Resolving the graft ischemia-reperfusion injury during liver transplantation at the single cell resolution

AbstractIschemia–reperfusion injury (IRI) remains the major reason for impaired donor graft function and increased mortality post-liver transplantation. The mechanism of IRI involves multiple pathophysiological processes and numerous types of cells. However, a systematic and comprehensive single-cell transcriptional profile of intrahepatic cells during liver transplantation is still unclear. We performed a single-cell transcriptome analysis of 14,313 cells from liver tissues collected from pre-procurement, at the end of preservation and 2 h post-reperfusion. We made detailed annotations of mononuclear phagocyte, endothelial cell, NK/T, B and plasma cell clusters, and we described the dynamic changes of the transcriptome of these clusters during IRI and the interaction between mononuclear phagocyte clusters and other cell clusters. In addition, we found that TNFAIP3 interacting protein 3 (TNIP3), specifically and highly expressed in Kupffer cell clusters post-reperfusion, may have a protective effect on IRI. In summary, our study provides the first dynamic transcriptome map of intrahepatic cell clusters during liver transplantation at single-cell resolution.

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Sequence of reperfusion influences ischemia/reperfusion injury and primary graft function following porcine liver transplantation

Liver Transplantation ◽

10.1002/lt.20480 ◽

2005 ◽

Vol 11 (10) ◽

pp. 1214-1222 ◽

Cited By ~ 22

Author(s):

Jens G. Brockmann ◽

Christian August ◽

Heiner H. Wolters ◽

Ralf Hömme ◽

Daniel Palmes ◽

...

Keyword(s):

Liver Transplantation ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Graft Function ◽

Porcine Liver ◽

Porcine Liver Transplantation

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Beneficial effects of end-ischemic oxygenated machine perfusion preservation for split-liver transplantation in recovering graft function and reducing ischemia–reperfusion injury

Scientific Reports ◽

10.1038/s41598-021-01467-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daisuke Ishii ◽

Naoto Matsuno ◽

Mikako Gochi ◽

Hiroyoshi Iwata ◽

Tatsuya Shonaka ◽

...

Keyword(s):

Liver Transplantation ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Autologous Blood ◽

Graft Function ◽

Machine Perfusion ◽

Perfusion System ◽

Split Liver Transplantation ◽

Split Liver

AbstractThis study examined the efficacy of end-ischemic hypothermic oxygenated machine perfusion preservation (HOPE) using an originally developed machine perfusion system for split-liver transplantation. Porcine split-liver grafts were created via 75% liver resection after 10 min of warm ischemia. In Group 1, grafts were preserved by simple cold storage (CS) for 8 h (CS group; n = 4). In Group 2, grafts were preserved by simple CS for 6 h and end-ischemic HOPE for 2 h (HOPE group; n = 5). All grafts were evaluated using an isolated ex vivo reperfusion model with autologous blood for 2 h. Biochemical markers (aspartate aminotransferase and lactate dehydrogenase levels) were significantly better immediately after reperfusion in the HOPE group than in the CS group. Furthermore, the HOPE group had a better histological score. The levels of inflammatory cytokines (tumor necrosis factor-α, interferon-γ, interleukin-1β, and interleukin-10) were significantly lower after reperfusion in the HOPE group. Therefore, we concluded that end-ischemic HOPE for split-liver transplantation can aid in recovering the graft function and reducing ischemia–reperfusion injury. HOPE, using our originally developed machine perfusion system, is safe and can improve graft function while attenuating liver injury due to preservation.

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New Insights in Mechanisms and Therapeutics for Short- and Long-Term Impacts of Hepatic Ischemia Reperfusion Injury Post Liver Transplantation

International Journal of Molecular Sciences ◽

10.3390/ijms22158210 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8210

Author(s):

Hui Liu ◽

Kwan Man

Keyword(s):

Liver Transplantation ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Graft Function ◽

Cancer Recurrence ◽

Short Term ◽

Hepatic Ischemia ◽

Hepatic Ischemia Reperfusion

Liver transplantation has been identified as the most effective treatment for patients with end-stage liver diseases. However, hepatic ischemia reperfusion injury (IRI) is associated with poor graft function and poses a risk of adverse clinical outcomes post transplantation. Cell death, including apoptosis, necrosis, ferroptosis and pyroptosis, is induced during the acute phase of liver IRI. The release of danger-associated molecular patterns (DAPMs) and mitochondrial dysfunction resulting from the disturbance of metabolic homeostasis initiates graft inflammation. The inflammation in the short term exacerbates hepatic damage, leading to graft dysfunction and a higher incidence of acute rejection. The subsequent changes in the graft immune environment due to hepatic IRI may result in chronic rejection, cancer recurrence and fibrogenesis in the long term. In this review, we mainly focus on new mechanisms of inflammation initiated by immune activation related to metabolic alteration in the short term during liver IRI. The latest mechanisms of cancer recurrence and fibrogenesis due to the long-term impact of inflammation in hepatic IRI is also discussed. Furthermore, the development of therapeutic strategies, including ischemia preconditioning, pharmacological inhibitors and machine perfusion, for both attenuating acute inflammatory injury and preventing late-phase disease recurrence, will be summarized in the context of clinical, translational and basic research.

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The impact of desflurane and sevoflurane on the intraoperative and early postoperative period in liver transplantation

Transplantologiya The Russian Journal of Transplantation ◽

10.23873/2074-0506-2021-13-4-328-338 ◽

2021 ◽

Vol 13 (4) ◽

pp. 328-338

Author(s):

S. V. Zhuravel ◽

N. K. Kuznetsova ◽

V. E. Aleksandrova ◽

I. I. Goncharova

Keyword(s):

Liver Transplantation ◽

Reperfusion Injury ◽

Postoperative Period ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Graft Function ◽

Early Postoperative Period ◽

Liver Graft ◽

Inhalation Anesthetics ◽

The Impact

Background. A pressing issue is the choice of an anesthetic agent for liver transplantation. The mechanism of the organprotective properties of desflurane and sevoflurane is not fully understood. It is important to understand the effects of desflurane and sevoflurane on the severity of ischemia-reperfusion injury of the liver graftAim. To study the effect of desflurane and sevoflurane on the intraoperative and early postoperative period in liver transplantation.Material and methods. The study included 47 patients with liver cirrhosis of various etiologies who underwent cadaveric liver transplantation between February and December 2020. The groups compared in the study included 24 patients who received desflurane and 23 patients who received sevoflurane.Results. There were no statistically significant differences in the effect of desflurane and sevoflurane on hemodynamic parameters, on the need for vasopressor drugs. Episodes of bradycardia and cardiac arrhythmias were significantly more frequent when using sevoflurane. Patients were extubated significantly faster after surgery in the desflurane group. In the early postoperative period, desflurane and sevoflurane did not adversely affect significantly the liver graft function and the degree of its ischemia-reperfusion injury. The groups appeared comparable in rates of using the renal replacement therapy, the incidence of the graft dysfunction development in the postoperative period, and the surgery outcomes.Conclusions. The use of modern inhalation anesthetics desflurane and sevoflurane to maintain anesthesia during liver transplantation does not adversely affect the course of the intraoperative and early postoperative period.

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Impact of Three Methods of Ischemic Preconditioning on Ischemia-Reperfusion Injury in a Pig Model of Liver Transplantation

Journal of Investigative Surgery ◽

10.1080/08941939.2021.1933274 ◽

2021 ◽

pp. 1-10

Author(s):

Alessandro Rodrigo Belon ◽

Ana Cristina Aoun Tannuri ◽

Daniel de Albuquerque Rangel Moreira ◽

Jose Luiz Figueiredo ◽

Alessandra Matheus da Silva ◽

...

Keyword(s):

Liver Transplantation ◽

Reperfusion Injury ◽

Ischemic Preconditioning ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Pig Model

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Attenuation of lung reperfusion injury after transplantation using an inhibitor of nuclear factor-κB

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2000.279.3.l528 ◽

2000 ◽

Vol 279 (3) ◽

pp. L528-L536 ◽

Cited By ~ 76

Author(s):

Scott D. Ross ◽

Irving L. Kron ◽

James J. Gangemi ◽

Kimberly S. Shockey ◽

Mark Stoler ◽

...

Keyword(s):

Lung Function ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Graft Function ◽

Nuclear Factor Κb ◽

Pyrrolidine Dithiocarbamate ◽

Nuclear Factor ◽

Mean Pulmonary Arterial Pressure ◽

Pulmonary Arterial

A central role for nuclear factor-κB (NF-κB) in the induction of lung inflammatory injury is emerging. We hypothesized that NF-κB is a critical early regulator of the inflammatory response in lung ischemia-reperfusion injury, and inhibition of NF-κB activation reduces this injury and improves pulmonary graft function. With use of a porcine transplantation model, left lungs were harvested and stored in cold Euro-Collins preservation solution for 6 h before transplantation. Activation of NF-κB occurred 30 min and 1 h after transplant and declined to near baseline levels after 4 h. Pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of NF-κB, given to the lung graft during organ preservation (40 mmol/l) effectively inhibited NF-κB activation and significantly improved lung function. Compared with control lungs 4 h after transplant, PDTC-treated lungs displayed significantly higher oxygenation, lower Pco2, reduced mean pulmonary arterial pressure, and reduced edema and cellular infiltration. These results demonstrate that NF-κB is rapidly activated and is associated with poor pulmonary graft function in transplant reperfusion injury, and targeting of NF-κB may be a promising therapy to reduce this injury and improve lung function.

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Isoglycyrrhizinate Magnesium Enhances Hepatoprotective Effect of FK506 on Ischemia-Reperfusion Injury Through HMGB1 Inhibition in a Rat Model of Liver Transplantation

Transplantation Journal ◽

10.1097/tp.0000000000001941 ◽

2017 ◽

Vol 101 (12) ◽

pp. 2862-2872 ◽

Cited By ~ 7

Author(s):

Weichen Zhang ◽

Feibo Li ◽

Yufu Ye ◽

Yuanxing Liu ◽

Songfeng Yu ◽

...

Keyword(s):

Liver Transplantation ◽

Reperfusion Injury ◽

Rat Model ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Hepatoprotective Effect

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Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation

JCI Insight ◽

10.1172/jci.insight.89679 ◽

2016 ◽

Vol 1 (20) ◽

Cited By ~ 21

Author(s):

Rebecca A. Sosa ◽

Ali Zarrinpar ◽

Maura Rossetti ◽

Charles R. Lassman ◽

Bita V. Naini ◽

...

Keyword(s):

Liver Transplantation ◽

Reperfusion Injury ◽

Orthotopic Liver Transplantation ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion

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Gut Lymph Purification in Rats With Acute Lung Injury Caused By Gut Ischemia Reperfusion Injury

10.21203/rs.3.rs-606735/v1 ◽

2021 ◽

Author(s):

Can Jin ◽

Shucheng Zhang ◽

Linlin Wu ◽

Bohan Li ◽

Meimei Shi ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Reperfusion Injury ◽

Lung Tissue ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Mononuclear Phagocyte ◽

Alveolar Epithelial Cells ◽

Expression Level ◽

Tissue Samples

Abstract Rationale: It is unclear whether removing the danger-associated molecular patterns (DAMPs) of gut lymph (GL) in the rats of gut ischemia-reperfusion injury (GIRI) model may reduce the distant organ lung injury.Objective: To determine whether oXiris gut lymph purification (GLP) may remove the DAMPs of GL in the rats’ model of acute lung injury (ALI) caused by GIRI.Methods: The experimental rats were divided into four groups: Sham group, GIRI group, GIRI + gut lymph drainage (GLD) group, and GIRI + GLP group. After successful modeling, the lung tissue samples of rats in each group were taken for hematoxylin-eosin (HE) staining and detection of expression levels of apoptotic indexes. The level of DAMPs was detected in blood and lymph. We observed its microstructure of type II alveolar epithelial cells (AECⅡ), and detected the expression level of apoptosis indexes.Measurements and Main Results: GIRI-induced destruction of alveolar structure, thickened alveolar walls, inflammatory cell infiltration emerged in the GIRI group, HMGB-1 and IL-6 levels significantly increased, and HSP70 and IL-10 levels reduced in lymph and serum. Compared with GIRI group, the lung tissue damage in GIRI + GLP group significantly improved, the expression level of HMGB-1 and IL-6 in the lymph and serum reduced, and HSP70 and IL-10 increased. The organelle structure of AECII in GIRI + GLP group was significantly improved compared with the GIRI group. Conclusions: oXiris GLP blocks the key link between DAMPs and mononuclear phagocyte system to inhibit inflammation and cell apoptosis, thereby reducing ALI induced by GIRI.

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