The role of ischaemia-reperfusion injury and mitochondrial dysfunction in organ transplantation

Summary The role of ischaemia-reperfusion injury and mitochondrial dysfunction in organ transplantation Ischaemia and subsequent reperfusion is inherent to solid organ transplantation and contributes to tissue damage, organ dysfunction, and worse recipient outcome. Demand for organs for transplantation in the UK has led to the increasing use of ‘less-than-ideal’ deceased organs that are less tolerant of ischaemia or have been exposed to greater ischaemic insults. Furthermore, outcomes from clinical transplantation suggest that increasing ischaemia-reperfusion (IR) injury influences not only short-term outcomes but also longer-term outcomes by increasing the rate of chronic organ rejection. Mitochondria are recognised as being integral to IR injury generating a burst of reactive oxygen species that initiates downstream tissue damage. There is emerging evidence that this process is driven by a specific metabolic pathway rather than by a series of random damaging events. A better understanding of this pathophysiology and the mechanisms underpinning IR injury will increase the opportunity for the development of rational therapeutic approaches. In this work, I have characterised ischaemic metabolism during warm and cold organ storage in murine, porcine and human myocardial tissue. I have demonstrated succinate accumulation to be a conserved signature of ischaemia across species and have demonstrated the ability to moderate metabolic pathways in the mouse heart during organ storage using metabolic inhibitors. In order to investigate the effects of the metabolic changes during ischaemia on reperfusion I developed a novel, small animal model of solid organ transplantation incorporating a warm ischaemic insult. I then used this model to examine the therapeutic efficacy of ameliorating succinate accumulation during ischaemia to reduce organ dysfunction upon reperfusion. Finally, I explored the impact of reperfusion injury on chronic rejection in a previously well characterised model of organ rejection. Jack Lewis Martin

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2019

Author dc:creator

• Martin, Jack

Advisors dc:contributor.advisor

• Saeb-Parsy, Kourosh
• Murphy, Michael

• Organ transplantation
• Mitochondria
• Ischaemia-Reperfusion

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/d4171454-13cf-4e95-b2b4-ed31b2b21860/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.41449

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/294351