Role of Reactive Oxygen Species in Mediating Hepatic Ischemia-Reperfusion Injury and Its Therapeutic Applications in Liver Transplantation

Zhang, W.; Wang, M.; Xie, Haiyang; Zhou, Lin; Meng, Xianghong; Shi, Jianhui; Zheng, Shusen

doi:10.1016/j.transproceed.2006.11.021

Cited by 115 publications

(103 citation statements)

References 53 publications

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“…Protein carbonyl (PC) and MDA levels did not significantly change during ischemia and immediately after reperfusion respect to pre-anesthesia levels but significantly increased after 10 min of reperfusion (by 4.4-and 1.6-folds, respectively). This trend well agrees with the well-known burst of oxidative stress that occurs during the reperfusion stage [30]. In particular, the oxidative damage and the consequent formation of lipid peroxidation products occur during reperfusion [31].…”

Section: Discussionsupporting

confidence: 89%

Albumin Cys34 adducted by acrolein as a marker of oxidative stress in ischemia-reperfusion injury during hepatectomy

Witort

Capaccioli

Becatti

et al. 2016

Free Radical Research

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The aim of this study was to measure and identify the reactive carbonyl species (RCSs) released in the blood of humans subjected to hepatic resection. Pre-anesthesia malondialdehyde (MDA) plasma content (0.36 ± 0.11 nmol/mg protein) remained almost unchanged immediately after anaesthesia, before clamping and at the 10th min after ischemia, while markedly increased (to 0.59 ± 0.07 nmol/mg; p < 0.01, Tukey's post test) at the 10th min of reperfusion. A similar trend was observed for the protein carbonyls (PCs), whose pre-anesthesia levels (0.17 ± 0.13 nmol/mg) did not significantly change during ischemia, while increased more than fourfold at the 10th min of reperfusion (0.75 ± 0.17 nmol/mg; p < 0.01, Tukey's post test). RCSs were then identified as covalent adducts to the albumin Cys34, which we previously found as the most reactive protein nucleophilic site in plasma. By using a mass spectrometry (MS) approach based on precursor ion scanning, we found that acrolein (ACR) is the main RCS adducted to albumin Cys34. In basal conditions, the adducted albumin was 0.6 ± 0.4% of the native form but it increased by almost fourfold at the 10th min of reperfusion (2.3 ± 0.7%; p < 0.01, t-test analysis). Since RCSs are damaging molecules, we propose that RCSs, and ACR in particular, are new targets for novel molecular treatments aimed at reducing the ischemia/reperfusion damage by the use of RCS sequestering agents. ARTICLE HISTORY

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Section: Discussionsupporting

confidence: 89%

Albumin Cys34 adducted by acrolein as a marker of oxidative stress in ischemia-reperfusion injury during hepatectomy

Witort

Capaccioli

Becatti

et al. 2016

Free Radical Research

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“…This model would generate the accumulation of intracellular reactive oxygen species, which are crucial to part of hepatic IRI. 7 Certainly, if JAK2 were to inhibit cellular apoptosis in this in vitro model of warm hepatic IRI, a stronger, more convincing argument could be made about the potential therapeutic benefit of AG490.…”

Section: To the Editorsmentioning

confidence: 96%

Blockade of janus kinase 2 signaling ameliorates mouse liver damage due to ischemia and reperfusion

Bhogal

Afford

2010

Liver Transpl

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TO THE EDITORS:We read with great interest the article by Freitas and colleagues, 1 who reported the important role of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 signaling in the pathophysiology of hepatic ischemia/reperfusion injury (IRI). However, there are some methodological concerns about the study that do not allow firm conclusions to be drawn about the data. Using a standard model of warm hepatic IRI, the authors demonstrated that C57BL mice, treated with the selective JAK2 inhibitor AG490, showed reduced hepatocellular injury and decreased macrophage and neutrophil infiltration.The authors used mouse hepatoma cells in some of their in vitro experiments. They showed that AG490 decreased lipopolysaccharide (LPS)-mediated mouse hepatoma cell apoptosis. However, previous studies have shown that human hepatoma cells do not accurately reflect the biological responses of primary human hepatocytes.2 This presents 2 problems for the interpretation of the study. First, there are no data within the study showing that mouse hepatoma cells respond to LPS in a way similar to that of primary mouse hepatocytes. Previous studies have also shown that mouse hepatoma cells differ phenotypically from primary mouse hepatocytes.3 Moreover, hepatoma cells differ functionally from primary hepatocyte cell cultures.2,4 Second, the authors did not use a suitable in vitro model of warm IRI to adequately demonstrate the effects of AG490. This is surprising because of the number of previously published studies that have used such models. 5,6 Indeed, previous work has illustrated the different responses of the human hepatocyte cell line HL-7702 to the tumor necrosis factor superfamily ligand and tumor necrosis factor-related apoptosis-inducing ligand, during hypoxia and with hypoxia/reoxygenation. 5 Therefore, the effects of JAK2 inhibition should be investigated during hypoxia and hypoxia/reoxygenation because cells will be exposed to oxygen tensions akin to those experienced in vivo. Experiments conducted with this type of in vitro model are more relevant to hepatic IRI than investigations of the effects of LPS during normoxia. This model would generate the accumulation of intracellular reactive oxygen species, which are crucial to part of hepatic IRI.7 Certainly, if JAK2 were to inhibit cellular apoptosis in this in vitro model of warm hepatic IRI, a stronger, more convincing argument could be made about the potential therapeutic benefit of AG490.We believe that the in vivo data of this study by Freitas et al.1 do show some clinical promise with respect to the amelioration of hepatic IRI by JAK2 inhibition. However, the in vitro data do not provide a clear explanation of the effects of JAK2 inhibition on hepatocyte cell death. We encourage the use of primary mouse hepatocytes in a suitable in vitro model of warm IRI to further delineate the effects of JAK2 on hepatocyte function. At present, no clear conclusion can be drawn about the benefits of JAK2 inhibition during hepatic IRI.

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“…18,19 Sinusoidal endothelial cells in LDLT recipients are exposed to the cytotoxic agent tacrolimus, 11 as well as to reactive oxygen species induced by liver ischemia/reperfusion injury. 20 The relative deficiency of glutathione in zone 3 hepatocytes might result in greater damage to sinusoidal endothelial cells in this zone. 21 Additionally, the shear stress of portal hypertension because of small-sized grafts likely exacerbated sinusoidal endothelial cell damage in EPA-positive patients, resulting in a greater likelihood of EPA in zone 3.…”

Section: Shinichi Nakanuma Et Al/experimental and Clinical Transplantmentioning

confidence: 99%

Untitled

2015

Exp Clin Transplant

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Objectives: Continuous thrombocytopenia after liver transplant is associated with a less favorable prognosis, but this pathogenesis remains unclear. We focused on the consumption of platelets in the allograft. We assessed platelet consumption in allografts, and evaluated the pathology of platelet aggregation in an allograft tissue and its involvement in clinical outcomes. Materials and Methods: We took biopsy specimens from 20 patients. To examine the localization of platelet aggregation, CD42b was assayed immunohistochemically, and its level of expression correlated with clinical data and outcomes. Results: Platelet aggregation in zone 3 was 70%, compared with 30% in zone 1 and 50% in zone 2. Platelets were found mainly as extravasated platelet aggregates in local microenvironments. Patients were stratified according to the extent of extravasated platelet aggregates in zone 3 into extravasated platelet aggregate-negative andpositive groups. Graft weight/recipient body weight ratio with the extravasated platelet aggregatepositive group was significantly lower than that of the extravasated platelet aggregate-negative group. Platelet count after surgery was lower, while total bilirubin and prothrombin time/international normalized ratio were higher in the extravasated platelet aggregate-positive than they were in the extravasated platelet aggregate-negative group. Conclusions: Extravasated platelet aggregates in the zone 3 of allograft tissue cause the consumption of platelets and continuous thrombocytopenia after transplant, and may be the clinical marker for deterioration of graft function. Platelet activation and degranulation following the release by platelets of some negative regulators may be involved partially in liver damage.

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Role of Reactive Oxygen Species in Mediating Hepatic Ischemia-Reperfusion Injury and Its Therapeutic Applications in Liver Transplantation

Cited by 115 publications

References 53 publications

Albumin Cys34 adducted by acrolein as a marker of oxidative stress in ischemia-reperfusion injury during hepatectomy

Albumin Cys34 adducted by acrolein as a marker of oxidative stress in ischemia-reperfusion injury during hepatectomy

Blockade of janus kinase 2 signaling ameliorates mouse liver damage due to ischemia and reperfusion

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