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Garcia KB, Hussein A, Satish S, Wehrle CJ, Karakaya O, Panconesi R, Sun K, Jiao C, Fernandes E, Pinna A, Hashimoto K, Miller C, Aucejo F, Schlegel A. Machine Perfusion as a Strategy to Decrease Ischemia-Reperfusion Injury and Lower Cancer Recurrence Following Liver Transplantation. Cancers (Basel) 2024; 16:3959. [PMID: 39682147 DOI: 10.3390/cancers16233959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 12/18/2024] Open
Abstract
Liver transplantation (LT) is a key treatment for primary and secondary liver cancers, reducing tumor burden with concurrent improvement of liver function. While significant improvement in survival is noted with LT, cancer recurrence rates remain high. Mitochondrial dysfunction caused by ischemia-reperfusion injury (IRI) is known to drive tumor recurrence by creating a favorable microenvironment rich in pro-inflammatory and angiogenic factors. Therefore, strategies that decrease reperfusion injury and mitochondrial dysfunction may also decrease cancer recurrence following LT. Machine perfusion techniques are increasingly used in routine clinical practice of LT with improved post-transplant outcomes and increased use of marginal grafts. Normothermic (NMP) and hypothermic oxygenated machine perfusion (HOPE) provide oxygen to ischemic tissues, and impact IRI and potential cancer recurrence through different mechanisms. This article discussed the link between IRI-associated inflammation and tumor recurrence after LT. The current literature was screened for the role of machine perfusion as a strategy to mitigate the risk of cancer recurrence. Upfront NMP ("ischemia free organ transplantation") and end-ischemic HOPE were shown to reduce hepatocellular carcinoma recurrence in retrospective studies. Three prospective randomized controlled trials are ongoing in Europe to provide robust evidence on the impact of HOPE on cancer recurrence in LT.
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Affiliation(s)
- Karla Bracho Garcia
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL 33331, USA
| | - Ahmed Hussein
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL 33331, USA
| | - Sangeeta Satish
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Chase J Wehrle
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Omer Karakaya
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Rebecca Panconesi
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Keyue Sun
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Chunbao Jiao
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Eduardo Fernandes
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL 33331, USA
| | - Antonio Pinna
- Department of Liver Transplantation, Cleveland Clinic Weston Hospital, Weston, FL 33331, USA
| | - Koji Hashimoto
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Charles Miller
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Federico Aucejo
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Andrea Schlegel
- Transplantation Center, Department of Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
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How Machine Perfusion Ameliorates Hepatic Ischaemia Reperfusion Injury. Int J Mol Sci 2021; 22:ijms22147523. [PMID: 34299142 PMCID: PMC8307386 DOI: 10.3390/ijms22147523] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 07/07/2021] [Accepted: 07/11/2021] [Indexed: 02/07/2023] Open
Abstract
The increasing disparity between the number of patients listed for transplantation and the number of suitable organs has led to the increasing use of extended criteria donors (ECDs). ECDs are at increased risk of developing ischaemia reperfusion injury and greater risk of post-transplant complications. Ischaemia reperfusion injury is a major complication of organ transplantation defined as the inflammatory changes seen following the disruption and restoration of blood flow to an organ—it is a multifactorial process with the potential to cause both local and systemic organ failure. The utilisation of machine perfusion under normothermic (37 degrees Celsius) and hypothermic (4–10 degrees Celsius) has proven to be a significant advancement in organ preservation and restoration. One of the key benefits is its ability to optimise suboptimal organs for successful transplantation. This review is focused on examining ischaemia reperfusion injury and how machine perfusion ameliorates the graft’s response to this.
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Dossi CG, Vargas RG, Valenzuela R, Videla LA. Beneficial effects of natural compounds on experimental liver ischemia-reperfusion injury. Food Funct 2021; 12:3787-3798. [PMID: 33977997 DOI: 10.1039/d1fo00289a] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Liver ischemia-reperfusion injury (IRI) is a phenomenon inherent to hepatic surgery that severely compromises the organ functionality, whose underlying mechanisms involve cellular and molecular interrelated processes leading to the development of an excessive inflammatory response. Liver resident cells and those recruited in response to injury generate pro-inflammatory signals such as reactive oxygen species, cytokines, chemokines, proteases and lipid mediators that contribute to hepatocellular necrosis and apoptosis. Besides, dying hepatocytes release damage-associated molecular patterns that actívate inflammasomes to further stimulate inflammatory responses leading to massive cell death. Since liver IRI is a complication of hepatic surgery in man, extensive preclinical studies have assessed potential protective strategies, including the supplementation with natural compounds, with the objective to downregulate nuclear factor-κB functioning, the main effector of inflammatory responses. This can be accomplished by either the activation of peroxisome proliferator-activated receptor-α, G protein-coupled receptor 120 or antioxidant signaling pathways, the synthesis of specific pro-resolving mediators, downregulation of Toll-like receptor 4 activity or additional contributory mechanisms that are beginning to be understood. The latter aspect is a crucial issue to be accomplished in preclinical studies, in order to establish adequate conditions for the supplementation with natural products before major liver surgeries in man involving warm IR, such as hepatic trauma or resection of large intrahepatic tumors.
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Affiliation(s)
- Camila G Dossi
- Escuela de Medicina Veterinaria, Facultad Ciencias de La Vida, Universidad Andres Bello, Viña del Mar, Chile.
| | - Romina G Vargas
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Rodrigo Valenzuela
- Department of Nutrition, Faculty of Medicine, Uiversity of Chile, Santiago, Chile and Nutritional Sciences Department, Faculty of Medicine, University of Toronto, Toronto, ON M2J4A6, Canada
| | - Luis A Videla
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
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Zhang H, Li Z, Li W. M2 Macrophages Serve as Critical Executor of Innate Immunity in Chronic Allograft Rejection. Front Immunol 2021; 12:648539. [PMID: 33815407 PMCID: PMC8010191 DOI: 10.3389/fimmu.2021.648539] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 02/10/2021] [Indexed: 12/19/2022] Open
Abstract
Allograft functional failure due to acute or chronic rejection has long been a major concern in the area of solid organ transplantation for decades. As critical component of innate immune system, the macrophages are unlikely to be exclusive for driving acute or chronic sterile inflammation against allografts. Traditionally, macrophages are classified into two types, M1 and M2 like macrophages, based on their functions. M1 macrophages are involved in acute rejection for triggering sterile inflammation thus lead to tissue damage and poor allograft survival, while M2 macrophages represent contradictory features, playing pivotal roles in both anti-inflammation and development of graft fibrosis and resulting in chronic rejection. Macrophages also contribute to allograft vasculopathy, but the phenotypes remain to be identified. Moreover, increasing evidences are challenging traditional identification and classification of macrophage in various diseases. Better understanding the role of macrophage in chronic rejection is fundamental to developing innovative strategies for preventing late graft loss. In this review, we will update the recent progress in our understanding of diversity of macrophage-dominated innate immune response, and reveal the roles of M2 macrophages in chronic allograft rejection as well.
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Affiliation(s)
- Hanwen Zhang
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhuonan Li
- Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Wei Li
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
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Guo L, Wu X, Zhang Y, Wang F, Li J, Zhu J. Protective effects of gastrin-releasing peptide receptor antagonist RC-3095 in an animal model of hepatic ischemia/reperfusion injury. Hepatol Res 2019; 49:247-255. [PMID: 30656798 DOI: 10.1111/hepr.13315] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/21/2018] [Accepted: 01/10/2019] [Indexed: 12/14/2022]
Abstract
AIM We aimed to evaluate effects of RC-3095 on mice with hepatic ischemia followed by reperfusion (I/R) injury and further explore the possible underlying mechanism. METHODS Mice were subjected to partial hepatic ischemia for 60 min followed by different durations of reperfusion. Levels of gastrin-releasing peptide (GRP) and GRP receptor (GRPR) in the blood and liver were detected by enzyme-linked immunosorbent assay (ELISA) or western blotting (WB) after 3, 6, 12, or 24 h of reperfusion. RC-3095 or normal saline (control) was given i.p. at the time of reperfusion. Expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 in blood and liver samples were examined with ELISA. Neutrophil influx into the liver was assessed by flow cytometry and myeloperoxidase assay. Hematoxylin-eosin staining of the liver and terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling assay were used to determine hepatic injury and hepatocellular necrosis. Activation of nuclear factor (NF)-κB and p38/extracellular regulated protein kinase (ERK) mitogen activated protein kinase (MAPK) was investigated with WB. RESULTS The expression of GRP was upregulated within 3 h after reperfusion and remained elevated for up to 24 h in the liver, whereas GRPR was also upregulated after 3 or 6 h of reperfusion, but returned to baseline levels within 24 h. RC-3095 significantly reduced the inflammatory hepatic injury, liver neutrophil accumulation, and hepatocellular apoptosis, probably by inhibiting activation of NF-κB or p38/ERK MAPK. CONCLUSION These findings supported that GRP-GRPR played an important role in hepatic I/R injury, and RC-3095 ameliorated liver damage by suppressing the inflammatory response and hepatocellular necrosis.
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Affiliation(s)
- Long Guo
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinwan Wu
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Zhang
- Department of Anesthesiology, Central Hospital of Jiading District, Shanghai, China
| | - Fang Wang
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinbao Li
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiali Zhu
- Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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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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Abstract
Hepatic ischemia/reperfusion (I/R) injury is a major complication of liver surgery, including liver resection, liver transplantation, and trauma surgery. Much has been learned about the inflammatory injury response induced by I/R, including the cascade of proinflammatory mediators and recruitment of activated leukocytes. In this review, we discuss the complex network of events that culminate in liver injury after I/R, including cellular, protein, and molecular mechanisms. In addition, we address the known endogenous regulatory mediators that function to maintain homeostasis and resolve injury. Finally, we cover more recent insights into how the liver repairs and regenerates after I/R injury, a setting in which physical mass remains unchanged, but functional liver mass is greatly reduced. In this regard, we focus on recent work highlighting a novel role of CXC chemokines as important regulators of hepatocyte proliferation and liver regeneration after I/R injury.
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Affiliation(s)
- Takanori Konishi
- Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Alex B. Lentsch
- Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
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Radojkovic M, Stojanovic M, Stanojevic G, Radojkovic D, Gligorijevic J, Ilic I, Stojanovic N. Ischemic preconditioning vs adenosine vs prostaglandin E1 for protection against liver ischemia/reperfusion injury. ACTA ACUST UNITED AC 2017; 50:e6185. [PMID: 28746468 PMCID: PMC5520221 DOI: 10.1590/1414-431x20176185] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Accepted: 05/23/2017] [Indexed: 11/21/2022]
Abstract
Ischemia/reperfusion injury is still a major cause of morbidity and mortality during liver surgery and transplantation. A variety of surgical and pharmacological therapeutic strategies have been investigated to minimize the effects of ischemia/reperfusion. The aim of our study was to analyze and compare preventive influences of ischemic preconditioning, adenosine and prostaglandin E1 in the experimental model of hepatic ischemia/reperfusion injury. Adult chinchilla rabbits were divided into four groups: 10 rabbits subjected to liver ischemic preconditioning (3-min period of inflow occlusion followed by a 5-min period of reperfusion) followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of adenosine followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of prostaglandin E1 followed by 45 min of Pringle maneuver; and control group of 10 rabbits subjected to 45 min of inflow liver ischemia without any preconditioning. On the second postoperative day, blood samples were obtained and biochemical parameters of liver function were measured and compared. Liver tissue samples were also obtained and histopathological changes were compared. Based on biochemical and histopathological parameters, it was demonstrated that ischemic preconditioning provided the best protection against hepatic ischemia/reperfusion injury. This was probably due to a wider range of mechanisms of action of this method oriented to reduce oxidative stress and inflammation, and restore liver microcirculation and hepatocyte energy compared to the examined pharmacological strategies.
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Affiliation(s)
- M Radojkovic
- Surgery Department, School of Medicine, University of Nis, Nis, Serbia
| | - M Stojanovic
- Surgery Department, School of Medicine, University of Nis, Nis, Serbia
| | - G Stanojevic
- Surgery Department, School of Medicine, University of Nis, Nis, Serbia
| | - D Radojkovic
- Internal Medicine Department, School of Medicine, University of Nis, Nis, Serbia
| | - J Gligorijevic
- Pathology Department, School of Medicine, University of Nis, Nis, Serbia
| | - I Ilic
- Pathology Department, School of Medicine, University of Nis, Nis, Serbia
| | - N Stojanovic
- School of Medicine, University of Nis, Nis, Serbia
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Ding VA, Zhu Z, Mantz AA, Xiao H, Wakefield MR, Bai Q, Fang Y. The Role of IL-37 in Non-Cancerous Diseases. Pathol Oncol Res 2016; 23:463-470. [DOI: 10.1007/s12253-016-0137-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Accepted: 10/12/2016] [Indexed: 11/24/2022]
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Cannistrà M, Ruggiero M, Zullo A, Gallelli G, Serafini S, Maria M, Naso A, Grande R, Serra R, Nardo B. Hepatic ischemia reperfusion injury: A systematic review of literature and the role of current drugs and biomarkers. Int J Surg 2016; 33 Suppl 1:S57-70. [PMID: 27255130 DOI: 10.1016/j.ijsu.2016.05.050] [Citation(s) in RCA: 250] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatic ischemia reperfusion injury (IRI) is not only a pathophysiological process involving the liver, but also a complex systemic process affecting multiple tissues and organs. Hepatic IRI can seriously impair liver function, even producing irreversible damage, which causes a cascade of multiple organ dysfunction. Many factors, including anaerobic metabolism, mitochondrial damage, oxidative stress and secretion of ROS, intracellular Ca(2+) overload, cytokines and chemokines produced by KCs and neutrophils, and NO, are involved in the regulation of hepatic IRI processes. Matrix Metalloproteinases (MMPs) can be an important mediator of early leukocyte recruitment and target in acute and chronic liver injury associated to ischemia. MMPs and neutrophil gelatinase-associated lipocalin (NGAL) could be used as markers of I-R injury severity stages. This review explores the relationship between factors and inflammatory pathways that characterize hepatic IRI, MMPs and current pharmacological approaches to this disease.
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Affiliation(s)
- Marco Cannistrà
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy.
| | - Michele Ruggiero
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy.
| | - Alessandra Zullo
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Giuseppe Gallelli
- Department of Emergency, Pugliese-Ciaccio Hospital, Catanzaro, Italy.
| | - Simone Serafini
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy.
| | - Mazzitelli Maria
- Department of Primary Care, Provincial Health Authority of Vibo Valentia, 89900 Vibo Valentia, Italy.
| | - Agostino Naso
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Raffaele Grande
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Raffaele Serra
- Department of Medical and Surgical Sciences, University of Catanzaro, Italy.
| | - Bruno Nardo
- Department of Surgery, Annunziata Hospital of Cosenza, Cosenza, Italy; Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Italy.
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Shimada S, Fukai M, Wakayama K, Ishikawa T, Kobayashi N, Kimura T, Yamashita K, Kamiyama T, Shimamura T, Taketomi A, Todo S. Hydrogen sulfide augments survival signals in warm ischemia and reperfusion of the mouse liver. Surg Today 2014; 45:892-903. [PMID: 25362520 DOI: 10.1007/s00595-014-1064-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 06/19/2014] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND PURPOSE Hydrogen sulfide (H2S) ameliorates hepatic ischemia and reperfusion injury (IRI), but the precise mechanism remains elusive. We investigated whether sodium hydrogen sulfide (NaHS), a soluble derivative of H2S, would ameliorate hepatic IRI, and if so, via what mechanism. METHODS Mice were subjected to partial warm ischemia for 75 min followed by reperfusion. Either NaHS or saline was administered intravenously 10 min before reperfusion. The liver and serum were collected 3, 6, and 24 h after reperfusion. RESULTS In the NaHS(-) group, severe IRI was apparent by the ALT leakage, tissue injury score, apoptosis, lipid peroxidation, and inflammation (higher plasma TNF-α, IL-6, IL-1β, IFN-γ, IL-23, IL-17, and CD40L), whereas IRI was significantly ameliorated in the NaHS(+) group. These effects could be explained by the augmented nuclear translocation of Nrf2, and the resulting up-regulation of HO-1 and thioredoxin-1. Phosphorylation of the PDK-1/Akt/mTOR/p70S6k axis, which is known to mediate pro-survival and anti-apoptotic signals, was significantly augmented in the NaHS(+) group, with a higher rate of PCNA-positive cells thereafter. CONCLUSION NaHS ameliorated hepatic IRI by direct and indirect anti-oxidant activities by augmenting pro-survival, anti-apoptotic, and anti-inflammatory signals via mechanisms involving Nrf-2, and by accelerating hepatic regeneration via mechanisms involving Akt-p70S6k.
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Affiliation(s)
- Shingo Shimada
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, 060-8638, Japan
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Guan LY, Fu PY, Li PD, Li ZN, Liu HY, Xin MG, Li W. Mechanisms of hepatic ischemia-reperfusion injury and protective effects of nitric oxide. World J Gastrointest Surg 2014; 6:122-128. [PMID: 25068009 PMCID: PMC4110529 DOI: 10.4240/wjgs.v6.i7.122] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 05/26/2014] [Accepted: 06/20/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) is a pathophysiological event post liver surgery or transplantation and significantly influences the prognosis of liver function. The mechanisms of IRI remain unclear, and effective methods are lacking for the prevention and therapy of IRI. Several factors/pathways have been implicated in the hepatic IRI process, including anaerobic metabolism, mitochondria, oxidative stress, intracellular calcium overload, liver Kupffer cells and neutrophils, and cytokines and chemokines. The role of nitric oxide (NO) in protecting against liver IRI has recently been reported. NO has been found to attenuate liver IRI through various mechanisms including reducing hepatocellular apoptosis, decreasing oxidative stress and leukocyte adhesion, increasing microcirculatory flow, and enhancing mitochondrial function. The purpose of this review is to provide insights into the mechanisms of liver IRI, indicating the potential protective factors/pathways that may help to improve therapeutic regimens for controlling hepatic IRI during liver surgery, and the potential therapeutic role of NO in liver IRI.
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Ishida H, Imai T, Suzue K, Hirai M, Taniguchi T, Yoshimura A, Iwakura Y, Okada H, Suzuki T, Shimokawa C, Hisaeda H. IL-23 protection against Plasmodium berghei infection in mice is partially dependent on IL-17 from macrophages. Eur J Immunol 2013; 43:2696-706. [PMID: 23843079 DOI: 10.1002/eji.201343493] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 06/20/2013] [Accepted: 07/05/2013] [Indexed: 12/31/2022]
Abstract
Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19KO) had higher parasitemia and died earlier than wild-type (WT) controls. Interestingly, p19KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19KO and 17KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites.
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Affiliation(s)
- Hidekazu Ishida
- Department of Parasitology, Graduate School of Medicine, Gunma University, Maebashi, Japan
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van Golen RF, Reiniers MJ, Olthof PB, van Gulik TM, Heger M. Sterile inflammation in hepatic ischemia/reperfusion injury: present concepts and potential therapeutics. J Gastroenterol Hepatol 2013; 28:394-400. [PMID: 23216461 DOI: 10.1111/jgh.12072] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/23/2012] [Indexed: 12/12/2022]
Abstract
Ischemia and reperfusion (I/R) injury is an often unavoidable consequence of major liver surgery and is characterized by a sterile inflammatory response that jeopardizes the viability of the organ. The inflammatory response results from acute oxidative and nitrosative stress and consequent hepatocellular death during the early reperfusion phase, which causes the release of endogenous self-antigens known as damage-associated molecular patterns (DAMPs). DAMPs, in turn, are indirectly responsible for a second wave of reactive oxygen and nitrogen species (ROS and RNS) production by driving the chemoattraction of various leukocyte subsets that exacerbate oxidative liver damage during the later stages of reperfusion. In this review, the molecular mechanisms underlying hepatic I/R injury are outlined, with emphasis on the interplay between ROS/RNS, DAMPs, and the cell types that either produce ROS/RNS and DAMPs or respond to them. This theoretical background is subsequently used to explain why current interventions for hepatic I/R injury have not been very successful. Moreover, novel therapeutic modalities are addressed, including MitoSNO and nilotinib, and metalloporphyrins on the basis of the updated paradigm of hepatic I/R injury.
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Affiliation(s)
- Rowan F van Golen
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Loi P, Yuan Q, Torres D, Delbauve S, Laute MA, Lalmand MC, Pétein M, Goriely S, Goldman M, Flamand V. Interferon regulatory factor 3 deficiency leads to interleukin-17-mediated liver ischemia-reperfusion injury. Hepatology 2013; 57:351-61. [PMID: 22911673 DOI: 10.1002/hep.26022] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Accepted: 08/01/2012] [Indexed: 01/08/2023]
Abstract
UNLABELLED Interferon regulatory factor 3 (IRF3) is an important transcription factor in Toll-like receptor 4 (TLR4) signaling, a pathway that is known to play a critical role in liver ischemia-reperfusion injury. In order to decipher the involvement of IRF3 in this setting, we first compared the intensity of hepatic lesions in IRF3-deficient versus wildtype mice. We found increased levels of blood transaminases, enhanced liver necrosis, and more pronounced neutrophil infiltrates in IRF3-deficient mice. Neutrophil depletion by administration of anti-Ly6G monoclonal antibody indicated that neutrophils play a dominant role in the development of severe liver necrosis in IRF3-deficient mice. Quantification of cytokine genes expression revealed increased liver expression of interleukin (IL)-12/IL-23p40, IL-23p19 messenger RNA (mRNA), and IL-17A mRNA in IRF3-deficient versus wildtype (WT) mice, whereas IL-27p28 mRNA expression was diminished in the absence of IRF3. The increased IL-17 production in IRF3-deficient mice was functionally relevant, as IL-17 neutralization prevented the enhanced hepatocellular damages and liver inflammation in these animals. Evidence for enhanced production of IL-23 and decreased accumulation of IL-27 cytokine in M1 type macrophage from IRF3-deficient mice was also observed after treatment with lipopolysaccharide, a setting in which liver gamma-delta T cells and invariant natural killer T cells were found to be involved in IL-17A hyperproduction. CONCLUSION IRF3-dependent events downstream of TLR4 control the IL-23/IL-17 axis in the liver and this regulatory role of IRF3 is relevant to liver ischemia-reperfusion injury.
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Affiliation(s)
- Patrizia Loi
- Institut d'Immunologie Médicale, Université Libre de Bruxelles, Gosselies, Belgium
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Sakai N, Van Sweringen HL, Belizaire RM, Quillin RC, Schuster R, Blanchard J, Burns JM, Tevar AD, Edwards MJ, Lentsch AB. Interleukin-37 reduces liver inflammatory injury via effects on hepatocytes and non-parenchymal cells. J Gastroenterol Hepatol 2012; 27:1609-16. [PMID: 22646996 PMCID: PMC3448792 DOI: 10.1111/j.1440-1746.2012.07187.x] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM The purpose of the present study was to determine the effects of interleukin-37 (IL-37) on liver cells and on liver inflammation induced by hepatic ischemia/reperfusion (I/R). METHODS Mice were subjected to I/R. Some mice received recombinant IL-37 (IL-37) at the time of reperfusion. Serum levels of alanine aminotransferase, and liver myeloperoxidase content were assessed. Serum and liver tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-2 (MIP-2) and keratinocyte chemokine (KC) were also assessed. Hepatic reactive oxygen species (ROS) levels were assessed. For in vitro experiments, isolated hepatocytes and Kupffer cells were treated with IL-37 and inflammatory stimulants. Cytokine and chemokine production by these cells were assessed. Primary hepatocytes underwent induced cell injury and were treated with IL-37 concurrently. Hepatocyte cytotoxicity and Bcl-2 expression were determined. Isolated neutrophils were treated with TNF-α and IL-37 and neutrophil activation and respiratory burst were assessed. RESULTS IL-37 reduced hepatocyte injury and neutrophil accumulation in the liver after I/R. These effects were accompanied by reduced serum levels of TNF-α and MIP-2 and hepatic ROS levels. IL-37 significantly reduced MIP-2 and KC productions from lipopolysaccharide-stimulated hepatocytes and Kupffer cells. IL-37 significantly reduced cell death and increased Bcl-2 expression in hepatocytes. IL-37 significantly suppressed TNF-α-induced neutrophil activation. CONCLUSIONS IL-37 is protective against hepatic I/R injury. These effects are related to the ability of IL-37 to reduce proinflammatory cytokine and chemokine production by hepatocytes and Kupffer cells as well as having a direct protective effect on hepatocytes. In addition, IL-37 contributes to reduce liver injury through suppression of neutrophil activity.
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Affiliation(s)
- Nozomu Sakai
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
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Sakai N, Van Sweringen HL, Quillin RC, Schuster R, Blanchard J, Burns JM, Tevar AD, Edwards MJ, Lentsch AB. Interleukin-33 is hepatoprotective during liver ischemia/reperfusion in mice. Hepatology 2012; 56:1468-78. [PMID: 22782692 PMCID: PMC3465516 DOI: 10.1002/hep.25768] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
UNLABELLED Interleukin (IL)-33 is a recently identified member of the IL-1 family that binds to the receptor, ST2L. In the current study, we sought to determine whether IL-33 is an important regulator in the hepatic response to ischemia/reperfusion (I/R). Male C57BL/6 mice were subjected to 90 minutes of partial hepatic ischemia, followed by up to 8 hours of reperfusion. Some mice received recombinant IL-33 (IL-33) intraperitoneally (IP) before surgery or anti-ST2 antibody IP at the time of reperfusion. Primary hepatocytes and Kupffer cells were isolated and treated with IL-33 to assess the effects of IL-33 on inflammatory cytokine production. Primary hepatocytes were treated with IL-33 to assess the effects of IL-33 on mediators of cell survival in hepatocytes. IL-33 protein expression increased within 4 hours after reperfusion and remained elevated for up to 8 hours. ST2L protein expression was detected in healthy liver and was up-regulated within 1 hour and peaked at 4 hours after I/R. ST2L was primarily expressed by hepatocytes, with little to no expression by Kupffer cells. IL-33 significantly reduced hepatocellular injury and liver neutrophil accumulation at 1 and 8 hours after reperfusion. In addition, IL-33 treatment increased liver activation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB), p38 mitogen-activated protein kinase (MAPK), cyclin D1, and B-cell lymphoma 2 (Bcl-2), but reduced serum levels of CXC chemokines. In vitro experiments demonstrated that IL-33 significantly reduced hepatocyte cell death as a result of increased NF-κB activation and Bcl-2 expression in hepatocytes. CONCLUSION The data suggest that IL-33 is an important endogenous regulator of hepatic I/R injury. It appears that IL-33 has direct protective effects on hepatocytes, associated with the activation of NF-κB, p38 MAPK, cyclin D1, and Bcl-2 that limits liver injury and reduces the stimulus for inflammation.
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Affiliation(s)
- Nozomu Sakai
- Department of Surgery, University of Cincinnati, Cincinnati, OH 45267-0558, USA
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Lentsch AB. Regulatory mechanisms of injury and repair after hepatic ischemia/reperfusion. SCIENTIFICA 2012; 2012:513192. [PMID: 24278708 PMCID: PMC3820555 DOI: 10.6064/2012/513192] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 09/12/2012] [Indexed: 06/02/2023]
Abstract
Hepatic ischemia/reperfusion injury is an important complication of liver surgery and transplantation. The mechanisms of this injury as well as the subsequent reparative and regenerative processes have been the subject of thorough study. In this paper, we discuss the complex and coordinated responses leading to parenchymal damage after liver ischemia/reperfusion as well as the manner in which the liver clears damaged cells and regenerates functional mass.
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Affiliation(s)
- Alex B. Lentsch
- Department of Surgery, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267-0558, USA
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van Golen RF, van Gulik TM, Heger M. The sterile immune response during hepatic ischemia/reperfusion. Cytokine Growth Factor Rev 2012; 23:69-84. [PMID: 22609105 DOI: 10.1016/j.cytogfr.2012.04.006] [Citation(s) in RCA: 123] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Accepted: 04/16/2012] [Indexed: 12/14/2022]
Abstract
Hepatic ischemia and reperfusion elicits an immune response that lacks a microbial constituent yet poses a potentially lethal threat to the host. In this sterile setting, the immune system is alarmed by endogenous danger signals that are release by stressed and dying liver cells. The detection of these immunogenic messengers by sentinel leukocyte populations constitutes the proximal trigger for a self-perpetuating cycle of inflammation, in which consecutive waves of cytokines and chemokines orchestrate the influx of various leukocyte subsets that ultimately confer tissue destruction. This review focuses on the temporal organization of sterile hepatic inflammation, using surgery-induced trauma as a template disease state.
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Affiliation(s)
- Rowan F van Golen
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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20
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Sakai N, Van Sweringen HL, Schuster R, Blanchard J, Burns JM, Tevar AD, Edwards MJ, Lentsch AB. Receptor activator of nuclear factor-κB ligand (RANKL) protects against hepatic ischemia/reperfusion injury in mice. Hepatology 2012; 55:888-97. [PMID: 22031462 PMCID: PMC3276725 DOI: 10.1002/hep.24756] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2011] [Accepted: 10/04/2011] [Indexed: 12/16/2022]
Abstract
UNLABELLED The transcription factor nuclear factor kappaB (NF-κB) plays diverse roles in the acute injury response to hepatic ischemia/reperfusion (I/R). Activation of NF-κB in Kupffer cells promotes inflammation through cytokine expression, whereas activation in hepatocytes may be cell protective. The interaction of receptor activator of NF-κB (RANK) and its ligand (RANKL) promotes NF-κB activation; however, this ligand-receptor system has not been studied in acute liver injury. In the current study, we sought to determine if RANK and RANKL were important in the hepatic response to I/R. Mice were subjected to partial hepatic ischemia followed by reperfusion. In some experiments, mice received recombinant RANKL or neutralizing antibodies to RANKL 1 hour prior to surgery or at reperfusion to assess the role of RANK/RANKL signaling during I/R injury. RANK was constitutively expressed in the liver and was not altered by I/R. RANK was strongly expressed in hepatocytes and very weakly expressed in Kupffer cells. Serum RANKL concentrations increased after I/R and peaked 4 hours after reperfusion. Serum levels of osteoprotegerin (OPG), a decoy receptor for RANKL, steadily increased over the 8-hour period of reperfusion. Treatment with RANKL, before ischemia or at reperfusion, increased hepatocyte NF-κB activation and significantly reduced liver injury. These beneficial effects occurred without any effect on cytokine expression or liver inflammation. Treatment with anti-RANKL antibodies had no effect on liver I/R injury. CONCLUSION During the course of injury, endogenous OPG appears to suppress the effects of RANKL. However, exogenous administration of RANKL, given either prophylactically or postinjury, reduces liver injury in a manner associated with increased hepatocyte NF-κB activation. The data suggest that RANK/RANKL may be a viable therapeutic target in acute liver injury.
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21
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Van Sweringen HL, Sakai N, Tevar AD, Burns JM, Edwards MJ, Lentsch AB. CXC chemokine signaling in the liver: impact on repair and regeneration. Hepatology 2011; 54:1445-53. [PMID: 21626524 PMCID: PMC3175305 DOI: 10.1002/hep.24457] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2011] [Accepted: 05/17/2011] [Indexed: 01/12/2023]
Abstract
The process of liver repair and regeneration following hepatic injury is complex and relies on a temporally coordinated integration of several key signaling pathways. Pathways activated by members of the CXC family of chemokines play important roles in the mechanisms of liver repair and regeneration through their effects on hepatocytes. However, little is known about the signaling pathways used by CXC chemokine receptors in hepatocytes. Here we review our current understanding of the pathways involved in both CXC chemokine receptor signaling in other cell types, most notably neutrophils, and similar pathways operant during hepatocyte proliferation/liver regeneration to formulate a basis for the function of CXC chemokine receptor signaling in hepatocytes.
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22
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von Rossum A, Krall R, Escalante NK, Choy JC. Inflammatory cytokines determine the susceptibility of human CD8 T cells to Fas-mediated activation-induced cell death through modulation of FasL and c-FLIP(S) expression. J Biol Chem 2011; 286:21137-44. [PMID: 21518761 DOI: 10.1074/jbc.m110.197657] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The nature of inflammatory signals determines the outcome of T cell responses. However, little is known about how inflammatory cytokines provided to human CD8 T cells during activation affects their susceptibility to post-activation cell death. We have examined and compared the effects of the inflammatory cytokine IL-12, as well as the combination of IL-1, IL-6, and IL-23 (IL-1/6/23) on the susceptibility of primary human CD8 T cells to post-activation cell death. Human CD8 T cells activated in the presence of IL-1/6/23 underwent significantly less cell death after activation as compared with those activated in IL-12. This was due to reduced susceptibility to Fas-mediated activation-induced cell death (AICD). Mechanistically, the reduced level of cell death in CD8 T cells activated in IL-1/6/23 was a result of a low level of FasL expression and high level of c-FLIP(S) expression. When the effect of IL-1, IL-6, and IL-23 individually was examined, IL-1 or IL-6 alone was sufficient to inhibit CD8 T cell death that occurs after activation in IL-12. IL-1, but not IL-6, inhibited expression of FasL, whereas IL-6, but not IL-1, increased c-FLIP(S) expression. Our findings show that the presence of IL-1 and/or IL-6 during activation of human CD8 T cells attenuates Fas-mediated AICD, whereas IL-12 increases the susceptibility of activated CD8 T cells to this form of cell death.
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Affiliation(s)
- Anna von Rossum
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A1S6
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23
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Lv M, Liu Y, Zhang J, Sun L, Liu Z, Zhang S, Wang B, Su D, Su Z. Roles of inflammation response in microglia cell through Toll-like receptors 2/interleukin-23/interleukin-17 pathway in cerebral ischemia/reperfusion injury. Neuroscience 2011; 176:162-72. [DOI: 10.1016/j.neuroscience.2010.11.066] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Revised: 11/30/2010] [Accepted: 11/30/2010] [Indexed: 02/06/2023]
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Abu-Amara M, Yang SY, Tapuria N, Fuller B, Davidson B, Seifalian A. Liver ischemia/reperfusion injury: processes in inflammatory networks--a review. Liver Transpl 2010; 16:1016-32. [PMID: 20818739 DOI: 10.1002/lt.22117] [Citation(s) in RCA: 261] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver ischemia/reperfusion (IR) injury is typified by an inflammatory response. Understanding the cellular and molecular events underpinning this inflammation is fundamental to developing therapeutic strategies. Great strides have been made in this respect recently. Liver IR involves a complex web of interactions between the various cellular and humoral contributors to the inflammatory response. Kupffer cells, CD4+ lymphocytes, neutrophils, and hepatocytes are central cellular players. Various cytokines, chemokines, and complement proteins form the communication system between the cellular components. The contribution of the danger-associated molecular patterns and pattern recognition receptors to the pathophysiology of liver IR injury are slowly being elucidated. Our knowledge on the role of mitochondria in generating reactive oxygen and nitrogen species, in contributing to ionic disturbances, and in initiating the mitochondrial permeability transition with subsequent cellular death in liver IR injury is continuously being expanded. Here, we discuss recent findings pertaining to the aforementioned factors of liver IR, and we highlight areas with gaps in our knowledge, necessitating further research.
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Affiliation(s)
- Mahmoud Abu-Amara
- Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital, London, United Kingdom
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25
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Frangen TM, Bogdanski D, Schinkel C, Roetman B, Kälicke T, Muhr G, Köller M. Systemic IL-17 after severe injuries. Shock 2008; 29:462-7. [PMID: 17909455 DOI: 10.1097/shk.0b013e3181598a9d] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
IL-17 is a cytokine produced by a newly identified T-cell subpopulation (THl7/THIL-17). It is a central mediator in inflammatory processes that connects T-cell stimulation with neutrophil mobilization. The role of IL-17 in the immune dysfunction after polytrauma is still not clarified. In a retrospective study, the systemic concentration of IL-17 and IL-6 of 71 polytraumatized patients were analyzed daily by enzyme-linked immunosorbent assay. The patients' collective consist of 55 men and 16 women (43 +/- 16 years; injury severity score, 33 +/- 13). In only 6% of the patients, an increase in systemic IL-17 was detected. In most patients (94%), no systemic IL-17 was detectable or the IL-17 concentrations in plasma were in the range of the healthy donor group. To identify a possible role of systemic IL-17 in the posttraumatic phase, the patients were divided into two groups. Group A (47 men, 15 women) consists of patients with IL-17 concentrations in the range of normal healthy donors. Group B (8 men, 1 woman) consists of patients with elevated (>45 pg ml(-1) on at least 3 consecutive days) systemic IL-17 concentrations. Three patients in group B showed highly increased systemic IL-17 concentrations (median, >200 pg mL(-1)). These patients were male and showed all blunt chest and abdominal trauma with lung contusion and pneumohemothorax. However, there was no conformity in other injury patterns, injury severity score, age, outcome, intensive care period, or clinical complications. After a period of 4 years, we were able to obtain a new blood sample from one patient with high IL-17 level. The systemic IL-17 value of this former patient was now less than the detection limit. However, stimulation of peripheral blood mononuclear cells from thlise patient revealed elevated numbers of cells with the capacity to produce IL-17 as determined by enzyme-linked immuno spot assay and flow cytometry compared with peripheral blood mononuclear cells obtained from current polytrauma patients and healthy donors. In conclusion, IL-17 is not suitable as a pathophysiological or predictive marker after polytrauma. Whether highly increased systemic IL-17 concentrations detected in single patients are due to individually increased numbers of TH17 cells as we have demonstrated with one rerecruited patient has to be further analyzed.
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Affiliation(s)
- Thomas M Frangen
- Berufsgenossenshaftliches Universitätsklinikum Bergmannsheil GmbH, Department of Surgery, Ruhr-University Bochum, Bochum, Germany
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Liu ZJ, Yan LN. Advances in the relationship between Kupffer cells and liver ischemia reperfusion injury. Shijie Huaren Xiaohua Zazhi 2008; 16:2741-2745. [DOI: 10.11569/wcjd.v16.i24.2741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Kupffer cells, residing within the lumen of liver sinusoids, constitute 80%-90% of tissue macrophages present in the body. Upon activation Kupffer cells release various products, including cytokines, prostanoides, nitric oxide and reactive oxygen species. These factors regulate the phenotype of Kupffer cells themselves, and the phenotypes of neighboring cells, such as hepatocytes, stellate cells, endothelial cells and other immune cells that traffic through the liver. Therefore, Kupffer cells are intimately involved in the liver's response to warm or cold ischemia reperfusion injury (IRI). This review summarizes the role of Kupffer cells in the pathogenesis of liver IRI to explore the reasonable therapeutic target.
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