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Zhao B, Wei J, Jiang Z, Long Y, Xu Y, Jiang B. Mesenchymal stem cell-derived exosomes: an emerging therapeutic strategy for hepatic ischemia-reperfusion injury. Stem Cell Res Ther 2025; 16:178. [PMID: 40229893 PMCID: PMC11998454 DOI: 10.1186/s13287-025-04302-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 04/01/2025] [Indexed: 04/16/2025] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) severely threatens the success rates of liver surgery and transplantation. Its complex pathological process involves multiple factors such as oxidative stress, inflammatory responses, and ferroptosis, creating an urgent need for new therapeutic strategies. Exosomes derived from mesenchymal stem cells (MSCs) are emerging as a next-generation acellular therapeutic approach. With their outstanding immune-regulatory capabilities, significant reparative functions, and good biocompatibility, they are leading innovations in the field of HIRI treatment. This article provides a systematic comparison of the therapeutic characteristics of MSC-derived exosomes(MSC-EXOs) from four different sources: adipose tissue, bone marrow, umbilical cord, and induced pluripotent stem cells. Although the clinical translation of MSC-EXOs still faces challenges such as variations in isolation methods, large-scale production, and safety assessments, their remarkable therapeutic effects and vast application potential signal the arrival of a new era of precision treatment for HIRI. This review not only provides a comprehensive theoretical foundation to promote the clinical application of MSC-EXOs but also opens up innovative research directions in the field of regenerative medicine.
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Affiliation(s)
- Bo Zhao
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, Hubei Province, P. R. China
- Department of Urology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, 228 Jingui Road, Xian an District, Xianning, 437100, Hubei Province, P. R. China
| | - Jiping Wei
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, Hubei Province, P. R. China
- Department of Urology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, 228 Jingui Road, Xian an District, Xianning, 437100, Hubei Province, P. R. China
| | - Zijian Jiang
- Yangtze University, Jingzhou, 434000, Hubei Province, P. R. China
| | - Yiming Long
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, Hubei Province, P. R. China
- Department of Urology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, 228 Jingui Road, Xian an District, Xianning, 437100, Hubei Province, P. R. China
| | - Yan Xu
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, Hubei Province, P. R. China
| | - Botao Jiang
- Department of Urology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, 228 Jingui Road, Xian an District, Xianning, 437100, Hubei Province, P. R. China.
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Antwi-Baah R, Acquah MEE, Dapaah MF, Chen X, Walker J, Liu H. Juxtaposing the antibacterial activities of different ZIFs in photodynamic therapy and their oxidative stress approach. Colloids Surf B Biointerfaces 2025; 247:114397. [PMID: 39615429 DOI: 10.1016/j.colsurfb.2024.114397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 11/05/2024] [Accepted: 11/21/2024] [Indexed: 01/22/2025]
Abstract
Instigating oxidative stress is a crucial aspect of antibacterial therapy. Yet, its behavior is poorly understood in the context of zeolitic imidazolate frameworks (ZIFs) - a group of highly promising antibacterial agents. To address this gap, a series of ZIF@Ce6 particles were synthesized to investigate the impact of particle shape, size, and metal ion type on oxidative stress and bactericidal activity. For the first time, the interplay between the physicochemical properties and antibacterial activities of different ZIF@Ce6 particles is demonstrated, while unearthing their oxidative stress strategy in photodynamic therapy. Notably, the incorporation of chlorin e6 (Ce6), combined with light irradiation, amplified the bactericidal effect of the ZIFs and achieved a rare minimum inhibition concentration (MIC) of 12.5 µgmL-1 for ZIF-8. We discovered that singlet oxygen (1O2) production varies with particle shape and size, while photodynamic activity reshuffles the antibacterial performance sequence from pristine to modified ZIF-8. Interestingly, reactive oxygen species (ROS) accumulation and glutathione depletion tests revealed that oxidative stress in pristine ZIF-8 is predominantly induced by ROS, whereas both ROS and glutathione contribute to the oxidative stress in ZIF@Ce6 and pristine ZIF-67. When bacteria are preincubated with the antioxidant N-acetyl cysteine, the bactericidal activity of ZIF@Ce6 increases while the activity of pristine ZIF-8 is reduced and that of ZIF-67 remains unchanged. This study deepens our understanding of the antibacterial properties of ZIFs and their oxidative stress paths, paving way for the fabrication of ZIF-based materials with enriched and targeted antibacterial properties.
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Affiliation(s)
- Ruth Antwi-Baah
- School of Physical Science and Technology, Sichuan University, Chengdu, Sichuan 610065, China.
| | - Mirabel Ewura Esi Acquah
- Shanghai Key Laboratory of Orthopaedic Surgery of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Malcom Frimpong Dapaah
- Institute of Environmental Health and Ecological Security, School of the Environment and Safety Engineering, Jiangsu University, Zhenjiang, Jiangsu 212013, China
| | - Xiaoqin Chen
- Engineering Research Center in Biomaterials, Sichuan University, Chengdu, Sichuan 610065, China
| | - Joojo Walker
- School of International Education, Chengdu University of Technology, Chengdu, Sichuan 610059, China
| | - Heyang Liu
- School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, Zhejiang 310023, China; School of Environment and Natural Resources, Zhejiang University of Science and Technology, Hangzhou, Zhejiang 310023, China
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Pantanali CA, Rocha-Santos V, Kubrusly MS, Castro IA, Carneiro-D'Albuquerque LA, Galvão FH. The Protective Effect of Nutraceuticals on Hepatic Ischemia-Reperfusion Injury in Wistar Rats. Int J Mol Sci 2023; 24:10264. [PMID: 37373409 DOI: 10.3390/ijms241210264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/09/2023] [Accepted: 06/10/2023] [Indexed: 06/29/2023] Open
Abstract
Nutraceuticals are bioactive compounds present in foods, utilized to ameliorate health, prevent diseases, and support the proper functioning of the human body. They have gained attention due to their ability to hit multiple targets and act as antioxidants, anti-inflammatory agents, and modulators of immune response and cell death. Therefore, nutraceuticals are being studied to prevent and treat liver ischemia-reperfusion injury (IRI). This study evaluated the effect of a nutraceutical solution formed by resveratrol, quercetin, omega-3 fatty acid, selenium, ginger, avocado, leucine, and niacin on liver IRI. IRI was performed with 60 min of ischemia and 4 h of reperfusion in male Wistar rats. Afterward, the animals were euthanized to study hepatocellular injury, cytokines, oxidative stress, gene expression of apoptosis-related genes, TNF-α and caspase-3 proteins, and histology. Our results show that the nutraceutical solution was able to decrease apoptosis and histologic injury. The suggested mechanisms of action are a reduction in gene expression and the caspase-3 protein and a reduction in the TNF-α protein in liver tissue. The nutraceutical solution was unable to decrease transaminases and cytokines. These findings suggest that the nutraceuticals used favored the protection of hepatocytes, and their combination represents a promising therapeutic proposal against liver IRI.
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Affiliation(s)
- Carlos Andrés Pantanali
- Liver and Gastrointestinal Transplant Division, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo 05403-900, Brazil
| | - Vinicius Rocha-Santos
- Liver and Gastrointestinal Transplant Division, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo 05403-900, Brazil
| | - Márcia Saldanha Kubrusly
- Liver and Gastrointestinal Transplant Division, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo 05403-900, Brazil
| | - Inar Alves Castro
- LADAF, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo 01246-000, Brazil
| | - Luiz Augusto Carneiro-D'Albuquerque
- Liver and Gastrointestinal Transplant Division, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo 05403-900, Brazil
| | - Flávio Henrique Galvão
- Liver and Gastrointestinal Transplant Division, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo 05403-900, Brazil
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Teodoro JS, Da Silva RT, Machado IF, Panisello-Roselló A, Roselló-Catafau J, Rolo AP, Palmeira CM. Shaping of Hepatic Ischemia/Reperfusion Events: The Crucial Role of Mitochondria. Cells 2022; 11:688. [PMID: 35203337 PMCID: PMC8870414 DOI: 10.3390/cells11040688] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/09/2022] [Accepted: 02/11/2022] [Indexed: 12/10/2022] Open
Abstract
Hepatic ischemia reperfusion injury (HIRI) is a major hurdle in many clinical scenarios, including liver resection and transplantation. Various studies and countless surgical events have led to the observation of a strong correlation between HIRI induced by liver transplantation and early allograft-dysfunction development. The detrimental impact of HIRI has driven the pursuit of new ways to alleviate its adverse effects. At the core of HIRI lies mitochondrial dysfunction. Various studies, from both animal models and in clinical settings, have clearly shown that mitochondrial function is severely hampered by HIRI and that its preservation or restoration is a key indicator of successful organ recovery. Several strategies have been thus implemented throughout the years, targeting mitochondrial function. This work briefly discusses some the most utilized approaches, ranging from surgical practices to pharmacological interventions and highlights how novel strategies can be investigated and implemented by intricately discussing the way mitochondrial function is affected by HIRI.
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Affiliation(s)
- João S. Teodoro
- MitoLab, Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal; (J.S.T.); (A.P.R.)
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
- IIIUC–Institute of Interdisciplinary Research, University of Coimbra, Pólo II da Universidade de Coimbra, 3000 Coimbra, Portugal
| | - Rui T. Da Silva
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Ivo F. Machado
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
- IIIUC–Institute of Interdisciplinary Research, University of Coimbra, Pólo II da Universidade de Coimbra, 3000 Coimbra, Portugal
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institute of Biomedical Research of Barcelona (IIBB), CSIC-IDIBAPS, 08036 Barcelona, Spain; (A.P.-R.); (J.R.-C.)
| | - Anabela P. Rolo
- MitoLab, Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal; (J.S.T.); (A.P.R.)
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
| | - Carlos M. Palmeira
- MitoLab, Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal; (J.S.T.); (A.P.R.)
- MitoLab, Mitochondria, Metabolism and Disease Group, Center for Neurosciences and Cell Biology, Faculdade de Medicina, University of Coimbra, 3000 Coimbra, Portugal; (R.T.D.S.); (I.F.M.)
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Advanced Oxidation Protein Products and Carbonylated Proteins Levels in Endovascular and Open Repair of an Abdominal Aortic Aneurysm: The Effect of Pre-, Intra-, and Postoperative Treatment. BIOMED RESEARCH INTERNATIONAL 2019; 2019:7976043. [PMID: 31205945 PMCID: PMC6530117 DOI: 10.1155/2019/7976043] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 04/04/2019] [Accepted: 04/17/2019] [Indexed: 11/29/2022]
Abstract
Background In recent years, a rapid increase in studies focusing on the role of oxidative stress in the pathogenesis of an abdominal aortic aneurysm (AAA) has been observed. Oxidative modifications of proteins are infrequently evaluated in reference to AAA. Objectives The intensity of oxidative protein modifications, presented as advanced oxidation protein products (AOPP) and carbonylated proteins (C=O), in AAA patients qualified for surgery was estimated. The effect of surgical techniques and intraoperative and postoperative treatment on AOPP and C=O levels was evaluated. Patients The EVAR group, consisting of 30 patients, was classified for endovascular aneurysm repair, whereas 28 patients were classified for conventional open repair (OR). Methods AOPP and C=O were measured using a colorimetric assay kit. Results A significantly lower AOPP level obtained 2-4 days after EVAR surgery in comparison with the value found before surgery was noted. In the case of OR postoperative treatment, a tendency of AOPP level to increase was observed. The tendency of C=O to decrease after surgery in the EVAR group was indicated. However, the C=O level tended to increase after OR surgery and reached a significantly higher value 5-7 days after surgery compared with the value obtained before surgery. Conclusions Based on our results, it may be concluded that AAA as well as surgical technique contribute to the formation of AOPP and C=O. The analysis of changes in AOPP and C=O values obtained after surgery revealed a significant effect of a patient's condition before surgery as well as the choice of surgery technique on the values of the studied parameters revealed during postoperative treatment.
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Grupp K, Erbes J, Poppe A, Wodack K, Gocht A, Trepte C, Havel J, Mann O, Izbicki JR, Bachmann K. Melatonin treatment of pigs with acute pancreatitis reduces inflammatory reaction of pancreatic tissue and enhances fitness score of pigs: experimental research. World J Emerg Surg 2019; 14:18. [PMID: 31007709 PMCID: PMC6458612 DOI: 10.1186/s13017-019-0237-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 03/25/2019] [Indexed: 12/27/2022] Open
Abstract
Background Severe acute pancreatitis is associated with high morbidity and mortality. Melatonin is known as the activator of antioxidant enzymes. The main purpose of this study was to evaluate the clinical effect of melatonin treatment in a pig model with induced acute pancreatitis. Methods In this study, acute pancreatitis was induced in 38 German domestic pigs (German Hybrid). After induction of acute pancreatitis, 18 animals were treated with melatonin. Intraoperative clinical data, postoperative blood parameters, fitness, and Porcine Well-being (PWB) score, and post-mortal histopathological data were analyzed in both study groups. Results The matching procedure created two groups (melatonin group and control group) which were very similar. The fitness and PWB score were postoperative significantly enhanced in the melatonin group as compared to the control group (p = 0.005 and p = 0.003). Additionally, histological analysis revealed that acinar necrosis, fat tissue necrosis, and edema were significantly reduced in the melatonin group as compared to the non-melatonin group (p = 0.025, p = 0.003, and p = 0.028). Conclusions Pigs, which were treated with melatonin, were characterized by higher fitness and PWB scores than those of the control group. Moreover, melatonin treatment reduces the acinar necrosis, fat tissue necrosis, and edema of pancreatic tissue. Thus, melatonin might be a useful therapeutic option in severe acute pancreatitis.
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Affiliation(s)
- Katharina Grupp
- 1Department of General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Erbes
- 1Department of General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Annika Poppe
- 2Centre of Anesthesiology and Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Karin Wodack
- 2Centre of Anesthesiology and Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas Gocht
- 3Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Constantin Trepte
- 2Centre of Anesthesiology and Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Jan Havel
- 1Department of General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Oliver Mann
- 1Department of General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R Izbicki
- 1Department of General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Kai Bachmann
- 1Department of General, Visceral and Thoracic Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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Rampes S, Ma D. Hepatic ischemia-reperfusion injury in liver transplant setting: mechanisms and protective strategies. J Biomed Res 2019; 33:221-234. [PMID: 32383437 DOI: 10.7555/jbr.32.20180087] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatic ischemia-reperfusion injury is a major cause of liver transplant failure, and is of increasing significance due to increased use of expanded criteria livers for transplantation. This review summarizes the mechanisms and protective strategies for hepatic ischemia-reperfusion injury in the context of liver transplantation. Pharmacological therapies, the use of pre-and post-conditioning and machine perfusion are discussed as protective strategies. The use of machine perfusion offers significant potential in the reconditioning of liver grafts and the prevention of hepatic ischemia-reperfusion injury, and is an exciting and active area of research, which needs more study clinically.
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Affiliation(s)
- Sanketh Rampes
- Faculty of Life Sciences & Medicine, King's College London, London SE1 1U, UK
| | - Daqing Ma
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London SW10 9NH, UK
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Jeong JS, Kim D, Kim KY, Ryu S, Han S, Shin BS, Kim GS, Gwak MS, Ko JS. Ischemic Preconditioning Produces Comparable Protection Against Hepatic Ischemia/Reperfusion Injury Under Isoflurane and Sevoflurane Anesthesia in Rats. Transplant Proc 2018; 49:2188-2193. [PMID: 29149981 DOI: 10.1016/j.transproceed.2017.07.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 07/30/2017] [Indexed: 11/27/2022]
Abstract
BACKGROUND Various volatile anesthetics and ischemic preconditioning (IP) have been demonstrated to exert protective effect against ischemia/reperfusion (I/R) injury in liver. We aimed to determine whether application of IP under isoflurane and sevoflurane anesthesia would confer protection against hepatic I/R injury in rats. METHODS Thirty-eight rats weighing 270 to 300 grams were randomly divided into 2 groups: isoflurane (1.5%) and sevoflurane (2.5%) anesthesia groups. Each group was subdivided into sham (n = 3), non-IP (n = 8; 45 minutes of hepatic ischemia), and IP (n = 8, IP consisting of 10-minute ischemia plus 15-minute reperfusion before prolonged ischemia) groups. The degree of hepatic injury and expressions of B-cell lymphoma 2 (Bcl-2) and caspase 3 were compared at 2 hours after reperfusion. RESULTS Hepatic ischemia induced significant degree of I/R injuries in both isoflurane and sevoflurane non-IP groups. In both anesthetic groups, introduction of IP dramatically attenuated I/R injuries as marked by significantly lower aspartate aminotransferase and aminotransferase levels and better histologic grades compared with corresponding non-IP groups. There were 2.3- and 1.7-fold increases in Bcl-2 mRNA levels in isoflurane and sevoflurane IP groups, respectively, compared with corresponding non-IP groups (both P < .05). Caspase 3 level was significantly high in the isoflurane non-IP group compared with the sham group; however, there were no differences among the sevoflurane groups. CONCLUSIONS The degree of hepatic I/R injury was significantly high in both isoflurane and sevoflurane groups in rats. However, application of IP significantly protected against I/R injury in both volatile anesthetic groups to similar degrees, and upregulation of Bcl-2 might be an important mechanism.
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Affiliation(s)
- J S Jeong
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - D Kim
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - K Y Kim
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - S Ryu
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - S Han
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - B S Shin
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - G S Kim
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - M S Gwak
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - J S Ko
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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Abstract
Reactive oxygen species have long been implicated in the pathophysiology of acute liver injury. However, the translation of these findings to the clinic and the development of therapeutic agents have been slow mainly due to the poor mechanistic understanding of the pathophysiology and the many indirect approaches used to characterize the role of oxidant stress in liver injury. The current review discusses in depth the sources of reactive oxygen, the oxidants involved and the impact of this oxidant stress in the mechanism of cell death in 3 different clinically relevant acute liver injury models.
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Affiliation(s)
- Anup Ramachandran
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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10
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Hu C, Li L. Pre-conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion. J Cell Mol Med 2017; 21:1719-1731. [PMID: 28301072 PMCID: PMC5571537 DOI: 10.1111/jcmm.13129] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 01/13/2017] [Indexed: 12/16/2022] Open
Abstract
The liver, the largest organ with multiple synthesis and secretion functions in mammals, consists of hepatocytes and Kupffer, stem, endothelial, stellate and other parenchymal cells. Because of early and extensive contact with the external environment, hepatic ischaemia reperfusion (IR) may result in mitochondrial dysfunction, autophagy and apoptosis of cells and tissues under various pathological conditions. Because the liver requires a high oxygen supply to maintain normal detoxification and synthesis functions, it is extremely susceptible to ischaemia and subsequent reperfusion with blood. Consequently, hepatic IR leads to acute or chronic liver failure and significantly increases the total rate of morbidity and mortality through multiple regulatory mechanisms. An increasing number of studies indicate that mitochondrial structure and function are impaired after hepatic IR, but that the health of liver tissues or liver grafts can be effectively rescued by attenuation of mitochondrial dysfunction. In this review, we mainly focus on the subsequent therapeutic interventions related to the conservation of mitochondrial function involved in mitigating hepatic IR injury and the potential mechanisms of protection. Because mitochondria are abundant in liver tissue, clarification of the regulatory mechanisms between mitochondrial dysfunction and hepatic IR should shed light on clinical therapies for alleviating hepatic IR‐induced injury.
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Affiliation(s)
- Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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SO4 = uptake and catalase role in preconditioning after H2O2-induced oxidative stress in human erythrocytes. Pflugers Arch 2016; 469:235-250. [DOI: 10.1007/s00424-016-1927-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 12/04/2016] [Accepted: 12/06/2016] [Indexed: 10/20/2022]
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12
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Ming-Ch'eng Adams CI, Baker JE, Kjellerup BV. Toxicological effects of polychlorinated biphenyls (PCBs) on freshwater turtles in the United States. CHEMOSPHERE 2016; 154:148-154. [PMID: 27043381 DOI: 10.1016/j.chemosphere.2016.03.102] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 12/15/2015] [Accepted: 03/22/2016] [Indexed: 05/18/2023]
Abstract
Prediction of vertebrate health effects originating from persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) has remained a challenge for decades thus making the identification of bioindicators difficult. POPs are predominantly present in soil and sediment, where they adhere to particles due to their hydrophobic characteristics. Animals inhabiting soil and sediment can be exposed to PCBs via dermal exposure while others may obtain PCBs through contaminated trophic interaction. Freshwater turtles can serve as bioindicators due to their strong site fidelity, longevity and varied diet. Previous research observed the health effects of PCBs on turtles such as decreased bone mass, changed sexual development and decreased immune responses through studying both contaminated sites along with laboratory experimentation. Higher deformity rates in juveniles, increased mortality and slower growth have also been observed. Toxicological effects of PCBs vary between species of freshwater turtles and depend on the concertation and configuration of PCB congeners. Evaluation of ecotoxicological effects of PCBs in non-endangered turtles could provide important knowledge about the health effects of endangered turtle species thus inform the design of remediation strategies. In this review, the PCB presence in freshwater turtle habitats and the ecotoxicological effects were investigated with the aim of utilizing the health status to identify areas of focus for freshwater turtle conservation.
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Affiliation(s)
- Clare Isabel Ming-Ch'eng Adams
- Iowa State University, 353 Bessey Hall, Department of Ecology, Evolution, and Organismal Biology, Ames, IA 50011-1020, USA
| | - Joel E Baker
- University of Washington Tacoma, The Center for Urban Waters, 1900 Commerce Street, Tacoma, WA 98402-3100, USA
| | - Birthe V Kjellerup
- University of Maryland at College Park, A. James Clark School of Engineering, Department of Civil and Environmental Engineering, 1147 Glenn L. Martin Hall, College Park, MD 20742, USA.
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Mitochondrial Dysfunction and Autophagy in Hepatic Ischemia/Reperfusion Injury. BIOMED RESEARCH INTERNATIONAL 2015; 2015:183469. [PMID: 26770970 PMCID: PMC4684839 DOI: 10.1155/2015/183469] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 11/10/2015] [Accepted: 11/11/2015] [Indexed: 12/26/2022]
Abstract
Ischemia/reperfusion (I/R) injury remains a major complication of liver resection, transplantation, and hemorrhagic shock. Although the mechanisms that contribute to hepatic I/R are complex and diverse involving the interaction of cell injury in hepatocytes, immune cells, and endothelium, mitochondrial dysfunction is a cardinal event culminating in hepatic reperfusion injury. Mitochondrial autophagy, so-called mitophagy, is a key cellular process that regulates mitochondrial homeostasis and eliminates damaged mitochondria in a timely manner. Growing evidence accumulates that I/R injury is attributed to defective mitophagy. This review aims to summarize the current understanding of autophagy and its role in hepatic I/R injury and highlight the various therapeutic approaches that have been studied to ameliorate injury.
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Videla LA, Fernández V, Cornejo P, Vargas R, Carrasco J, Fernández J, Varela N. Causal role of oxidative stress in unfolded protein response development in the hyperthyroid state. Free Radic Biol Med 2015; 89:401-8. [PMID: 26434419 DOI: 10.1016/j.freeradbiomed.2015.09.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 09/09/2015] [Accepted: 09/11/2015] [Indexed: 02/07/2023]
Abstract
L-3,3',5-Triiodothyronine (T3)-induced liver oxidative stress underlies significant protein oxidation, which may trigger the unfolded protein response (UPR). Administration of daily doses of 0.1mg T3 for three consecutive days significantly increased the rectal temperature of rats and liver O2 consumption rate, with higher protein carbonyl and 8-isoprostane levels, glutathione depletion, and absence of morphological changes in liver parenchyma. Concomitantly, liver protein kinase RNA-like endoplasmic reticulum (ER) kinase and eukaryotic translation initiator factor 2α were phosphorylated in T3-treated rats compared to controls, with increased protein levels of binding immunoglobulin protein and activating transcription factor 4. In addition, higher mRNA levels of C/EBP homologous protein, growth arrest and DNA damage 34, protein disulfide isomerase, and ER oxidoreductin 1α were observed, changes that were suppressed by N-acetylcysteine (0.5 g/kg) given before each dose of T3. In conclusion, T3-induced liver oxidative stress involving higher protein oxidation status has a causal role in UPR development, a response that is aimed to alleviate ER stress and promote cell survival.
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Affiliation(s)
- Luis A Videla
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago-7, Chile.
| | - Virginia Fernández
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago-7, Chile
| | - Pamela Cornejo
- School of Medical Technology, Faculty of Health and Odontology, Diego Portales University, Santiago, Chile
| | - Romina Vargas
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago-7, Chile
| | - Juan Carrasco
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago-7, Chile
| | - Javier Fernández
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago-7, Chile
| | - Nelson Varela
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago-7, Chile; Department of Medical Technology, Faculty of Medicine, University of Chile, Santiago-7, Chile
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15
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Pedemonte JC, Vargas R, Castillo V, Hodali T, Gutiérrez S, Tapia G, Castillo I, Videla LA, Fernández V. A combined iron and thyroid hormone protocol suppresses ischemia–reperfusion injury in rat livers. RSC Adv 2015. [DOI: 10.1039/c4ra15863f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Liver preconditioning (PC) against ischemia–reperfusion (IR) injury is attained by iron (Fe) or thyroid hormone (T3) administration.
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Affiliation(s)
- J. C. Pedemonte
- Program of Molecular and Clinical Pharmacology
- Institute of Biomedical Sciences
- Faculty of Medicine
- University of Chile
- Santiago
| | - R. Vargas
- Program of Molecular and Clinical Pharmacology
- Institute of Biomedical Sciences
- Faculty of Medicine
- University of Chile
- Santiago
| | - V. Castillo
- Program of Molecular and Clinical Pharmacology
- Institute of Biomedical Sciences
- Faculty of Medicine
- University of Chile
- Santiago
| | - T. Hodali
- Program of Molecular and Clinical Pharmacology
- Institute of Biomedical Sciences
- Faculty of Medicine
- University of Chile
- Santiago
| | - S. Gutiérrez
- Program of Molecular and Clinical Pharmacology
- Institute of Biomedical Sciences
- Faculty of Medicine
- University of Chile
- Santiago
| | - G. Tapia
- Program of Molecular and Clinical Pharmacology
- Institute of Biomedical Sciences
- Faculty of Medicine
- University of Chile
- Santiago
| | - I. Castillo
- School of Medicine
- Faculty of Medicine
- Catholic University of Talca
- Chile
| | - L. A. Videla
- Program of Molecular and Clinical Pharmacology
- Institute of Biomedical Sciences
- Faculty of Medicine
- University of Chile
- Santiago
| | - V. Fernández
- Program of Molecular and Clinical Pharmacology
- Institute of Biomedical Sciences
- Faculty of Medicine
- University of Chile
- Santiago
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Healy DA, Clarke Moloney M, McHugh SM, Grace PA, Walsh SR. Remote ischaemic preconditioning as a method for perioperative cardioprotection: Concepts, applications and future directions. Int J Surg 2014; 12:1093-9. [DOI: 10.1016/j.ijsu.2014.08.352] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 08/11/2014] [Indexed: 12/25/2022]
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Angiotensin II removes kidney resistance conferred by ischemic preconditioning. BIOMED RESEARCH INTERNATIONAL 2014; 2014:602149. [PMID: 25243156 PMCID: PMC4163347 DOI: 10.1155/2014/602149] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 07/06/2014] [Accepted: 08/06/2014] [Indexed: 01/13/2023]
Abstract
Ischemic preconditioning (IPC) by ischemia/reperfusion (I/R) renders resistance to the kidney. Strong IPC triggers kidney fibrosis, which is involved in angiotensin II (AngII) and its type 1 receptor (AT1R) signaling. Here, we investigated the role of AngII/AT1R signal pathway in the resistance of IPC kidneys to subsequent I/R injury. IPC of kidneys was generated by 30 minutes of bilateral renal ischemia and 8 days of reperfusion. Sham-operation was performed to generate control (non-IPC) mice. To examine the roles of AngII and AT1R in IPC kidneys to subsequent I/R, IPC kidneys were subjected to either 30 minutes of bilateral kidney ischemia or sham-operation following treatment with AngII, losartan (AT1R blocker), or AngII plus losartan. IPC kidneys showed fibrotic changes, decreased AngII, and increased AT1R expression. I/R dramatically increased plasma creatinine concentrations in non-IPC mice, but not in IPC mice. AngII treatment in IPC mice resulted in enhanced morphological damage, oxidative stress, and inflammatory responses, with functional impairment, whereas losartan treatment reversed these effects. However, AngII treatment in non-IPC mice did not change I/R-induced injury. AngII abolished the resistance of IPC kidneys to subsequent I/R via the enhancement of oxidative stress and inflammatory responses, suggesting that the AngII/AT1R signaling pathway is associated with outcome in injury-experienced kidney.
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Patel RP, Lang JD, Smith AB, Crawford JH. Redox therapeutics in hepatic ischemia reperfusion injury. World J Hepatol 2014; 6:1-8. [PMID: 24653789 PMCID: PMC3953809 DOI: 10.4254/wjh.v6.i1.1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 09/17/2013] [Accepted: 12/11/2013] [Indexed: 02/06/2023] Open
Abstract
Ischemia-reperfusion plays a major role in the injury experienced by the liver during transplantation. Much work has been done recently investigating the role of redox species in hepatic ischemia-reperfusion. As animal models are better characterized and developed, and more insights are gained into the pathophysiology of hepatic ischemia reperfusion injury in humans the questions into exactly how oxidants participate in this injury are becoming more refined. These questions include effects of cellular location, timing of injury, and ability of therapeutics to access this site are increasing our appreciation of the complexity of ischemia reperfusion and improving attempts to ameliorate its effects. In this review, we aim to discuss the various methods to alter redox chemistry during ischemia reperfusion injury and future prospects for preventing organ injury during hepatic ischemia reperfusion.
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Morales P, Vargas R, Videla LA, Fernández V. Nrf2 activation in the liver of rats subjected to a preconditioning sub-chronic iron protocol. Food Funct 2014; 5:243-50. [DOI: 10.1039/c3fo60265f] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Reestablishment of ischemia-reperfusion liver injury by N-acetylcysteine administration prior to a preconditioning iron protocol. ScientificWorldJournal 2013; 2013:607285. [PMID: 24288495 PMCID: PMC3826321 DOI: 10.1155/2013/607285] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Accepted: 09/15/2013] [Indexed: 01/10/2023] Open
Abstract
The role of iron (Fe)-induced prooxidant status in Fe preconditioning against ischemia (1 h)-reperfusion (20 h) induced liver injury was assessed using N-acetylcysteine (NAC) (1 g/kg) before Fe (50 mg/kg), given to male Sprague Dawley rats on alternate days during 10 days. IR significantly increased serum aspartate transaminase (AST) and alanine transaminase (ALT) levels, with drastic changes in liver histology, hepatic glutathione depletion, and nuclear factor-κB (NF-κB) p65 diminution (P < 0.05) (ELISA). Fe-induced liver oxidative stress, as evidenced by higher protein carbonyl/glutathione content ratios (P < 0.05) at days 11 and 12 after treatment, was abolished by NAC. Under these conditions, short-term Fe administration exerted significant protection against IR liver injury, as shown by 85% and 60% decreases in IR-induced serum AST and ALT (P < 0.05), respectively, and normalization of hepatic histology, glutathione levels, and NF-κB activation, changes that were suppressed by NAC administration prior to Fe. Results of this study indicate that NAC administration prior to an iron protocol reestablishes IR liver injury, supporting the role of Fe-induced transient oxidative stress in hepatoprotection and its potential clinical application.
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Complex Hepatectomy under Total Vascular Exclusion of the Liver: Impact of Ischemic Preconditioning on Clinical Outcomes. World J Surg 2013; 37:838-46. [DOI: 10.1007/s00268-012-1865-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Protection of pharmacological postconditioning in liver surgery: results of a prospective randomized controlled trial. Ann Surg 2013; 256:837-44; discission 844-5. [PMID: 23095629 DOI: 10.1097/sla.0b013e318272df7c] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES : To elucidate the possible organ-protective effect of pharmacological postconditioning in patients undergoing liver resection with inflow occlusion. BACKGROUND : Inflow occlusion reduces blood loss during liver transection in selected patients but is potentially harmful due to ischemia-reperfusion injury. Preventive strategies include the use of repetitive short periods of ischemia interrupted by a reperfusion phase (intermittent clamping), application of a short period of ischemia before transection (ischemic preconditioning), or pharmacological preconditioning before transection. Whether intervention after resection (postconditioning) may confer protection is unknown. METHODS : A 3 arm, prospective, randomized trial was designed for patients undergoing liver resection with inflow occlusion to compare the effects of pharmacological postconditioning with the volatile anesthetic agent sevoflurane (n = 48), intermittent clamping (n = 50), or no protective intervention (continuous inflow occlusion, n = 17). Endpoints included peak serum aspartate transaminase level, postoperative complications, and hospital stay. All patients were intravenously anesthetized with propofol. In patients with postconditioning, propofol infusion was stopped upon reperfusion and replaced with sevoflurane for 10 minutes. RESULTS : Compared with the control group, both postconditioning (P = 0.044) and intermittent clamping (P = 0.015) significantly reduced aspartate transaminase levels. The risk of complications was significantly decreased by postconditioning, odds ratio, 0.08 [95% confidence interval (CI), 0.02-0.36; P = 0.001]) and intermittent clamping, odds ratio, 0.50 [95% CI, 0.26-0.96; P = 0.038], compared with controls. Both interventions reduced length of hospital stay, postconditioning -4 days [95% CI, -6 to -1; P = 0.009], and intermittent clamping -2 days, [95% CI, -4 to 0; P = 0.019]. CONCLUSIONS : Pharmacological postconditioning reduces organ injury and postoperative complications. This easily applicable strategy should be used in patients with prolonged continuous inflow occlusion.
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Wang M, Shen J, Feng B, Gui L, Chen Q, Zhang B, Tang J, Li X. Remote ischemic preconditioning promotes early liver cell proliferation in a rat model of small-for-size liver transplantation. J Surg Res 2013; 179:e245-e253. [PMID: 22487396 DOI: 10.1016/j.jss.2012.02.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Revised: 01/31/2012] [Accepted: 02/03/2012] [Indexed: 11/30/2022]
Abstract
BACKGROUND The size of the liver donor graft is a major concern in living donor liver transplantation. Rapid regeneration is essential for the survival of these grafts. The purpose of this study was to investigate the effect of remote ischemic preconditioning (RIPC) on liver regeneration in a rat small-for-size liver transplantation model. METHODS We established rat models of small-for-size liver transplantation (30%) in the presence or absence (control) of remote ischemic preconditioning. We observed liver mass regeneration, serum alanine aminotransferase, hepatic pathologic alterations, flow cytometry, and Ki-67 antigen immunohistochemistry. In addition, using Western blotting and reverse-transcriptase-polymerase chain reaction, we assessed the activation of cell cycle progression as well as tumor necrosis factor-α and interleukin-6 expression. RESULTS Compared with the control group, serum alanine aminotransferase activity was significantly lower and histopathology changes were significantly attenuated in the RIPC group. Remote ischemic preconditioning induced a high level of interleukin-6 mRNA in small grafts, but suppressed the expression of tumor necrosis factor-α. The proliferation index, indicated by the S-phase and G2/M-phase ratio [(S+G2/M)/(G0/G1+S+G2/M)], was significantly increased in the RIPC group at 24 h (58.25% ± 0.506% versus 53.405% ± 1.25%; P = .007). Meanwhile, cell cycle progression and regeneration (Ki-67) were initiated early in liver grafts treated with RIPC. CONCLUSIONS These results suggest that RIPC can protect liver cells against ischemia reperfusion injury in the small grafts and enhance liver regeneration. Interleukin-6 may be a critical mediator in the stimulatory effect on liver cell regeneration, which may make RIPC valuable as a hepatoprotective modality.
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Affiliation(s)
- Meng Wang
- Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, China
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25
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Knudsen AR, Kannerup AS, Dich R, Funch-Jensen P, Grønbaek H, Kruhøffer M, Mortensen FV. Ischemic pre- and postconditioning has pronounced effects on gene expression profiles in the rat liver after ischemia/reperfusion. Am J Physiol Gastrointest Liver Physiol 2012; 303:G482-9. [PMID: 22679003 DOI: 10.1152/ajpgi.00337.2011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Ischemic pre (IPC)- and postconditioning (IPO) protect the liver against ischemia/reperfusion injuries (IRI). Conditioning involves several different trigger factors, mediators, and effectors, many of which are affected during the early phase of reperfusion, ultimately resulting in decreased liver injuries. The aim of the present study was to investigate the genomic response induced by IPC and IPO in ischemia/reperfusion-damaged rat liver biopsies. Forty-eight male Wistar rats were divided into five groups: sham (n = 8), IRI (n = 10), IPC (n = 10), IPO (n = 10), and IPC + IPO (n = 10). The rat livers were subjected to 30 min of ischemia. Liver biopsies and blood samples were taken after 30 min of reperfusion. The biopsies were analyzed using cDNA microarrays with validation by quantitative RT-PCR. The significance analysis of microarray was used to identify genes with changed expression levels. A comparison analysis of the intervention groups showed a highly increased number of genes, with significantly different expression in the conditioned groups compared with the IRI group. A total of 172 genes were identified as the most highly affected, and these genes showed similar patterns with regard to the up- and downregulated expression levels within the conditioned groups. Pathway analysis of the 172 genes identified four networks that were involved in increased gene expression, cellular growth, and proliferation. In conclusion, the present study demonstrated that IPC, IPO, and IPC + IPO had pronounced effects on the expression levels of a large number of genes during early reperfusion. IPC, IPO, and IPC + IPO seem to mediate their protective effects by regulating the same genes and genetic networks. These identified networks are known to be involved in maintaining cellular homeostasis.
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26
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Grezzana Filho TDJM, Mendonça TBD, Gabiatti G, Rodrigues G, Marroni NAP, Treis L, De Rossi SD, Corso CO. Topical hepatic hypothermia plus ischemic preconditioning: analysis of bile flow and ischemic injuries after initial reperfusion in rats. Acta Cir Bras 2012; 26:194-201. [PMID: 21537521 DOI: 10.1590/s0102-86502011000300007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Accepted: 02/14/2011] [Indexed: 12/23/2022] Open
Abstract
PURPOSE To evaluate the effects of the topical liver hypothermia and IPC combination against I/R injury after initial reperfusion. METHODS In 32 Wistar rats, partial liver ischemia was induced for 90 minutes in normothermia (IN), ischemic preconditioning (IPC), 26ºC topical hypothermia (H) and 26ºC topical hypothermia plus IPC (H+IPC). MAP, body temperature and bile flow were recorded each 15 minutes. Plasmatic injury markers and tissue antioxidant defenses were assessed after 120 minutes of reperfusion. RESULTS MAP and body temperature remained constant during all experiment. Bile flow returned to levels similar to controls after 45 minutes of reperfusion in the H and H+IPC groups and increased significantly in comparison to the NI and IPC groups after 105 and 120 minutes. AST and ALT increased significantly in the normothermic groups in comparison to controls. TBARS levels decreased significantly in the H+IPC group in comparison to the other groups whereas Catalase levels increased significantly in the IPC group. SOD levels were significantly higher in the H group in comparison to all groups. CONCLUSION The induction of 26ºC topical hypothermia associated or not to IPC protected the ischemic liver against ischemia/reperfusion injuries and allowed an early recovery of the hepatic function.
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Salomão LS, Young SB, Galhardo MA, Pereira LA, Pires ARC, Boaventura GT, Ferreira AMR, Martinho JM. Avaliação da regeneração hepática com modulação pelo pré-condicionamento isquêmico após isquemia e reperfusão e hepatectomia parcial. Rev Col Bras Cir 2012. [DOI: 10.1590/s0100-69912012000300009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
OBJETIVO: Avaliar a regeneração hepática com modulação pelo pré-condicionamento isquêmico após isquemia, reperfusão e hepatectomia parcial. MÉTODOS: Foram usadas 24 ratas Wistar, de 12 semanas de idade, distribuídas randomicamente em quatro grupos: Grupo Controle (SHAM), Grupo Hepatectomia (HEP), Grupo Isquemia e Reperfusão (GIR) e Grupo Pré-condicionamento Isquêmico (PRE). Foi feita a análise das enzimas hepáticas ALT e AST, avaliação da regeneração através dos pesos inicial e final do fígado e da proliferação dos hepatócitos pela análise imunoistoquímica com o Proliferating Cell Nuclear Antigen (PCNA). RESULTADOS: Em todos os grupos ocorreu regeneração do fígado, não havendo significância estatística entre eles. Houve diferenças significativas em relação a ALT e AST entre os grupos HEP-SHAM, GIR-PRE, GIR-SHAM E PRE-SHAM (p< 0,05). Também houve diferença significativa em relação à marcação de PCNA do grupo SHAM quando comparado aos demais grupos (p< 0,05). CONCLUSÃO: O pré-condicionamento isquêmico diminuiu a lesão hepática, mas não influenciou na regeneração até 48 horas.
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Fernández V, Tapia G, Videla LA. Recent advances in liver preconditioning: Thyroid hormone, n-3 long-chain polyunsaturated fatty acids and iron. World J Hepatol 2012; 4:119-28. [PMID: 22567184 PMCID: PMC3345536 DOI: 10.4254/wjh.v4.i4.119] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Revised: 11/08/2011] [Accepted: 04/24/2012] [Indexed: 02/06/2023] Open
Abstract
Liver preconditioning (PC), defined as an enhanced tolerance to injuring stimuli induced by previous specific maneuvers triggering beneficial functional and molecular changes, is of crucial importance in human liver transplantation and major hepatic resection. For these reasons, numerous PC strategies have been evaluated in experimental models of ischemia-reperfusion liver injury, which have not been transferred to clinical application due to side effects, toxicity and difficulties in implementation, with the exception of the controversial ischemic PC. In recent years, our group has undertaken the assessment of alternate experimental liver PC protocols that might have application in the clinical setting. These include thyroid hormone (T(3)), n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA), or iron, which suppressed liver damage due to the 1 h ischemia-20 h reperfusion protocol. T(3), n-3 LCPUFA and iron are hormetic agents that trigger biologically beneficial effects in the low-dose range, whose multifactorial mechanisms of action are discussed in the work.
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Affiliation(s)
- Virginia Fernández
- Virginia Fernández, Gladys Tapia, Luis A Videla, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70000, Santiago-7, Chile
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Weisz J, Shearer DA, Murata E, Patrick SD, Han B, Berg A, Clawson GA. Identification of mammary epithelial cells subject to chronic oxidative stress in mammary epithelium of young women and teenagers living in USA: implication for breast carcinogenesis. Cancer Biol Ther 2012; 13:101-13. [PMID: 22231390 DOI: 10.4161/cbt.13.2.18873] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Current knowledge of changes in the mammary epithelium relevant to breast carcinogenesis is limited to when histological changes are already present because of a lack of biomarkers needed to identify where such molecular changes might be ongoing at earlier during the of decades-long latent stages of breast carcinogenesis. Breast reduction tissues from young women and teenagers, representative of USA's high breast cancer incidence population, were studies using immunocytochemistry and targeted PCR arrays in order to learn whether a marker of chronic oxidative-stress [protein adducts of 4-hydroxy-2-nonenal (4HNE)] can identify where molecular changes relevant to carcinogenesis might be taking place prior to any histological changes. 4HNE-immunopositive (4HNE+) mammary epithelial cell-clusters were identified in breast tissue sections from most women and from many teenagers (ages 14-30 y) and, in tissues from women ages 17-27 y with many vs. few 4HNE+ cells, the expression of 30 of 84 oxidative-stress associated genes was decreased and only one was increased > 2-fold. This is in contrast to increased expression of many of these genes known to be elicited by acute oxidative-stress. The findings validate using 4HNE-adducts to identify where molecular changes of potential relevance to carcinogenesis are taking place in histologically normal mammary epithelium and highlight differences between responses to acute vs. chronic oxidative-stress. We posit that the altered gene expression in 4HNE+ tissues reflect adaptive responses to chronic oxidative-stress that enable some cells to evade mechanisms that have evolved to prevent propagation of cells with oxidatively-damaged DNA and to accrue heritable changes needed to establish a cancer.
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Affiliation(s)
- Judith Weisz
- Department of Obstetrics and Gynecology; College of Medicine; Pennsylvania State University; Hershey, PA USA.
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Park JB, Joh JW, Kim SJ, Kwon CHD, Chun JM, Kim JM, Moon JI, Lee SK. Effect of intermittent hepatic inflow occlusion with the Pringle maneuver during donor hepatectomy in adult living donor liver transplantation with right hemiliver grafts: a prospective, randomized controlled study. Liver Transpl 2012; 18:129-37. [PMID: 21837746 DOI: 10.1002/lt.22409] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
To evaluate the effects of intermittent hepatic inflow occlusion (IHIO) during donor hepatectomy for living donor liver transplantation (LDLT) in recipients and donors, we performed a single-center, open-label, prospective, parallel, randomized controlled study. Adult donor-recipient pairs undergoing LDLT with right hemiliver grafts were randomized into IHIO and control groups (1:1). In the IHIO group, IHIO was performed during donor hepatectomy. The primary endpoint was the peak serum alanine aminotransferase (ALT) concentration in the recipients within 5 days after the operation. Blood samples for measurements of interleukin-6 (IL-6), IL-8, tumor necrosis factor α (TNF-α), and hepatocyte growth factor (HGF) were taken from the donors and the recipients during the operation and postoperatively. Biopsy samples for measurements of caspase-3 and malondialdehyde (MDA) were taken from the donors and the recipients. In all, 50 donor-recipient pairs (ie, 25 pairs in each group) completed this study. The mean peak serum ALT levels within 5 days after the operation did not differ in the recipients between the 2 groups (P = 0.32) but were higher in the donors of the IHIO group (P = 0.002). There were no differences in the prothrombin times or total bilirubin levels in the recipients or donors between the 2 groups. The amount of blood loss during donor hepatectomy was significantly lower in the IHIO group versus the control group (P = 0.02). The mean hospital stay for donors was 19.3 ± 7.2 days in the control group and 15.8 ± 4.6 days in the IHIO group (P = 0.046). There were no in-hospital deaths within 1 month and no cases of primary nonfunction or initially poor function in the 2 groups. The concentrations of IL-6, IL-8, TNF-α, and HGF did not differ between the 2 groups, nor did the concentrations of caspase-3 and MDA. In conclusion, although we found differences in postoperative peak serum ALT levels in donors, donor hepatectomy with IHIO for LDLT using a right hemiliver graft with a graft-to-recipient body weight ratio > 0.9% and <30% steatosis can be a tolerable procedure for donors and recipients.
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Affiliation(s)
- Jae Berm Park
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Ulsan, Korea
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Coriat R, Leconte M, Kavian N, Bedda S, Nicco C, Chereau C, Goulvestre C, Weill B, Laurent A, Batteux F. Mangafodipir protects against hepatic ischemia-reperfusion injury in mice. PLoS One 2011; 6:e27005. [PMID: 22073237 PMCID: PMC3206884 DOI: 10.1371/journal.pone.0027005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Accepted: 10/07/2011] [Indexed: 12/15/2022] Open
Abstract
Introduction and Aim Mangafodipir is a contrast agent used in magnetic resonance imaging that concentrates in the liver and displays pleiotropic antioxidant properties. Since reactive oxygen species are involved in ischemia-reperfusion damages, we hypothesized that the use of mangafodipir could prevent liver lesions in a mouse model of hepatic ischemia reperfusion injury. Mangafodipir (MnDPDP) was compared to ischemic preconditioning and intermittent inflow occlusion for the prevention of hepatic ischemia-reperfusion injury in the mouse. Methods Mice were subjected to 70% hepatic ischemia (continuous ischemia) for 90 min. Thirty minutes before the ischemic period, either mangafodipir (10 mg/kg) or saline was injected intraperitoneally. Those experimental groups were compared with one group of mice preconditioned by 10 minutes' ischemia followed by 15 minutes' reperfusion, and one group with intermittent inflow occlusion. Hepatic ischemia-reperfusion injury was evaluated by measurement of serum levels of aspartate aminotransferase (ASAT) activity, histologic analysis of the livers, and determination of hepatocyte apoptosis (cytochrome c release, caspase 3 activity). The effect of mangafodipir on the survival rate of mice was studied in a model of total hepatic ischemia. Results Mangafodipir prevented experimental hepatic ischemia-reperfusion injuries in the mouse as indicated by a reduction in serum ASAT activity (P<0.01), in liver tissue damages, in markers of apoptosis (P<0.01), and by higher rates of survival in treated than in untreated animals (P<0.001). The level of protection by mangafodipir was similar to that observed following intermittent inflow occlusion and higher than after ischemic preconditioning. Conclusions Mangafodipir is a potential new preventive treatment for hepatic ischemia-reperfusion injury.
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Affiliation(s)
- Romain Coriat
- Laboratoire d'immunologie, EA1833 Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
- Service d'hépatogastroentérologie, Université Paris Descartes,Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
| | - Mahaut Leconte
- Laboratoire d'immunologie, EA1833 Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
- Service de Chirurgie Digestive, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
| | - Niloufar Kavian
- Laboratoire d'immunologie, EA1833 Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
- Laboratoire d'immunologie biologique Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
| | - Sassia Bedda
- Laboratoire d'immunologie, EA1833 Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
| | - Carole Nicco
- Laboratoire d'immunologie, EA1833 Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
| | - Christiane Chereau
- Laboratoire d'immunologie, EA1833 Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
| | - Claire Goulvestre
- Laboratoire d'immunologie, EA1833 Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
- Laboratoire d'immunologie biologique Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
| | - Bernard Weill
- Laboratoire d'immunologie, EA1833 Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
| | - Alexis Laurent
- Laboratoire d'immunologie, EA1833 Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
- Service de Chirurgie Digestive, Hôpital Henri Mondor, Université Paris XII, Créteil, France
| | - Frédéric Batteux
- Laboratoire d'immunologie, EA1833 Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
- Laboratoire d'immunologie biologique Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, Paris, France
- * E-mail:
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Fernandez-Ruiz V, Kawa M, Berasain C, Iñiguez M, Schmitz V, Martinez-Ansó E, Iñarrairaegui M, Herrero I, Sangro B, D'Avola D, Quiroga J, Qian C, Prieto J. Treatment of murine fulminant hepatitis with genetically engineered endothelial progenitor cells. J Hepatol 2011; 55:828-37. [PMID: 21334399 DOI: 10.1016/j.jhep.2011.01.036] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2010] [Revised: 12/21/2010] [Accepted: 01/02/2011] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS Cell therapy has been used to attenuate liver injury. Here we evaluated whether genetic engineering of either bone marrow-derived mononuclear cells (MNC) or endothelial progenitor cells (EPC) many enhance their hepatoprotective properties. METHODS Mice with ConA-induced hepatitis or with lethal fulminant hepatitis resulting from administration of an adenovirus encoding CD40L (AdCD40L) received an intra-splenic injection of saline or 2 × 10(6) unmodified MNC or EPC or the same cells transduced ex vivo with an adenovirus expressing luciferase (MNCLUC and EPCLUC) or encoding the hepatoprotective cytokine cardiotrophin-1 (CT-1) (MNCCT-1 and EPCCT-1). We analyzed the extent of liver damage, the intensity of inflammatory reaction, and animal survival. RESULTS Luciferase immunohistochemistry showed that after injection into the spleen, the engineered cells migrated efficiently to the damaged liver. In mice with ConA hepatitis EPCCT-1, but not other forms of cell therapy, significantly decreased serum transaminases and induced more intense histological improvement than other treatments. This superior therapeutic effect was associated with upregulation of cytoprotective molecules including IGF-I and EGF, lower expression of proinflammatory cytokines, IL-1b and TNFα, and decreased granzyme B levels. In AdCD40L-induced lethal fulminant hepatitis, EPCCT-1 also exceeded other cell therapies in attenuating the expression of proinflammatory mediators and hepatic injury enabling 35.7% survival while mortality was 100% in the other treatment groups. CONCLUSIONS Genetic engineering of EPC to overexpress CT-1 enhances the hepatoprotective properties of EPC and constitutes a therapy that deserves consideration for acute liver failure.
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Abstract
This review begins with the premise that an organism's life span is determined by the balance between two countervailing forces: (i) the sum of destabilizing effects and (ii) the sum of protective longevity-assurance processes. Against this backdrop, the role of electrophiles is discussed, both as destabilizing factors and as signals that induce protective responses. Because most biological macromolecules contain nucleophilic centers, electrophiles are particularly reactive and toxic in a biological context. The majority of cellular electrophiles are generated from polyunsaturated fatty acids by a peroxidation chain reaction that is readily triggered by oxygen-centered radicals, but propagates without further input of reactive oxygen species (ROS). Thus, the formation of lipid-derived electrophiles such as 4-hydroxynon-2-enal (4-HNE) is proposed to be relatively insensitive to the level of initiating ROS, but to depend mainly on the availability of peroxidation-susceptible fatty acids. This is consistent with numerous observations that life span is inversely correlated to membrane peroxidizability, and with the hypothesis that 4-HNE may constitute the mechanistic link between high susceptibility of membrane lipids to peroxidation and shortened life span. Experimental interventions that directly alter membrane composition (and thus their peroxidizability) or modulate 4-HNE levels have the expected effects on life span, establishing that the connection is not only correlative but causal. Specific molecular mechanisms are considered, by which 4-HNE could (i) destabilize biological systems via nontargeted reactions with cellular macromolecules and (ii) modulate signaling pathways that control longevity-assurance mechanisms.
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Affiliation(s)
- Piotr Zimniak
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
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Galleano M, Tapia G, Puntarulo S, Varela P, Videla LA, Fernández V. Liver preconditioning induced by iron in a rat model of ischemia/reperfusion. Life Sci 2011; 89:221-8. [PMID: 21699906 DOI: 10.1016/j.lfs.2011.06.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2010] [Revised: 04/29/2011] [Accepted: 05/26/2011] [Indexed: 01/26/2023]
Abstract
AIMS Liver preconditioning against ischemia-reperfusion (IR) injury is a major area of experimental research, in which regulation of gene expression with cytoprotective responses due to transient oxidative stress development has been reported. Considering that significant cytoprotection occurs after exposure to low levels of iron (Fe), we tested the hypothesis that sub-chronic administration of Fe to rats underlying transient oxidative stress preconditions the liver against IR injury. MAIN METHODS Animals received six doses (50 mg Fe-dextran/kg ip) every second day during 10 days, before partial IR (vascular clamping) or sham laparotomy (control). Transient oxidative stress was defined by liver glutathione and protein carbonyl contents (24, 48, and 72 h after Fe treatment). Plasma and liver Fe status and ferritin content (western blot) were assessed in animals not subjected to IR. Liver injury and inflammatory response were evaluated by serum transaminases, liver morphology and serum TNF-α. Fe preconditioning against IR injury was correlated with liver glutathione content and the redox-sensitive NF-κB signaling pathway (EMSA) and western blot analysis of haptoglobin. KEY FINDINGS Significant hepatoprotection against IR injury, underlying transient oxidative stress and enhancement in the total and labile Fe pools, was achieved by Fe administration. Abrogation of IR injury is related to reduced TNF-α response (91%), abolishment of the IR-induced liver glutathione depletion and recovery of the NF-κB signaling pathway (75%), lost during IR. SIGNIFICANCE Sub-chronic Fe administration protects the liver against IR injury through antioxidant and anti-inflammatory responses, with recovery of NF-κB activation and related acute-phase response signaling.
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Affiliation(s)
- Mónica Galleano
- Physical Chemistry-PRALIB, School of Pharmacy and Biochemistry, University of Buenos Aires-CONICET, Buenos Aires, Argentina
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Pratap A, Pannakanti R, Yang N, Lakshmi R, Modanlou KA, Eason JD, Mahato RI. Cyclopamine attenuates acute warm ischemia reperfusion injury in cholestatic rat liver: hope for marginal livers. Mol Pharm 2011; 8:958-68. [PMID: 21491930 PMCID: PMC3121156 DOI: 10.1021/mp200115v] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Cholestasis is a significant risk factor for immediate hepatic failure due to ischemia reperfusion (I/R) injury in patients undergoing liver surgery or transplantation. We recently demonstrated that inhibition of Hedgehog (Hh) signaling with cyclopamine (CYA) before I/R prevents liver injury. In this study we hypothesized that Hh signaling may modulate I/R injury in cholestatic rat liver. Cholestasis was induced by bile duct ligation (BDL). Seven days after BDL, rats were exposed to either CYA or vehicle for 7 days daily before being subjected to 30 min of ischemia and 4 h of reperfusion. Expression of Hh ligands (Sonic Hedgehog, Patched-1 and Glioblastoma-1), assessment of liver injury, neutrophil infiltration, cytokines, lipid peroxidation, cell proliferation and apoptosis were determined. Significant upregulation of Hh ligands was seen in vehicle treated BDL rats. I/R injury superimposed on these animals resulted in markedly elevated serum alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin accompanied with increased neutrophil recruitment and lipid peroxidation. Preconditioning with CYA reduced the histological damage and serum liver injury markers. CYA also reduced neutrophil infiltration, proinflammatory cytokines such as TNF-α and IL-1β expression of α-smooth muscle actin and type 1 collagen resulting in reduced fibrosis. Furthermore CYA treated animals showed reduced cholangiocyte proliferation, and apoptosis. Hepatoprotection by CYA was conferred by reduced activation of protein kinase B (Akt) and extracellular signal regulated kinase (ERK). Endogenous Hh signaling in cholestasis exacerbates inflammatory injury during liver I/R. Blockade of Hh pathway represents a clinically relevant novel approach to limit I/R injury in cholestatic marginal liver.
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Affiliation(s)
- Akshay Pratap
- Division of Solid Organ Transplantation, Methodist University Hospital, Memphis, TN 38140
| | - Ravi Pannakanti
- Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN 38103
| | - Ningning Yang
- Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN 38103
| | - Ramasubramanian Lakshmi
- Department of Internal Medicine, University of Tennessee Health Sciences Center, Memphis, TN 38163
| | - Kian A Modanlou
- Division of Solid Organ Transplantation, Methodist University Hospital, Memphis, TN 38140
| | - James D Eason
- Division of Solid Organ Transplantation, Methodist University Hospital, Memphis, TN 38140
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN 38103
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Jegatheeswaran S, Siriwardena AK. Experimental and clinical evidence for modification of hepatic ischaemia-reperfusion injury by N-acetylcysteine during major liver surgery. HPB (Oxford) 2011; 13:71-8. [PMID: 21241423 PMCID: PMC3044340 DOI: 10.1111/j.1477-2574.2010.00263.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatic ischaemia-reperfusion (I/R) injury occurs in both liver resectional surgery and in transplantation. The biochemistry of I/R injury involves short-lived oxygen free radicals. N-acetylcysteine (NAC) is a thiol-containing synthetic compound used in the treatment of acetaminophen toxicity. The present study is a detailed overview of the experimental and clinical evidence for the use of NAC as a pharmaco-protection agent in patients undergoing major liver surgery or transplantation. METHODS A computerized search of the Medline, Embase and SCI databases for the period from 1st January 1988 to 31st December 2008 produced 40 reports. For clinical studies, the quality of reports was assessed according to the criteria reported by the Cochrane communication review group. RESULTS Nineteen studies evaluated NAC in experimental liver I/R injury. NAC was administered before induction of ischaemia in 13. The most widely used concentration was 150 mg/kg by intravenous bolus. Fifteen studies report an improvement in outcome, predominantly a reduction in transaminase. Seven studies used an isolated perfused liver model with all showing improvement (predominantly an improvement in bile production after N-acetylcysteine). Two out of four transplantation models showed an improvement in hepatic function. Clinical studies in transplantation show a modest improvement in transaminase levels with no beneficial effect on either patient or graft survival. CONCLUSION N-acetylcysteine, given before induction of a liver I/R injury in an experimental model can ameliorate liver injury. Clinical outcome data are limited and there is currently little evidence to justify use either in liver transplantation or in liver resectional surgery.
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Abstract
Liver cell death induced by stresses such as ischemia-reperfusion, cholestasis and drug toxicity can trigger a sterile inflammatory response with activation of innate immune cells through release of damage-associated molecular patterns (DAMPs). A similar inflammatory response can be induced by pathogen-associated molecular patterns (PAMPs) such as endotoxin. Both DAMPs and PAMPs activate through toll-like receptors the resident macrophages (Kupffer cells) and recruit activated neutrophils and monocytes into the liver. Central to this inflammatory response is promotion of reactive oxygen species (ROS) formation by these phagocytes. ROS are the principal toxic mediators by which inflammatory cells kill their targets, e.g. bacteria during host defense but also hepatocytes and other liver cells. The mechanism of ROS-induced cell killing during inflammation involves the promotion of mitochondrial dysfunction through an intracellular oxidant stress in hepatocytes leading mainly to oncotic necrosis and less apoptosis. The additional release of cell contents amplifies the inflammatory injury. However, an inflammatory oxidant stress insufficient to directly cause cell damage can induce transcription of stress defence genes including antioxidant genes. This preconditioning effect of ROS enhances the resistance against future inflammatory oxidant stress and promotes the initiation of tissue repair processes. Despite the substantial progress in our understanding of mechanisms of inflammatory liver injury during the last decade, more research is necessary to better understand the role of ROS in acute liver inflammation and to develop clinically applicable therapeutic strategies that selectively target the detrimental effects of oxidant stress without compromising the vital function of ROS in host defense.
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Affiliation(s)
- Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, 66160, USA.
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Brown JE, Zeiger SLH, Hettinger JC, Brooks JD, Holt B, Morrow JD, Musiek ES, Milne G, McLaughlin B. Essential role of the redox-sensitive kinase p66shc in determining energetic and oxidative status and cell fate in neuronal preconditioning. J Neurosci 2010; 30:5242-52. [PMID: 20392947 PMCID: PMC2869196 DOI: 10.1523/jneurosci.6366-09.2010] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Revised: 02/17/2010] [Accepted: 03/01/2010] [Indexed: 11/21/2022] Open
Abstract
Ischemic preconditioning is a phenomenon in which low-level stressful stimuli upregulate endogenous defensive programs, resulting in subsequent resistance to otherwise lethal injuries. We previously observed that signal transduction systems typically associated with neurodegeneration such as caspase activation are requisite events for the expression of tolerance and induction of HSP70. In this work, we sought to determine the extent and duration of oxidative and energetic dysfunction as well as the role of effector kinases on metabolic function in preconditioned cells. Using an in vitro neuronal culture model, we observed a robust increase in Raf and p66(Shc) activation within 1 h of preconditioning. Total ATP content decreased by 25% 3 h after preconditioning but returned to baseline by 24 h. Use of a free radical spin trap or p66(shc) inhibitor increased ATP content whereas a Raf inhibitor had no effect. Phosphorylated p66(shc) rapidly relocalized to the mitochondria and in the absence of activated p66(shc), autophagic processing increased. The constitutively expressed chaperone HSC70 relocalized to autophagosomes. Preconditioned cells experience significant total oxidative stress measured by F(2)-isoprostanes and neuronal stress evaluated by F(4)-neuroprostane measurement. Neuroprostane levels were enhanced in the presence of Shc inhibitors. Finally, we found that inhibiting either p66(shc) or Raf blocked neuroprotection afforded by preconditioning as well as upregulation of HSP70, suggesting both kinases are critical for preconditioning but function in fundamentally different ways. This is the first work to demonstrate the essential role of p66(shc) in mediating requisite mitochondrial and energetic compensation after preconditioning and suggests a mechanism by which protein and organelle damage mediated by ROS can increase HSP70.
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Affiliation(s)
| | - Stephanie L. H. Zeiger
- Departments of Neurology
- Medicine and
- Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tennessee 37232
| | | | | | | | | | | | | | - BethAnn McLaughlin
- Departments of Neurology
- Pharmacology, and
- Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tennessee 37232
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Duval H, Mbatchi SF, Grandadam S, Legendre C, Loyer P, Ribault C, Piquet-Pellorce C, Guguen-Guillouzo C, Boudjema K, Corlu A. Reperfusion stress induced during intermittent selective clamping accelerates rat liver regeneration through JNK pathway. J Hepatol 2010; 52:560-9. [PMID: 20207439 DOI: 10.1016/j.jhep.2010.01.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2009] [Revised: 09/15/2009] [Accepted: 10/07/2009] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Liver resection includes temporal vascular inflow occlusion resulting in ischemia/reperfusion injury in the remnant liver. Here, we developed a rat model of selective lobe occlusion to isolate reperfusion stress from ischemia and to analyze its effect on liver regeneration. METHODS Left lateral and median lobes of liver were either mobilized or subjected twice for 10min to ischemia followed by 5min reperfusion prior to resection while the regenerative lobes were only subjected to reperfusion. RESULTS Although intermittent reperfusion stress induced higher levels of serum transaminases, analysis of cell cycle regulators revealed accelerated regenerative response compared to standard partial hepatectomy. The G0/G1 transition occurred before tissue resection, as evidenced by c-fos, junB, and IL-6 induction. Following hepatectomy, Cyclin D1 up-regulation, G1/S transition, and cell division occurred earlier than normal. Unexpectedly, liver mobilization, a component of the clamping procedure, also resulted in earlier G1/S transition. The shortened G1-phase was driven by the c-Jun N-terminal Kinase pathway and was associated with an oxidative stress response as evidenced by the expression of inducible nitric oxide synthase. CONCLUSION Intermittent selective clamping of lobes to be resected induced reperfusion stress on remnant liver that was beneficial for liver regeneration, suggesting this procedure could be applied in clinical practice.
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Affiliation(s)
- Hélène Duval
- Inserm U522, CHU Pontchaillou, Rue Henri Le Guilloux, Rennes, France
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Czubkowski P, Socha P, Pawlowska J. Current status of oxidative stress in pediatric liver transplantation. Pediatr Transplant 2010; 14:169-77. [PMID: 20113425 DOI: 10.1111/j.1399-3046.2009.01256.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Generation of free radicals in children after liver transplantation is multifactorial from ischemia-reperfusion injury, immunosuppression and post-transplant complications. Thus, this group is at higher risk of oxidative imbalance with molecular and clinical consequences. We discuss pathogenesis and ways of action against oxidative stress in liver transplant recipients.
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Affiliation(s)
- Piotr Czubkowski
- Department of Gastroenterology, Hepatology and Immunology, The Children's Memorial Health Institute, Warsaw, Poland.
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Arkadopoulos N, Kostopanagiotou G, Theodoraki K, Farantos C, Theodosopoulos T, Stafyla V, Vassiliou J, Voros D, Pafiti A, Smyrniotis V. Ischemic preconditioning confers antiapoptotic protection during major hepatectomies performed under combined inflow and outflow exclusion of the liver. A randomized clinical trial. World J Surg 2009; 33:1909-15. [PMID: 19575143 DOI: 10.1007/s00268-009-0117-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Extensive experimental studies and a few clinical series have shown that ischemic preconditioning (IPC) attenuates oxidative ischemia/reperfusion (I/R) injuries in liver resections performed under inflow vascular control. Selective hepatic vascular exclusion (SHVE) employed during hepatectomies completely deprives the liver of blood flow, as it entails simultaneous clamping of the portal triad and the main hepatic veins. The aim of the present study was to identify whether IPC can also protect hepatocytes during liver resections performed under SHVE. METHODS Patients undergoing major liver resection were randomly assigned to have either only SHVE (control group, n = 43) or SHVE combined with IPC--10 min of ischemia followed by 15 min of reperfusion before SHVE was applied (IPC group, n = 41). RESULTS The two groups were comparable with regard to age, liver resection volume, blood loss and transfusions, warm ischemic time, and total operative time. In liver remnant biopsies obtained 60 min post-reperfusion, IPC patients had significantly fewer cells stained positive by TUNEL compared to controls (19% +/- 8% versus 45% +/- 12%; p < 0.05). Also IPC patients had attenuated hepatocyte necrosis, systemic inflammatory response, and oxidative stress as manifested by lower postoperative peak values of aspartate transaminase, interleukin-6, interleukin-8, and malondialdehyde compared to controls. Morbidity was similar for the two groups, as were duration of intensive care unit stay and extent of total hospital stay. CONCLUSIONS In major hepatectomies performed under SHVE, ischemic preconditioning appears to attenuate apoptotic response of the liver remnant, possibly through alteration of inflammatory and oxidative pathways.
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Affiliation(s)
- Nikolaos Arkadopoulos
- Second Department of Surgery, University of Athens School of Medicine, Aretaieion Hospital, 76 Vas. Sofias Ave., 11528, Athens, Greece.
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Marí M, Morales A, Colell A, García-Ruiz C, Fernández-Checa JC. Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal 2009; 11:2685-700. [PMID: 19558212 PMCID: PMC2821140 DOI: 10.1089/ars.2009.2695] [Citation(s) in RCA: 702] [Impact Index Per Article: 43.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Mitochondria are the primary intracellular site of oxygen consumption and the major source of reactive oxygen species (ROS), most of them originating from the mitochondrial respiratory chain. Among the arsenal of antioxidants and detoxifying enzymes existing in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for the maintenance of the appropriate mitochondrial redox environment to avoid or repair oxidative modifications leading to mitochondrial dysfunction and cell death. mGSH importance is based not only on its abundance, but also on its versatility to counteract hydrogen peroxide, lipid hydroperoxides, or xenobiotics, mainly as a cofactor of enzymes such as glutathione peroxidase or glutathione-S-transferase (GST). Many death-inducing stimuli interact with mitochondria, causing oxidative stress; in addition, numerous pathologies are characterized by a consistent decrease in mGSH levels, which may sensitize to additional insults. From the evaluation of mGSH influence on different pathologic settings such as hypoxia, ischemia/reperfusion injury, aging, liver diseases, and neurologic disorders, it is becoming evident that it has an important role in the pathophysiology and biomedical strategies aimed to boost mGSH levels.
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Affiliation(s)
- Montserrat Marí
- Liver Unit, Hospital Clinic , IDIBAPS-CIBEK, CIBEREHD, and Department of Cell Death and Proliferation, IIBB-CSIC, Barcelona, Spain.
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Cao Z, Yuan Y, Jeyabalan G, Du Q, Tsung A, Geller DA, Billiar TR. Preactivation of NKT cells with alpha-GalCer protects against hepatic ischemia-reperfusion injury in mouse by a mechanism involving IL-13 and adenosine A2A receptor. Am J Physiol Gastrointest Liver Physiol 2009; 297:G249-58. [PMID: 19556359 PMCID: PMC2724078 DOI: 10.1152/ajpgi.00041.2009] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatic preconditioning has emerged as a promising strategy of activating natural pathways to augment tolerance to liver ischemia-reperfusion (IR) injury. Liver-resident natural killer T (NKT) cells play an important role in modulating the local immune and inflammatory responses. This work was aimed to investigate whether preactivation of NKT cells could provide a beneficial "preconditioning" effect to ameliorate the subsequent hepatic IR injury. To selectively activate NKT cells, C57BL/6 mice were treated intraperitoneally with the glycolipid antigen alpha-galactosylceramide (alpha-GalCer) 1 h prior to hepatic ischemia. Significantly reduced liver IR injury was observed in mice pretreated with alpha- GalCer, and this protective effect was specifically abrogated by a CD1d blocking antibody. Serum TNF-alpha, IFN-gamma, and IL-13 levels were markedly increased shortly after alpha-GalCer injection. Pretreatment with a neutralizing antibody against TNF-alpha or IFN-gamma did not influence the protective effect of alpha-GalCer preconditioning, whereas preadministration of an IL-13 neutralizing antibody completely abolished the effect. Treatment with alpha-GalCer also led to an increased expression of adenosine A2A receptor (A2AR) in the liver, and blockade of A2AR by SH58261 diminished alpha-GalCer pretreatment-mediated attenuation of liver IR injury. In contrast, administration of the selective A2AR agonist CGS21680 reversed the counteracting effect of the IL-13 neutralizing antibody on alpha-GalCer preconditioning. Additionally, alpha-GalCer pretreatment was associated with a decreased neutrophil accumulation in the ischemic liver. These findings provide the first evidence that hepatic preconditioning by preactivation of NKT cells with alpha-GalCer protects the liver from IR injury via an IL-13 and adenosine A2AR-dependent mechanism.
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Affiliation(s)
- Zongxian Cao
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Youzhong Yuan
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Geetha Jeyabalan
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Qiang Du
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Allan Tsung
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - David A. Geller
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Timothy R. Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
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Abstract
We aimed to determine whether 3-nitropropionic acid (3-NPA) preconditioning protects rat livers against warm ischemia/reperfusion injury. We hypothesized that 3-NPA mediates its protective effects by Bcl-2 upregulation. Brown-Norway rats (200 g) were injected with 3-NPA (10 mg/kg intraperitoneally) 24 h before 90 min of selective warm in situ ischemia. In additional experiments, 30-day survival was studied after 90 min of warm liver ischemia and resection of nonischemic liver tissue. We demonstrate increased mRNA and protein levels of Bcl-2 by real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis in 3-NPA-pretreated rats. All treated animals survived, whereas all untreated rats died within 3 days after selective ischemia and resection of the nonischemic tissue. This corresponded well with a significant decrease of caspases 3 and 9 activity at 1 h of reperfusion after preconditioning with 3-NPA as compared with untreated rats. The histological sections showed protection of liver tissue after 3-NPA by reduction of apoptotic and oncotic tissue damage. Lipid peroxidation in liver tissue was reduced after 3-NPA preconditioning. We show that subtoxic doses of the mitochondrial toxin 3-NPA induces tolerance to warm liver ischemia in rats associated by synthesis of Bcl-2. Bcl-2 upregulation might protect against the postischemic burst of reactive oxygen species and therefore reduces apoptotic- and oncotic-related cell death.
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Llacuna L, Marí M, Lluis JM, García-Ruiz C, Fernández-Checa JC, Morales A. Reactive oxygen species mediate liver injury through parenchymal nuclear factor-kappaB inactivation in prolonged ischemia/reperfusion. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 174:1776-85. [PMID: 19349371 DOI: 10.2353/ajpath.2009.080857] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Nuclear factor (NF)-kappaB participates in ischemia/reperfusion (I/R) hepatic signaling, stimulating both protective mechanisms and the generation of inflammatory cytokines. After analyzing NF-kappaB activation during increasing times of ischemia in murine I/R, we observed that the nuclear translocation of p65 paralleled Src and IkappaB tyrosine phosphorylation, which peaked after 60 minutes of ischemia. After extended ischemic periods (90 to 120 minutes) however, nuclear p65 levels were inversely correlated with the progressive induction of oxidative stress. Despite this profile of NF-kappaB activation, inflammatory genes, such as tumor necrosis factor (TNF) and interleukin (IL)-1beta, predominantly induced by Kupffer cells, increased throughout time during ischemia (30 to 120 minutes), whereas protective NF-kappaB-dependent genes, such as manganese superoxide dismutase (Mn-SOD), expressed in parenchymal cells, decreased. Consistent with this behavior, gadolinium chloride pretreatment abolished TNF/IL-1beta up-regulation during ischemia without affecting Mn-SOD levels. Interestingly, specific glutathione (GSH) up-regulation in hepatocytes by S-adenosylmethionine increased Mn-SOD expression and protected against I/R-mediated liver injury despite TNF/IL-1beta induction. Similar protection was achieved by administration of the SOD mimetic MnTBAP. In contrast, indiscriminate hepatic GSH depletion by buthionine-sulfoximine before I/R potentiated oxidative stress and decreased both nuclear p65 and Mn-SOD expression levels, increasing TNF/IL-1beta up-regulation and I/R-induced liver damage. Thus, the divergent role of NF-kappaB activation in selective liver cell populations underlies the dichotomy of NF-kappaB in hepatic I/R injury, illustrating the relevance of specifically maintaining NF-kappaB activation in parenchymal cells.
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Affiliation(s)
- Laura Llacuna
- Liver Unit, Hospital Clinic, Institut de Investigacions Biomèdiques August Pi-Sunyer, Centro de Investigaciones Biomédicas Esther Koplowitz, Universitat de Barcelona, Barcelona, Spain
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A randomized controlled trial on pharmacological preconditioning in liver surgery using a volatile anesthetic. Ann Surg 2009; 248:909-18. [PMID: 19092335 DOI: 10.1097/sla.0b013e31818f3dda] [Citation(s) in RCA: 171] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To evaluate the effects of pharmacological preconditioning with a volatile anesthetic in patients undergoing liver resection with inflow occlusion. BACKGROUND In liver surgery, ischemic preconditioning and intermittent clamping are the only established protective strategies to reduce tissue damage due to ischemia during inflow occlusion. Preconditioning with volatile anesthetics has provided protection against cardiac and renal ischemic injury in several animal models through NO and HO-1 pathways. But pharmacological preconditioning has never been tested in patients undergoing liver surgery in a randomized trial. METHODS Sixty-four patients undergoing liver surgery with inflow occlusion were randomized intraoperatively for preconditioning with sevoflurane or not (ClinicalTrials.gov NCT00516711). Anesthesia was performed intravenously with propofol. Thirty minutes before inflow occlusion propofol was replaced by sevoflurane in the preconditioning group. Primary endpoint was postoperative liver injury assessed by peak values of liver transaminases. Postoperative complications were recorded according to an established scoring system. RESULTS Sevoflurane preconditioning significantly limited the postoperative increase of serum transaminase levels by 261 U/L (95% CI, 65 to 458; P = 0.01) for the ALT and by 239 (95% CI, -2 to 480; P = 0.05) for the AST corresponding to decreases of baseline levels of 35% and 31%, respectively. Patients with steatosis had an even better benefit than patients without steatosis. The rates of any complication (risk ratio 0.46; 95% CI, 0.25 to 0.85; P = 0.006) and of severe complications requiring invasive procedures (risk ratio 0.25; 95% CI, 0.06 to 1.08; P = 0.05) were also lowered by preconditioning. CONCLUSION This first randomized trial of pharmacological preconditioning in liver surgery in humans showed a protective effect of preconditioning with volatile anesthetics. This strategy may provide a new and easily applicable therapeutic option to protect the liver and to lower complication rates.
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Jang JH, Kang KJ, Kang Y, Lee IS, Graf R, Clavien PA. Ischemic preconditioning and intermittent clamping confer protection against ischemic injury in the cirrhotic mouse liver. Liver Transpl 2008; 14:980-8. [PMID: 18581460 DOI: 10.1002/lt.21467] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Surgery on cirrhotic livers is fraught with complications, and many surgeons refrain from operating on patients with cirrhosis. Surgical procedures include temporal occlusion of blood flow resulting in ischemia. The mechanisms of protective strategies to prevent ischemic injury in patients with cirrhosis are not fully understood. The aim of this study was to evaluate how the cirrhotic liver tolerates an ischemic insult, whether mechanisms other than those observed in the normal liver are active, and whether intermittent clamping and preconditioning, which are known as safe surgical strategies in normal and steatotic livers, confer protection to the cirrhotic liver. We applied partial hepatic inflow occlusion to cirrhotic mice fed carbon tetrachloride according to different vascular occlusion protocols: intermittent clamping with 15 or 30 minute cycles of ischemia or ischemic preconditioning prior to 60 or 75 minutes of ischemia. Continuous ischemia (60 or 75 minutes) served as controls. The results showed that the cirrhotic liver was significantly more susceptible to 60 minutes of ischemia than the normal liver. Apoptosis was higher in the normal liver, whereas necrosis was a predominant feature in the cirrhotic liver. Both protocols of intermittent vascular occlusion and ischemic preconditioning dramatically prevented injury compared to continuous occlusion for 60 minutes. This protection was associated with reduced necrosis and apoptosis, and particularly reduced activation of the apoptotic pathway through mitochondria. In conclusion, this study extends the protective effects of ischemic preconditioning and intermittent clamping to the cirrhotic liver, highlighting a diminished apoptotic pathway with dramatic improvement in the development of necrosis.
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Affiliation(s)
- Jae Hwi Jang
- Department of Surgery, School of Medicine, Institute for Medical Genetics, Keimyung University, Daegu, Korea
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Lanteri R, Acquaviva R, Di Giacomo C, Sorrenti V, Li Destri G, Santangelo M, Vanella L, Di Cataldo A. Rutin in rat liver ischemia/reperfusion injury: effect on DDAH/NOS pathway. Microsurgery 2007; 27:245-51. [PMID: 17477412 DOI: 10.1002/micr.20345] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Nitric oxide (NO) plays a key role in the relationship between microcirculatory disorders and I/R injuries. Our results demonstrated a significant modification in the hepatic function of I/R rats compared with the control group; treatment with rutin reported hepatic damage markers to control value. Levels of plasmatic and hepatic thiol groups decreased in the I/R untreated group, and this decrease was inhibited by rutin treatment. In addition, we observed an increase in the iNOS expression in I/R group compared with control and rutin administration attenuated this increase; in post-ischemic reperfused rutin-treated rats there was a significant increase in eNOS expression compared with the I/R untreated group. In the same experimental conditions an increase in DDAH 1 expression was observed in I/R group only; rutin treatment also counteracted this increased expression. These data suggest that rutin treatment could be useful for preventing oxidative damage associated with hepatic post-ischemic reperfusion injury.
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Affiliation(s)
- Raffael Lanteri
- Department of Surgical Sciences, Organ Transplantation and Advanced Technologies, University of Catania, Catania, Italy
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Duenschede F, Erbes K, Riegler N, Ewald P, Kircher A, Westermann S, Schad A, Miesmer I, Albrecht-Schöck S, Gockel I, Kiemer AK, Junginger T. Protective effects of ischemic preconditioning and application of lipoic acid prior to 90 min of hepatic ischemia in a rat model. World J Gastroenterol 2007; 13:3692-8. [PMID: 17659728 PMCID: PMC4250640 DOI: 10.3748/wjg.v13.i27.3692] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare different preconditioning strategies to protect the liver from ischemia/reperfusion injury focusing on the expression of pro- and anti-apoptotic proteins. Interventions comprised different modes of ischemic preconditioning (IP) as well as pharmacologic pretreatment by α-lipoic acid (LA).
METHODS: Several groups of rats were compared: sham operated animals, non-pretreated animals (nt), animals receiving IP (10 min of ischemia by clamping of the portal triad and 10 min of reperfusion) prior to sustained ischemia, animals receiving selective ischemic preconditioning (IPsel, 10 min of ischemia by selective clamping of the ischemic lobe and 10 min of reperfusion) prior to sustained ichemia, and animals receiving 500 μmol α-LA injected i.v. 15 min prior to the induction of 90 min of selective ischemia.
RESULTS: Cellular damage was decreased only in the LA group. TUNEL-positive hepatocytes as well as necrotic hepatocyte injury were also decreased only by LA (19 ± 2 vs 10 ± 1, P < 0.05 and 29 ± 5 vs 12 ± 1, P < 0.05). Whereas caspase 3- activities in liver tissue were unchanged, caspase 9- activity in liver tissue was decreased only by LA pretreatment (3.1 ± 0.3 vs 1.8 ± 0.2, P < 0.05). Survival rate as the endpoint of liver function was increased after IP and LA pretreatment but not after IPsel. Levels of lipid peroxidation (LPO) in liver tissue were decreased in the IP as well as in the LA group compared to the nt group. Determination of pro- and anti-apoptotic proteins showed a shift towards anti-apoptotic proteins by LA. In contrast, both our IP strategies failed to influence apototic cell death.
CONCLUSION: IP, consisting of 10 min of ischemia and 10 min of reperfusion, protects only partly against ischemia/reperfusion injury of the liver prior to 90 min of selective ischemia. IPsel did not influence ischemic tolerance of the liver. LA improved tolerance to ischemia, possibly by downregulation of pro-apoptotic Bax.
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Affiliation(s)
- Friedrich Duenschede
- University Hospital Mainz, Department of General and Abdominal Surgery, Langenbeckstrasse 1, 55131 Mainz, Germany.
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Lee WY, Lee JS, Lee SM. Protective effects of combined ischemic preconditioning and ascorbic acid on mitochondrial injury in hepatic ischemia/reperfusion. J Surg Res 2007; 142:45-52. [PMID: 17559880 DOI: 10.1016/j.jss.2006.08.043] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2006] [Revised: 07/25/2006] [Accepted: 08/09/2006] [Indexed: 11/23/2022]
Abstract
BACKGROUND This study examined the in vivo effects of ischemic preconditioning (IPC), ascorbic acid (AA), or a combination (IPC + AA) on the level of mitochondrial injury caused by hepatic ischemia/reperfusion (I/R). MATERIALS AND METHODS A rat liver was preconditioned with 10 min of ischemia followed by 10 min of reperfusion, and then subjected to 90 min of ischemia followed by 5 h of reperfusion. The rats were pretreated with AA (100 mg/kg, i.v.) 5 min before the sustained ischemia. RESULTS I/R increased the aminotransferase activity and level of mitochondrial lipid peroxidation, whereas it decreased the reduced glutathione:oxidized glutathione ratio. Either the IPC or AA pretreatment alone attenuated these changes, with the effect being enhanced by IPC + AA. The level of mitochondrial glutamate dehydrogenase, which is specifically located in the matrix, decreased after I/R but this was prevented by IPC + AA. Significant peroxide production was observed after 10 min of reperfusion after sustained ischemia. This change was attenuated by either IPC or AA alone and was further attenuated by IPC + AA. The mitochondria isolated after I/R were rapidly swollen, indicating an opening of the permeability transition pore. However, this was markedly reduced by IPC + AA. The hepatic ATP level was lower after I/R, which was restored by IPC alone and IPC + AA. CONCLUSIONS Our findings suggest that IPC and AA synergistically reduce the level of mitochondrial damage during I/R as a result of decreased postischemic oxidant stress.
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Affiliation(s)
- Woo-Yong Lee
- College of Pharmacy, Sungkyunkwan University, Suwon, South Korea
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