Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.626077
Title: Investigating the molecular mechanisms of hypothermia-mediated hepatic protection following intestinal ischaemia-reperfusion injury
Author: Parkinson, E. J.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Abstract:
The pathophysiology of hepatic energy failure following intestinal ischaemia-reperfusion injury (IIR) is not fully understood. In an experimental model of IIR, moderate hypothermia reduces hepatic dysfunction. The aim of this thesis was to investigate the molecular mechanisms of hypothermia-mediated hepatic protection following IIR. Results: Although heat shock proteins (HSPs) can be induced by hypothermia, there were no differences in levels of cytosolic HSPs between normothermic and hypothermic IIR groups. Normothermic IIR (NIIR), however, caused a significant increase in activated (phosphorylated) STAT (Signal Transducers and Activators of Transcription) proteins compared with normothermic sham (NS), an action which was completely abolished by moderate hypothermia. Microarray technology revealed increased hepatic gene expression of several acute phase proteins following NIIR which decreased following hypothermia. These effects were investigated further using PCR and measurement of protein amount of targets identified from the gene array. NIIR results in a significant increase in both IL-1β protein and IL-1 receptor antagonist (IL-1Ra) compared with sham operation. In contrast, hypothermic IIR (HIIR) results in a significant decrease in hepatic IL-1β as compared to NIIR but did not significantly change the level of IL-1Ra. In order to investigate whether mitochondrial dysfunction was central to the pathogenesis of hepatic energy failure, biochemical measurements of mitochondrial function and proteomic studies of isolated hepatic mitochondria was performed. Although there were no differences in mitochondrial function, there were several differences observed in important mitochondrial proteins (e.g. mitochondrial HSPs and thioredoxin-dependent peroxidise reductase) revealed by 2D-DIGE. Conclusions: Hypothermic protection does not appear to act via cytosolic HSPs, but activation of STAT pathways may be involved, which may subsequently reduce the hepatic acute phase response. Although primary energetic failure of hepatic mitochondria does not appear to occur following NIIR, there may be other mitochondrial effects mediated at the protein level which ultimately lead to hepatic energy failure.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.626077  DOI: Not available
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