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dc.contributor.advisorBhatia, Madhav
dc.contributor.advisorGiles, Greg
dc.contributor.authorAng, Abel Damien
dc.date.available2016-02-15T23:13:53Z
dc.date.copyright2016
dc.identifier.citationAng, A. D. (2016). Role of endogenous hydrogen sulfide synthesised by cystathionine-gamma-lyase in the inflammatory response in acute pancreatitis (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/6219en
dc.identifier.urihttp://hdl.handle.net/10523/6219
dc.description.abstractMammals have the ability to synthesise endogenous hydrogen sulfide via desulfhydration enzymes though the physiological effects are still relatively unclear particularly in the inflammatory response. Endogenous hydrogen sulfide has been shown to be both pro and anti-inflammatory in numerous models of disease in animals. Common aspects of these studies are the reported dysregulation of tissue cystathionine-gamma-lyase (CSE) expression (the major hydrogen sulfide producing enzyme in the periphery) and the use of D,L-propargylglycine (PAG) to inhibit CSE activity. However, PAG is not a specific inhibitor and very few studies have correlated CSE dysregulation with changes in endogenous tissue hydrogen sulfide levels. Therefore the aims of this thesis were to investigate pancreatic and macrophage CSE dysregulation in acute pancreatitis, to correlate this dysregulation with changes in endogenous hydrogen sulfide levels/ hydrogen sulfide modified proteins and to determine the effect of CSE gene deletion on disease severity and the inflammatory response. Results in this thesis show that acute pancreatitis directly mediated upregulation in pancreatic CSE expression which was a gap in the existing body of knowledge. I have also found novel evidence of acute pancreatitis induced upregulation of CSE in macrophages with in vitro studies using plasma from pancreatitic mice and elucidated the molecular mechanisms involved. CSE gene deletion resulted in an amelioration of acute pancreatitis with reduced plasma amylase levels, pancreatic and lung neutrophil infiltration, oedema as well as acinar cell damage. There was also a reduction in pancreatic pro-inflammatory mediators, MCP-1, MIP-2alpha, IL-6, and PGE2 as well as NFkappaB activation. Similar findings were found in vitro using isolated primary pancreatic acini. The results of this thesis incontrovertibly show that CSE exerts pro-inflammatory effects in acute pancreatitis and corroborates with previous studies using PAG. It also shows upregulation of CSE in stimulated macrophages thus suggesting a role for endogenous hydrogen sulfide in the modulation of macrophage activation.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjecth2s
dc.subjecthydrogen sulfide
dc.subjectinflammation
dc.subjectcse
dc.subjectendogenous
dc.subjectacute pancreatitis
dc.subjectmacrophage
dc.titleRole of endogenous hydrogen sulfide synthesised by cystathionine-gamma-lyase in the inflammatory response in acute pancreatitis
dc.typeThesis
dc.date.updated2016-02-15T22:38:03Z
dc.language.rfc3066en
thesis.degree.disciplinePathology
thesis.degree.nameDoctor of Philosophy
thesis.degree.grantorUniversity of Otago
thesis.degree.levelDoctoral
otago.openaccessOpen
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