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Title: Molecular mechanisms and therapeutic perspectives of xenon in attenuating renal graft ischemia-reperfusion injury
Author: Zhao, Halin
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Ischaemia-reperfusion injury (IRI) following prolonged hypothermic storage contributes to the occurrence of delayed graft function and progression of end-stage graft failure. The objective of my thesis is to evaluate xenon in preventing graft ischaemia-reperfusion injury in a rat model of kidney transplantation. The ultimate aim is to improve the long-term transplant outcome through preserving the graft quality. I have demonstrated that exposure of human proximal tubular cells (HK-2) to xenon activated IGF-1, HIF-1a, VEGF, HO-1, Bcl-2 and HSP-70. Xenon treatment prior to, or after, hypothermia-hypoxia challenge conferred protection against cell injury. In the Lewis to Lewis rat syngeneic renal grafts, xenon exposure before graft retrieval from donors or after engraftment in recipients decreased caspase-3 expression, and prevented TLR-4/NF-kB activation. The serum level of pro-inflammatory cytokines IL-1?, IL-6 and TNF-a was reduced and renal function was preserved. In the Brown-Norway to Lewis rat allogeneic renal grafts, xenon donor pre-treatment and recipient post-treatment decreased the renal tubular cell death, tubular inflammation and tubular MHC II expression. This in turn improved early graft function. T cell mediated alloresponse was therefore reduced. In combination with cyclosporine A, both xenon pre-treatment and xenon post-treatment prolonged the renal graft survival. In the Fischer-to-Lewis rat allogeneic grafts, xenon exposure to donors before graft retrieval or to recipients after engraftment enhanced tubular cell proliferation, decreased tubular cell death and graft inflammation associated with IRI. T cell infiltration and fibrosis were significantly suppressed with xenon treatment, chronic allograft nephropathy was attenuated. In summary, my thesis shows that either xenon donor pre-treatment or recipient post-treatment protected the renal graft against IRI, which in turn reduced acute immune rejection and attenuated chronic allograft nephropathy. This novel approach against IRI could be translated into clinical practice leading to considerable increase in viable organ availability and improvement in the long-term graft survival.
Supervisor: George, Andrew ; Ma, Daqing Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available