reduce risk of complications in surgery and transfusions in the future.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): School of Biological and Environmental Sciences
Notes: Note to the author: If you would like to make your thesis openly available on Murdoch University Library's Research Repository, please contact: Thank you.
Supervisor(s): Mead, Robert
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