Stephenson, Barney (2020). Development and evaluation of human ex vivo normothermic machine liver perfusion for viability testing and investigation of the role of TWEAK/Fn14 in ischaemia reperfusion injury. University of Birmingham. Ph.D.
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Abstract
Liver disease is characterised by ongoing inflammation and regeneration the mechanism of which is incompletely understood, although the Fn14/TWEAK receptor-ligand system may play a role in cholangiopathies. Currently, the only treatment for end stage disease is transplantation.
This thesis describes the development of ex vivo Normothermic Machine Liver Perfusion of discarded human livers for viability testing, before validation by transplantation and assessment as a novel model of ischaemia-reperfusion injury. Biliary epithelial cells were isolated, Fn14 expression determined and functional activity of Fn14 stimulation by TWEAK established using existing in vitro modelling. Ex vivo Normothermic Machine Liver Perfusion was evaluated as a model of Fn14 expression. Perfusate lactate <2.0mmol/L after 2 hours of normothermic perfusion and delta lactate concentrations were key determinants in the viability of discarded human livers. Viability could be predicted earlier using proteomics at commencement of perfusion. Evolution of this model included using a bovine haemoglobin-based oxygen carrier as the perfusate and successful liver splitting with concurrent perfusion. This ex vivo human system then investigated the potential role of Fn14 in this newly established, validated model.
Normothermic Machine Liver Perfusion has a significant role in determining viability of discarded human livers and establishing the Machine Criteria Donor
| Type of Work: | Thesis (Doctorates > Ph.D.) | |||||||||
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| Award Type: | Doctorates > Ph.D. | |||||||||
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| Licence: | All rights reserved | |||||||||
| College/Faculty: | Colleges (2008 onwards) > College of Medical & Dental Sciences | |||||||||
| School or Department: | Institute of Immunology and Immunotherapy | |||||||||
| Funders: | Medical Research Council | |||||||||
| Subjects: | Q Science > QR Microbiology > QR180 Immunology R Medicine > RC Internal medicine |
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| URI: | http://etheses.bham.ac.uk/id/eprint/9928 |
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