Tackling regulated cell death improves the quality of dcd grafts: mechanism and application
File(s)
Author(s)
Chen, Qian
Type
Thesis
Abstract
Graft availability of donation after circulatory death (DCD) is significantly limited by ischaemia reperfusion (IR) injury. α2-adrenergic receptor agonist dexmedetomidine (Dex) and noble gases xenon (Xe) and argon (Ar) have been demonstrated to reduce IR. This project investigated whether combining different concentrations of Xe, Ar, and Dex supplemented in the University of Wisconsin (UW) preservation solution provided better protection for cold storage of DCD grafts.
Human lung tissues preserved at 4°C for 24 h in the UW preservation solution supplemented with 0.1 nM Dex exhibited improved lung morphology and decreased apoptotic and necroptotic cell death caused by cold storage. Dex supplementation also reduced the activation of NLRP3 inflammasome and enhanced membrane self-resealing in pulmonary epithelial cells (A549 cell line) following hypothermic hypoxia-reoxygenation injury. In the case of kidney and liver grafts from DCD pig donors, when preserved at 4°C for 24 or 72 h in UW solutions supplemented with Dex, Xe and Ar, their quality significantly improved by reducing apoptosis and necroptosis and enhancing the antioxidant protein Glutathione Peroxidase 4 (GPX4). Among the options evaluated, the solution supplemented with 0.1 nM Dex combined with 50% Ar demonstrated the best results in maintaining the quality of kidney and liver grafts during cold preservation. In vitro, 0.1 nM Dex and 50% Ar effectively inhibited the translocation of thioredoxin-interacting protein (TXNIP), thereby increasing the expression of anti-oxidative stress proteins and inhibiting ferroptosis in hepatocytes (HepG2 cell line) subjected to hypothermic hypoxia-reoxygenation injury...
Human lung tissues preserved at 4°C for 24 h in the UW preservation solution supplemented with 0.1 nM Dex exhibited improved lung morphology and decreased apoptotic and necroptotic cell death caused by cold storage. Dex supplementation also reduced the activation of NLRP3 inflammasome and enhanced membrane self-resealing in pulmonary epithelial cells (A549 cell line) following hypothermic hypoxia-reoxygenation injury. In the case of kidney and liver grafts from DCD pig donors, when preserved at 4°C for 24 or 72 h in UW solutions supplemented with Dex, Xe and Ar, their quality significantly improved by reducing apoptosis and necroptosis and enhancing the antioxidant protein Glutathione Peroxidase 4 (GPX4). Among the options evaluated, the solution supplemented with 0.1 nM Dex combined with 50% Ar demonstrated the best results in maintaining the quality of kidney and liver grafts during cold preservation. In vitro, 0.1 nM Dex and 50% Ar effectively inhibited the translocation of thioredoxin-interacting protein (TXNIP), thereby increasing the expression of anti-oxidative stress proteins and inhibiting ferroptosis in hepatocytes (HepG2 cell line) subjected to hypothermic hypoxia-reoxygenation injury...
Version
Open Access
Date Issued
2023-10-12
Date Awarded
2024-04-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Ma, Daqing
Zhao, Hailin
Sponsor
The National Natural Science Foundation of the People's Republic of China
The Basic and Frontier Research Fund of Chongqing, China
Chelsea and Westminster Hospital NHS Foundation Trust
The Royal College of Anaesthetists
British Journal of Anaesthesia
Grant Number
No. 81801900
No. cstc2018jcyjAX0007
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)