Normothermic machine perfusion (NMP) inhibits proinflammatory responses in the liver and promotes regeneration
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PROVIDER: PRJNA448772 | ENA |
REPOSITORIES: ENA
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Project description:Background and Aims: Liver transplantation is a successful treatment for patients with liver failure. However, organ shortage results in over 11% of patients loosing their chance of a transplant due to worsening of their liver disease. Ischemia/reperfusion injury (IRI) is the major cause leading to graft loss after liver transplantation. Therefore, novel methods of organ-preservation have been developed in recent years to minimize IRI. One such device is the OrganOx metra, a normothermic machine perfusion (NMP) device providing oxygen and nutrition to allow aerobic metabolism and minimizing IRI. OrganOx metra has presented with several advantages compared to conventional cold storage (CS). We aimed to confirm the impact of NMP on reducing IRI and to define the underling mechanisms. Methods: We compared 12 NMP with 27 CS-preserved livers by performing gene microarray, immunoprofiling of hepatic lymphocytes and immunochemistry staining of liver tissues for assessing necrosis, platelet deposition and neutrophil infiltration, and the status of steatosis after NMP or CS pre- and post-reperfusion. Results: Recipients receiving NMP grafts showed significantly lower peak AST levels than those receiving CS grafts. NMP altered gene-expression profiles of liver tissue from pro-inflammation to pro-healing and regeneration. NMP also reduced the number of IFN- and IL-17 producing T cells and enlarged CD4posCD25highCD127negFOXP3pos Treg pool. NMP liver tissues showed less necrosis and apoptosis in the parenchyma and fewer neutrophils and platelet infiltration compared to CS liver tissues. Conclusion: Reduced IRI in NMP recipients was the consequence of the combination of inhibiting inflammation and promoting graft regeneration.
2019-04-10 | GSE112713 | GEO
Project description:Normothermic machine perfusion (NMP) has been successfully implemented in clinical routine of liver transplantation over the past years. However, little is known about the mechanisms how NMP impacts on the transcriptome of a human donor liver. We herein examined gene expression profiles in transplanted and non-transplanted livers over NMP time. 50 livers subjected to NMP were included in this study. 30 were transplanted after a maximum of 20 hours (h) perfusion, while 15 were discarded due to poor performance. Biopsies were collected befor eNP (PRE), 1h, 6h, 12h, 20h of NMP and after reperfusion. Next-generation sequencing was applied in liver biopsies to assess differential gene expression over perfusion time. Perfusate samples were collected regularly to monitor liver function. Comparison in differential gene expression between PRE and 20h NMP showed 415 upregulated and 727 downregulated genes. Most significantly upregulated genes were associated with extra cellular matrix organization, cell growth/differentiation processes and cytokine signaling. A set of genes were identified which were significantly differentially expressed and important for classification of non-transplanted vs transplanted biopsies, especially at 12 and 20h of NMP. A 7-gene-signature showed good separation already at 6H NMP, thereby CD274 (PD-L1) expression was ponted out as most important.
2024-08-29 | GSE263614 | GEO
Project description:Human kidneys which were accepted for transplantation and subsequently not used were subjected to ex vivo normothermic machine perfusion. During perfusion it was found the tubular epithelia synthesized fibrinogen which led to red blood cell aggregation and pathologic plugging of renal microvasculature. Sequential ex vivo delivery of plasminogen and tissue plasminogen activator (tPA) during normothermic machine perfusion effectively lyses these fibrinogen-mediated plugs.
2022-10-01 | GSE139017 | GEO
Project description:Access to liver transplantation is limited by a significant organ shortage. The recent introduction of machine perfusion technology allows surgeons to monitor and assess ex situ liver function prior to transplantation. However, many donated organs are of inadequate quality for transplant, though opportunities exist to rehabilitate organ function with adjunct therapeutics during normothermic machine perfusion. In this preclinical study, we targeted the apoptosis pathway as a potential method of improving hepatocellular function. Treatment of discarded human livers during normothermic perfusion with an irreversible pan-caspase inhibitor, emricasan, resulted in significant mitigation of ischemia-reperfusion injury at both the transcriptional and protein level. This was evidenced by significantly decreased circulating levels of the pro-inflammatory cytokines, interleukin-6, interleukin-8, and interferon-gamma, compared to control livers. Untreated livers also demonstrated transcriptional changes notable for enrichment in pathways involved in innate immunity, leukocyte migration, and cytokine-mediated signaling. Targeting of unregulated apoptosis may represent a viable therapeutic intervention for rehabilitating liver hepatocellular function during machine perfusion.
2022-07-11 | GSE202565 | GEO
Project description:Normothermic machine perfusion (NMP) after static cold storage is increasingly used for preservation and assessment of human donor livers prior to transplantation. Biliary viability assessment during NMP reduces the risk of post-transplant biliary complications. However, understanding molecular changes in the biliary system during NMP remains incomplete. Here, we performed RNA-seq analysis of donor livers undergoing NMP treatment and compared livers with biliary viability scores that were acceptable for transplantation vs those that were not.
2023-11-21 | E-MTAB-13501 | biostudies-arrayexpress
Project description:Background and Aims: Liver transplantation provides an effective cure for end-stage liver disease but is hampered by a severe organ shortage. Normothermic machine perfusion (NMP) of donor livers allows dynamic preservation in addition to viability assessment prior to transplantation. Little is known about the injury and repair mechanisms induced during NMP. Therefore, we examined gene and protein expression changes in a cohort of discarded human livers during NMP, stratified by liver viability. Approach and Results: 6 human livers from donation after circulatory death (DCD) underwent 12 hours of NMP, of which 3 met viability criteria. We applied bulk transcriptomics to evaluate differences in gene expression relating to injury, repair, and regenerative responses among livers based on viability. Viable livers demonstrated robust activation of innate immunity after 3 hours of NMP followed by enrichment of pro-repair and pro-survival mechanisms. Nonviable livers demonstrated delayed and persistent enrichment of innate immune responses. Viable livers demonstrated effective induction of autophagy, the cellular repair and homeostasis pathway, compared to nonviable livers. Enrichment of pro-survival signaling was also broader in these livers. Conclusions: NMP of discarded DCD human livers results in ischemia-reperfusion injury, but importantly activates autophagy as a means of cellular repair. More pronounced activation of autophagy was seen in livers that met viability criteria for transplantation. Therapeutic targeting of the autophagy mechanism may allow rehabilitation of nonviable livers for transplantation.
2022-01-25 | GSE165568 | GEO
Project description:Liver are frequently declined for transplantation due to the donor age. It is still unclear how donor age affects the graft quality. Normothermic machine perfusion (NMP) has been proposed as a useful assessment tool prior to transplantation. We aimed to compare the performance of young and elderly rat liver grafts in a small animal NMP model. Grafts from 24 rats were procured, either 3 or 12 months old and perfused for 6 hours at 37°C or stored on ice as a reference group (n=6/group). Livers in both NMP groups cleared lactate and produced bile, with similar pressure, bile production, and pH levels. However, older rat livers showed higher peak transaminase and urea levels. Proteomic analysis revealed differences in protein composition, particularly higher levels of proteins related to oxidoreductase and catalytic activity in older livers. Older age appeared to increase susceptibility to oxidative stress in the livers.
2024-08-09 | PXD045394 | Pride
Project description:To identify the main biological effects of the normothermic machine perfusion (NMP) in marginal kidneys, we measured, by mass spectrometry analysis, changes in the proteomic profile of kidney tissues and urines of eight organs reconditioned for 120 minutes (by a Kidney Assist device). Biopsy specimens were taken at the time of the pre-implantation histological evaluation (T-1), at the start of back table preparation (T0), and after 60 (T60) and 120(T120) minutes. Urine were collected at T0, T30, T60 and T120. Several bioinformatics/statistical algorithms (including SVM and PLS-DA) were used to select the most discriminative proteins. Bioinformatics analysis showed that, during NMP, a large number of proteins resulted down- or up-regulated in the kidneys (169 and 196, respectively). SVM and PLS-DA analysis restricted this panel to 50 top-discriminative proteins. Among these, 11 proteins resulted similarly up-regulated(LXN, ETFB, NUDT3, CYCS and UQCRC1)and down-regulated after NMP treatment (CFHR3, C1S, CFI, KNG1, SERPINC1, F9)in urine.Functional analysis, then, revealed that the most up-regulated proteins were involved in the oxidative phosphorylation system (OXPHOS) and ATPsynthesis, while thoseunder-expressed were implicated in the complement and coagulation cascade.Our proteomic analysis demonstrated that NMP (also for a brief period of time) may induce substantial metabolic and biochemical changes in marginal organs. This encourages use of this technology in clinic.
2023-05-10 | PXD036432 | Pride
Project description:Gene expression profiling of human livers during normothermic machine perfusion
| PRJNA1098409 | ENA
Project description:Kidneys which had been taken for transplant but later declined were perfused for up to 4 hours using a normothermic perfusion (MNP) rig or left on ice (CS) and samples were taken for RNASeq at different time points. The effect of the addition of a heamoadsorber (HA) to the perfusion rig was also assessed.
2020-10-17 | GSE121447 | GEO