A Novel Oxygen Carrier (M101) Attenuates Ischemia-Reperfusion Injuries during Static Cold Storage in Steatotic Livers

The combined impact of an increasing demand for liver transplantation and a growing incidence of nonalcoholic liver disease has provided the impetus for the development of innovative strategies to preserve steatotic livers. A natural oxygen carrier, HEMO2life®, which contains M101 that is extracted from a marine invertebrate, has been used for static cold storage (SCS) and has shown superior results in organ preservation. A total of 36 livers were procured from obese Zucker rats and randomly divided into three groups, i.e., control, SCS-24H and SCS-24H + M101 (M101 at 1 g/L), mimicking the gold standard of organ preservation. Ex situ machine perfusion for 2 h was used to evaluate the quality of the livers. Perfusates were sampled for functional assessment, biochemical analysis and subsequent biopsies were performed for assessment of ischemia-reperfusion markers. Transaminases, GDH and lactate levels at the end of reperfusion were significantly lower in the group preserved with M101 (p < 0.05). Protection from reactive oxygen species (low MDA and higher production of NO2-NO3) and less inflammation (HMGB1) were also observed in this group (p < 0.05). Bcl-1 and caspase-3 were higher in the SCS-24H group (p < 0.05) and presented more histological damage than those preserved with HEMO2life®. These data demonstrate, for the first time, that the addition of HEMO2life® to the preservation solution significantly protects steatotic livers during SCS by decreasing reperfusion injury and improving graft function.

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Oxygen Transport during Ex Situ Machine Perfusion of Donor Livers Using Red Blood Cells or Artificial Oxygen Carriers

International Journal of Molecular Sciences ◽

10.3390/ijms22010235 ◽

2020 ◽

Vol 22 (1) ◽

pp. 235

Author(s):

Silke B. Bodewes ◽

Otto B. van Leeuwen ◽

Adam M. Thorne ◽

Bianca Lascaris ◽

Rinse Ubbink ◽

...

Keyword(s):

Red Blood Cells ◽

Oxygen Transport ◽

Oxygen Delivery ◽

Blood Cells ◽

Marine Invertebrate ◽

Oxygen Carrier ◽

Ex Situ ◽

Machine Perfusion ◽

Oxygen Carriers ◽

Advantages And Disadvantages

Oxygenated ex situ machine perfusion of donor livers is an alternative for static cold preservation that can be performed at temperatures from 0 °C to 37 °C. Organ metabolism depends on oxygen to produce adenosine triphosphate and temperatures below 37 °C reduce the metabolic rate and oxygen requirements. The transport and delivery of oxygen in machine perfusion are key determinants in preserving organ viability and cellular function. Oxygen delivery is more challenging than carbon dioxide removal, and oxygenation of the perfusion fluid is temperature dependent. The maximal oxygen content of water-based solutions is inversely related to the temperature, while cellular oxygen demand correlates positively with temperature. Machine perfusion above 20 °C will therefore require an oxygen carrier to enable sufficient oxygen delivery to the liver. Human red blood cells are the most physiological oxygen carriers. Alternative artificial oxygen transporters are hemoglobin-based oxygen carriers, perfluorocarbons, and an extracellular oxygen carrier derived from a marine invertebrate. We describe the principles of oxygen transport, delivery, and consumption in machine perfusion for donor livers using different oxygen carrier-based perfusion solutions and we discuss the properties, advantages, and disadvantages of these carriers and their use.

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Organ Preservation in Liver Transplantation

Seminars in Liver Disease ◽

10.1055/s-0038-1666840 ◽

2018 ◽

Vol 38 (03) ◽

pp. 260-269 ◽

Cited By ~ 6

Author(s):

Alberto Zanetto ◽

Francesco Russo ◽

Giacomo Germani ◽

Patrizia Burra

Keyword(s):

Liver Transplantation ◽

Cold Storage ◽

Organ Preservation ◽

Clinical Applications ◽

Ex Situ ◽

Machine Perfusion ◽

Donor Pool ◽

Number Of Patients ◽

Pros And Cons ◽

Donor Shortage

AbstractThe discrepancy between the number of patients awaiting liver transplantation and the number of available donors has become a key issue in the transplant setting. Various strategies to cope with the donor shortage problem and to increase the use of suboptimal grafts have been explored. Machine perfusion has been applied ex situ to liver grafts in the effort to improve static cold-storage preservation. If a more extensive application of this technology confirms the preliminary results, machine perfusion will become crucial in increasing the donor pool as well as improving recipients' outcomes. In this review, the authors focused on the evolution of machine perfusion, from the first animal experiences to the latest evidence in humans, highlighting the pros and cons as well as the potential clinical applications of various types of machine.

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Inhibition of HDAC3 protects against kidney cold storage/transplantation injury and allograft dysfunction

Clinical Science ◽

10.1042/cs20210823 ◽

2021 ◽

Author(s):

Xiaohong Xiang ◽

Guie Dong ◽

Jiefu Zhu ◽

Gang Zhang ◽

Zheng Dong

Keyword(s):

Cell Death ◽

Kidney Transplantation ◽

Cold Storage ◽

Ischemia Reperfusion Injury ◽

Therapeutic Option ◽

Ischemia Reperfusion ◽

Dynamic Change ◽

Graft Function ◽

Recipient Mouse

Cold storage/rewarming is an inevitable process for kidney transplantation from deceased donors, which correlates closely with renal ischemia-reperfusion injury (IRI) and the occurrence of delayed graft function. Histone deacetylases (HDAC) are important epigenetic regulators but their involvement in cold storage/rewarming injury in kidney transplantation is unclear. In the present study, we showed a dynamic change of HDAC3 in a mouse model of kidney cold storage followed by transplantation. We then demonstrated that the selective HDAC3 inhibitor RGFP966 could reduce acute tubular injury and cell death after prolonged cold storage with transplantation. RGFP966 also improved renal function, kidney repair and tubular integrity when the transplanted kidney became the sole life-supporting graft in the recipient mouse. In vitro, cold storage of proximal tubular cells followed by rewarming induced remarkable cell death, which was suppressed by RGFP966 or knockdown of HDAC3 with shRNA. Inhibition of HDAC3 decreased the mitochondrial pathway of apoptosis and preserved mitochondrial membrane potential. Collectively, HDAC3 plays a pathogenic role in cold storage/rewarming injury in kidney transplantation and its inhibition may be a therapeutic option.

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Custodiol-N, a novel organ preservation solution reduces ischemia/reperfusion injury after heart transplantation

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0029-1247060 ◽

2010 ◽

Vol 58 (S 01) ◽

Author(s):

S Loganathan ◽

T Radovits ◽

K Hirschberg ◽

S Korkmaz ◽

A Koch ◽

...

Keyword(s):

Heart Transplantation ◽

Reperfusion Injury ◽

Organ Preservation ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Preservation Solution ◽

Organ Preservation Solution

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Characterizing Autophagy in the Cold Ischemic Injury of Small Bowel Grafts: Evidence from Rat Jejunum

Metabolites ◽

10.3390/metabo11060396 ◽

2021 ◽

Vol 11 (6) ◽

pp. 396

Author(s):

Ibitamuno Caleb ◽

Luca Erlitz ◽

Vivien Telek ◽

Mónika Vecsernyés ◽

György Sétáló ◽

...

Keyword(s):

Cold Storage ◽

Ischemia Reperfusion ◽

Ischemic Injury ◽

Degradation Pathway ◽

Metabolic Adaptation ◽

Cold Ischemia ◽

Cold Preservation ◽

Opposite Trend ◽

Preservation Injury ◽

Apoptotic Damage

Cold ischemic injury to the intestine during preservation remains an unresolved issue in transplantation medicine. Autophagy, a cytoplasmic protein degradation pathway, is essential for metabolic adaptation to starvation, hypoxia, and ischemia. It has been implicated in the cold ischemia (CI) of other transplantable organs. This study determines the changes in intestinal autophagy evoked by cold storage and explores the effects of autophagy on ischemic grafts. Cold preservation was simulated by placing the small intestines of Wistar rats in an IGL-1 (Institute George Lopez) solution at 4 °C for varying periods (3, 6, 9, and 12 h). The extent of graft preservation injury (mucosal and cellular injury) and changes in autophagy were measured after each CI time. Subsequently, we determined the differences in apoptosis and preservation injury after activating autophagy with rapamycin or inhibiting it with 3-methyladenine. The results revealed that ischemic injury and autophagy were induced by cold storage. Autophagy peaked at 3 h and subsequently declined. After 12 h of storage, autophagic expression was reduced significantly. Additionally, enhanced intestinal autophagy by rapamycin was associated with less tissue, cellular, and apoptotic damage during and after the 12-h long preservation. After reperfusion, grafts with enhanced autophagy still presented with less injury. Inhibiting autophagy exhibited the opposite trend. These findings demonstrate intestinal autophagy changes in cold preservation. Furthermore, enhanced autophagy was protective against cold ischemia–reperfusion damage of the small bowels.

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Viability Assessment in Liver Transplantation—What Is the Impact of Dynamic Organ Preservation?

Biomedicines ◽

10.3390/biomedicines9020161 ◽

2021 ◽

Vol 9 (2) ◽

pp. 161

Author(s):

Rebecca Panconesi ◽

Mauricio Flores Carvalho ◽

Matteo Mueller ◽

David Meierhofer ◽

Philipp Dutkowski ◽

...

Keyword(s):

Liver Function ◽

Organ Preservation ◽

Ex Situ ◽

Current Status ◽

Intensive Care Treatment ◽

Viability Assessment ◽

Great Opportunity ◽

Continuous Increase ◽

Diagnostic Time ◽

The Impact

Based on the continuous increase of donor risk, with a majority of organs classified as marginal, quality assessment and prediction of liver function is of utmost importance. This is also caused by the notoriously lack of effective replacement of a failing liver by a device or intensive care treatment. While various parameters of liver function and injury are well-known from clinical practice, the majority of specific tests require prolonged diagnostic time and are more difficult to assess ex situ. In addition, viability assessment of procured organs needs time, because the development of the full picture of cellular injury and the initiation of repair processes depends on metabolic active tissue and reoxygenation with full blood over several hours or days. Measuring injury during cold storage preservation is therefore unlikely to predict the viability after transplantation. In contrast, dynamic organ preservation strategies offer a great opportunity to assess organs before implantation through analysis of recirculating perfusates, bile and perfused liver tissue. Accordingly, several parameters targeting hepatocyte or cholangiocyte function or metabolism have been recently suggested as potential viability tests before organ transplantation. We summarize here a current status of respective machine perfusion tests, and report their clinical relevance.

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Ischemia-Reperfusion Injuries Assessment during Pancreas Preservation

International Journal of Molecular Sciences ◽

10.3390/ijms22105172 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5172

Author(s):

Thomas Prudhomme ◽

John F. Mulvey ◽

Liam A. J. Young ◽

Benoit Mesnard ◽

Maria Letizia Lo Faro ◽

...

Keyword(s):

Ex Vivo ◽

Ischemia Reperfusion ◽

Graft Function ◽

Impedance Analysis ◽

Experimental Models ◽

Caspase Activation ◽

Pancreas Perfusion ◽

Number Of Factors ◽

Pancreas Preservation ◽

Metabolite Concentrations

Maintaining organ viability between donation and transplantation is of critical importance for optimal graft function and survival. To date in pancreas transplantation, static cold storage (SCS) is the most widely practiced method of organ preservation. The first experiments in ex vivo perfusion of the pancreas were performed at the beginning of the 20th century. These perfusions led to organ oedema, hemorrhage, and venous congestion after revascularization. Despite these early hurdles, a number of factors now favor the use of perfusion during preservation: the encouraging results of HMP in kidney transplantation, the development of new perfusion solutions, and the development of organ perfusion machines for the lung, heart, kidneys and liver. This has led to a resurgence of research in machine perfusion for whole organ pancreas preservation. This review highlights the ischemia-reperfusion injuries assessment during ex vivo pancreas perfusion, both for assessment in pre-clinical experimental models as well for future use in the clinic. We evaluated perfusion dynamics, oedema assessment, especially by impedance analysis and MRI, whole organ oxygen consumption, tissue oxygen tension, metabolite concentrations in tissue and perfusate, mitochondrial respiration, cell death, especially by histology, total cell free DNA, caspase activation, and exocrine and endocrine assessment.

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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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