Reperfusion injury to donor livers stored for transplantation

Lemasters, John J.; Bunzendahl, H.; Thurman, Ronald G.

doi:10.1002/lt.500010211

Cited by 106 publications

(43 citation statements)

References 86 publications

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“…The longer waiting time and the increasing number of patients enlisted for transplantation further stress the importance of reducing the incidence of graft failure. I/R injury is one of the major contributors to post-transplant complications, including primary graft failure and acute rejection (1)(2)(3)(4)(5). The pathophysiology of hepatic ischemia reperfusion involves activation of Kupffer cells, which leads to reactive oxygen species formation (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Gene Transduction of an Active Mutant of Akt Exerts Cytoprotection and Reduces Graft Injury After Liver Transplantation

Morales-Ruíz¹,

Fondevila²,

Muñoz³

et al. 2007

American Journal of Transplantation

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Akt is expected to be an effective target for the treatment of ischemia-reperfusion injury (I/R) due to its anti-apoptotic properties and its ability to activate the endothelial nitric oxide synthase (eNOS) enzyme. Therefore, this study was aimed to determine the efficacy of an active mutant of Akt (myr-Akt) to decrease I/R injury in a model of orthotopic liver transplantation in pigs. In addition, we analyzed the contribution of nitric oxide in the Akt-mediated effects by using an eNOS mutant (S1179DeNOS) that mimics the phosphorylation promoted by Akt in the eNOS sequence. Donors were treated with adenoviruses codifying for myr-Akt, S1179DeNOS or b -galactosidase 24 h before liver harvesting. Then, liver grafts were orthotopically transplanted into their corresponding recipients. Levels of transaminases and lactate dehydrogenase (LDH) increased in all recipients after 24 h of transplant. However, transaminases and LDH levels were significantly lower in the myr-Akt group compared with vehicle. The percentage of apoptotic cells and the amount of activated-caspase 3 protein were also markedly reduced in myr-Akt-treated grafts after 4 days of liver transplant compared with vehicle and S1179DeNOS groups. In conclusion, myr-Akt gene therapy effectively exerts cytoprotection against hepatic I/R injury regardless of the Akt-dependent eNOS activation.

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Section: Introductionmentioning

confidence: 99%

Gene Transduction of an Active Mutant of Akt Exerts Cytoprotection and Reduces Graft Injury After Liver Transplantation

Morales-Ruíz¹,

Fondevila²,

Muñoz³

et al. 2007

American Journal of Transplantation

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“…Ischemia-reperfusion injury is responsible for primary liver dysfunction and failure after transplantation, [1][2][3][4][5] after liver resection (Pringle maneuver), 6 or after hemorrhagic shock. 7 Cold storage appears to cause injury mainly to sinusoidal endothelial cells (SEC), 8,9 whereas warm ischemia affects hepatocytes and endothelial cells.…”

mentioning

confidence: 99%

Mechanism of Cell Death During Warm Hepatic Ischemia–Reperfusion in Rats: Apoptosis or Necrosis?

2001

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Reperfusion injury can cause liver dysfunction after cold storage and warm ischemia. Recently it has been suggested that more than 50% of hepatocytes and sinusoidal endothelial cells (SEC) are undergoing apoptosis during the first 24 hours of reperfusion. The aim of our study was to quantify apoptotic and necrotic hepatocytes and apoptotic SEC after 60 or 120 minutes of warm, partial no-flow ischemia and 0 to 24 hours reperfusion in male SD rats. Apoptotic cells were identified by TUNEL assay in combination with morphological criteria. After 60 minutes of ischemia and 1 hour of reperfusion there was a significant increase of apoptotic hepatocytes (0.7 ؎ 0.1% vs. 0.3 ؎ 0.1% in controls) and SEC (1.5 ؎ 0.6% vs. 0.3 ؎ 0.1% in controls). The number of apoptotic SEC and hepatocytes was not different from controls at 6 hours or 24 hours of reperfusion. In contrast, the number of necrotic hepatocytes was quantified as 12 ؎ 2% at 1 hour, 34 ؎ 6% at 6 hours, and 57 ؎ 11% at 24 hours. These results correlated with the increase in plasma ALT levels at these time points. Longer (120 min) ischemia times did not affect the number of apoptotic cells but increased hepatocellular necrosis to 58 ؎ 4% at 6 hours reperfusion. No significant increase in caspase-3 activity and processing was detectable in any of these livers. Moreover, the caspase inhibitor Z-Asp-cmk (2 mg/kg IV) had no significant effect on reperfusion injury. Our results suggest that only a small minority of SEC and hepatocytes undergo apoptosis after 60 to 120 minutes of warm ischemia followed by 0 to 24 hours of reperfusion. Oncotic necrosis appears to be the principal mechanism of cell death for both cell types. (HEPATOLOGY 2001;33:397-405.)Ischemia-reperfusion injury is responsible for primary liver dysfunction and failure after transplantation, 1-5 after liver resection (Pringle maneuver), 6 or after hemorrhagic shock. 7 Cold storage appears to cause injury mainly to sinusoidal endothelial cells (SEC), 8,9 whereas warm ischemia affects hepatocytes and endothelial cells. 10 In addition, Kupffer cells are activated and primed, 11-13 which causes a substantial aggravation of the injury during the early reperfusion period. At the same time, activation of complement 14 and the formation of cytokines 15 and chemokines 16,17 lead to hepatic neutrophil sequestration and a neutrophil-dependent injury 18 several hours later. Injury by Kupffer cells and neutrophils is largely dependent on reactive oxygen species 19-21 and proteases. [22][23][24] Although the postischemic oxidant stress is not sufficient to kill hepatocytes by lipid peroxidation, 25 there is evidence that reactive oxygen species and proteases cause hepatocellular necrosis. 22,26,27 In recent years, several laboratories reported evidence for apoptotic cell death during hepatic ischemia and reperfusion. [28][29][30][31] According to these studies, 50% to 70% of endothelial cells and 40% to 60% of hepatocytes undergo apoptosis during reperfusion. 30,31 A high percentage of apoptotic hepatocytes were also ide...

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“…Early detection and monitoring of such complications as primary nonfunction, which requires immediate retransplantation, or primary dysfunction leading to prolonged intensive medical therapy and patient morbidity therefore are of great clinical importance. 2 The detection of vascular complications, such as arterial and portal vein thrombosis, is especially important in the early posttransplantation period. Hepatic artery thrombosis is one of the most devastating complications in orthotopic liver transplantation and occurs in 3% to 12% of all adult transplant recipients and up to 42% of pediatric patients.…”

mentioning

confidence: 99%

Metabolic changes in the liver graft monitored continuously with microdialysis during liver transplantation in a pig model

Nowak

Ungerstedt

Wernerman

et al. 2002

Liver Transplantation

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Microdialysis provides the opportunity to continuously monitor metabolic changes in tissue. The aim of the study is to monitor metabolic changes in the liver graft over time during transplantation in a pig model. Fourteen littermate female pigs with a body weight of 30 to 34 kg were used for seven orthotopic liver transplantations. Intrahepatic implantation of a microdialysis catheter into the liver graft was performed in the donor. Microdialysis samples were collected at 20-minute intervals during the donor operation, cold preservation, and for 7 hours after reperfusion in the recipient. Glucose, lactate, pyruvate, and glycerol concentrations were measured. After cold perfusion, glucose, lactate, and glycerol levels increased, whereas pyruvate levels decreased rapidly. During cold storage, glucose and glycerol levels increased, whereas lactate levels remained stable and pyruvate levels were undetectable. During implantation of the liver graft, glucose, lactate, and glycerol levels showed an accelerated increase. After portal reperfusion, glucose, lactate, and glycerol levels continued to increase for another 40 to 60 minutes, after which they decreased and finally settled at normal levels. At this time, pyruvate levels increased, with a peak within 2 hours after reperfusion, and then decreased to normal levels. Calculated lactate-pyruvate ratio increased after cold perfusion and remained stable during cold storage. During rewarming, it showed an accelerated increase, but after reperfusion, it decreased rapidly. Rewarming and reperfusion are most harmful to the liver, reflected by an accelerated increase in glucose and glycerol levels and lactate-pyruvate ratio. High intrahepatic glucose levels during ischemia appear to be a liver-specific event, which may represent glycogen degradation in injured hepatocytes. (Liver Transpl 2002;8:424-432.)

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Reperfusion injury to donor livers stored for transplantation

Cited by 106 publications

References 86 publications

Gene Transduction of an Active Mutant of Akt Exerts Cytoprotection and Reduces Graft Injury After Liver Transplantation

Gene Transduction of an Active Mutant of Akt Exerts Cytoprotection and Reduces Graft Injury After Liver Transplantation

Mechanism of Cell Death During Warm Hepatic Ischemia–Reperfusion in Rats: Apoptosis or Necrosis?

Metabolic changes in the liver graft monitored continuously with microdialysis during liver transplantation in a pig model

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