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Title: Mechanisms determining severity in acute pancreatitis
Author: McLaughlin, Euan William
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2012
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Background: Acute pancreatitis (AP) remains a significant cause of human morbidity and mortality, and for which therapy remains limited in its ability to prevent the development of severe disease. Urgent work is needed to elucidate the disease process at the cellular level to identify suitable targets for therapy. Extensive research as been undertaken in animal models, which have helped clarify the underlying complex cellular mechanisms involved, yet much still remains unclear. In particular the use of the hyperstimulation-induced animal model, particularly with cholecystokinin (or its analogue caerulein), has been controversial in recent years with detractors claiming there is no clear relevance to human disease. Work with human tissue is required to validate the findings of such animal models of acute pancreatitis. Cell death pathways are suggested to play a pivotal role in determining disease severity, with apoptosis favouring milder outcomes, and necrosis favouring increasing severity. However in recent years it has been suggested that this view may be simplistic. The Bcl-2 family of proteins have been found to be important regulators of cell death, but there have been no published work investigating their action in in vivo pancreatitis. Caffeine has been suggested as a potential therapeutic at it inhibits the abnormal Ca2+ signals associated with pancreatitis in vitro. However it's actions have not been tested in vivo. Methods: Experiments using confocal microscopy to test the responses of two subtypes of cholecystokinin (CCK-8 and CCK-58), in both isolated murine and human isolated pancreatic acinar cells, found both subtypes elicited very similar responses in both species. These responses were linked to metabolic activity (as measured by increase in mitochondrial NADH) and secretion (measured by loss of quinacrine from zymogen granules). These results validate continued use of the hyperstimulation model of acute pancreatitis. Results: Caerulein-induced AP in Bak, Bax and Bcl-2 knockout (KO) mice revealed surprising results. Bcl-2 KO had little effect on AP, Bak KO led to less severe disease, but no change in apoptosis. Bax KO led to more severe disease and early necrosis (first 8hrs), but subsequently increased apoptosis at later time points (12-24 hrs). This suggests the current understanding of Bcl-2 family proteins is incomplete. Conclusions: Caffeine was found to have protective effects in caerulein murine AP when administered at a concentration of 10 mglkg, and more so at 50 m glkg but this dose produced severe toxic side-effects. Further work is needed to optimise the correct dose and test caffeine metabolites and/or analogues.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available