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Succinate accumulation drives ischaemia-reperfusion injury during organ transplantation

ABSTRACT: During heart transplantation, storage in cold preservation solution is thought to protect the organ by slowing metabolism; by providing osmotic support; and by minimising ischaemia-reperfusion (IR) injury upon transplantation into the recipient. Despite its widespread use, our understanding of the metabolic changes prevented by cold storage and how warm ischaemia leads to damage is surprisingly poor. Here, we compared the metabolic changes during warm ischaemia (WI) and cold ischaemia (CI) in hearts from mouse, pig, and human. We identified common metabolic alterations during WI and those affected by CI, thereby elucidating mechanisms underlying the benefits of CI, and how WI causes damage. Succinate accumulation is a major feature within ischaemic hearts across species, and CI slows succinate generation, thereby reducing tissue damage upon reperfusion caused by the production of mitochondrial reactive oxygen species (ROS). Importantly, the inevitable periods of WI during organ procurement led to the accumulation of damaging levels of succinate during transplantation, despite cooling organs as rapidly as possible. This damage was ameliorated by metabolic inhibitors that prevented succinate accumulation and oxidation. Our findings suggest how WI and CI contribute to transplant outcome and indicate new therapies for improving the quality of transplanted organs.

INSTRUMENT(S): Liquid Chromatography MS -, Liquid Chromatography MS - alternating - hilic

SUBMITTER: Ana Sofia Henriques da Costa

PROVIDER: MTBLS1085 | MetaboLights | 2019-09-20

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS1085	Other
	FILES	Other
	a_MTBLS1085_human_HILIC_LC-MS.txt	Txt
	a_MTBLS1085_mouse_HILIC_LC-MS.txt	Txt
	a_MTBLS1085_mouse_pHILIC_LC-MS.txt	Txt

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Ischemia reperfusion injury (IRI) in organ transplantation and the effects of carbon monoxide treatment

Project description:Ischemia reperfusion injury (IRI) in organ transplantation remains a significant problem with limited alternative therapeutic options. Organs that undergo significant damage during IRI, particularly those enduring long warm ischemia times, undergo significant delayed graft function (DGF) after reperfusion and tend to have greater complications long term with the onset of chronic rejection. The gas molecule carbon monoxide (CO) has emerged as an agent that can suppress IRI in rodent models of solid organ transplantation. Since the use of CO is a potential therapeutic modality in humans, we tested if CO can prevent DGF in a pig model of kidney transplantation Keywords: stress response, treatment response 18 Samples from pig kidneys, two naïve controls, two timepoints, two conditions, 4 replicates

2009-01-20 | E-GEOD-14373 | biostudies-arrayexpress

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2023-11-21 | PXD046355 | Pride

Mapping Ischemia Reperfusion Inflammatory Responses in Human Lung Transplantation at Single-Cell Resolution

Project description:Ischemia reperfusion (IR) is an unavoidable step of organ transplantation. IR-induced injury constrains the number of donor lungs used for transplant. Here we performed longitudinal single-cell RNA sequencing (scRNA-seq) from human lungs of six individuals who underwent lung transplantation. Lung biopsies were collected after cold preservation and 2-hour reperfusion for each individual resulting in the profiling of 108,613 cells in total.

2024-10-12 | GSE220797 | GEO

Ischemia Reperfusion of Lung Transplant Setting Differentially Regulates Transcriptomic Profiles between Human Lung Endothelial and Epithelial Cells

Project description:Our understanding on mechanisms of ischemia-reperfusion induced lung injury during lung preservation and transplantation is based on clinical observations and animal studies. Herein, we used cell and systems biology approaches to explore these mechanisms at transcriptomics levels, especially by focusing on the differences between human lung endothelial and epithelial cells, which are crucial for maintaining essential lung structure and function. Human pulmonary microvascular endothelial cells and human lung epithelial cells were cultured to confluent, subjected to different cold ischemic time (CIT) to mimic static cold storage with preservation solution, and then subjected to warm reperfusion with serum containing culture medium to similar lung transplantation. Cell morphology, viability and transcriptomic profiles were studied. Ischemia-reperfusion induced a CIT time-dependent cell death, which was associated with dramatic changes in gene expression. Under normal control conditions, endothelial cells showed gene clusters enriched in vascular process and inflammation, while epithelial cells showed gene clusters enriched in protein biosynthesis and metabolism. CIT 6 h alone or after reperfusion had little effects on these phenotypic characteristics. After CIT 18 h, protein biosynthesis related gene clusters disappeared in epithelial cells; after reperfusion, metabolism-related gene cluster in epithelial cells and multiple gene clusters in the endothelial cells also disappeared. Human pulmonary endothelial and epithelial cells have distinct phenotypic transcriptomic signatures. Severe cellular injury reduces these gene expression signatures in a cell type dependent manner. Therapeutics that preserve these transcriptomic signatures may represent new treatment to prevent acute lung injury during lung transplantation.

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