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Kim BK, Goncharov T, Archaimbault SA, Roudnicky F, Webster JD, Westenskow PD, Vucic D. RIP1 inhibition protects retinal ganglion cells in glaucoma models of ocular injury. Cell Death Differ 2025; 32:353-368. [PMID: 39448868 PMCID: PMC11802773 DOI: 10.1038/s41418-024-01390-7] [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] [Indexed: 10/26/2024] Open
Abstract
Receptor-interacting protein 1 (RIP1, RIPK1) is a critical mediator of multiple signaling pathways that promote inflammatory responses and cell death. The kinase activity of RIP1 contributes to the pathogenesis of a number of inflammatory and neurodegenerative diseases. However, the role of RIP1 in retinopathies remains unclear. This study demonstrates that RIP1 inhibition protects retinal ganglion cells (RGCs) in preclinical glaucoma models. Genetic inactivation of RIP1 improves RGC survival and preserves retinal function in the preclinical glaucoma models of optic nerve crush (ONC) and ischemia-reperfusion injury (IRI). In addition, the involvement of necroptosis in ONC and IRI glaucoma models was examined by utilizing RIP1 kinase-dead (RIP1-KD), RIP3 knockout (RIP3-KO), and MLKL knockout (MLKL-KO) mice. The number of RGCs, retinal thickness, and visual acuity were rescued in RIP1-kinase-dead (RIP1-KD) mice in both models, while wild-type (WT) mice experienced significant retinal thinning, RGC loss, and vision impairment. RIP3-KO and MLKL-KO mice showed moderate protective effects in the IRI model and limited in the ONC model. Furthermore, we confirmed that a glaucoma causative mutation in optineurin, OPTN-E50K, sensitizes cells to RIP1-mediated inflammatory cell death. RIP1 inhibition reduces RGC death and axonal degeneration following IRI in mice expressing OPTN-WT and OPTN-E50K variant mice. We demonstrate that RIP1 inactivation suppressed microglial infiltration in the RGC layer following glaucomatous damage. Finally, this study highlights that human glaucomatous retinas exhibit elevated levels of TNF and RIP3 mRNA and microglia infiltration, thus demonstrating the role of neuroinflammation in glaucoma pathogenesis. Altogether, these data indicate that RIP1 plays an important role in modulating neuroinflammation and that inhibiting RIP1 activity may provide a neuroprotective therapy for glaucoma.
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Affiliation(s)
- Bo Kyoung Kim
- Department of Ophthalmology Discovery, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
- Institute of Chemical Sciences and Engineering (ISIC), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Tatiana Goncharov
- Department of Immunology Discovery, Genentech, 1 DNA Way, South San Francisco, CA, USA
| | - Sébastien A Archaimbault
- Department of Ophthalmology Discovery, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Filip Roudnicky
- Therapeutic Modalities, Pharmaceutical Research and Early Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Joshua D Webster
- Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA, USA
| | - Peter D Westenskow
- Department of Ophthalmology Discovery, Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Domagoj Vucic
- Department of Immunology Discovery, Genentech, 1 DNA Way, South San Francisco, CA, USA.
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Tang H, Yu Q, Chen X, Zhang J, Guo D, Guo W, Zhang S, Shi X. Phosphoglycerate mutase 5 exacerbates liver ischemia-reperfusion injury by activating mitochondrial fission. Sci Rep 2024; 14:8535. [PMID: 38609411 PMCID: PMC11014912 DOI: 10.1038/s41598-024-58748-7] [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: 12/21/2023] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Although the death of hepatocytes is a crucial trigger of liver ischemia-reperfusion (I/R) injury, the regulation of liver I/R-induced hepatocyte death is still poorly understood. Phosphoglycerate mutase 5 (PGAM5), a mitochondrial Serine/Threonine protein phosphatase, regulates mitochondrial dynamics and is involved in the process of both apoptosis and necrotic. However, it is still unclear what role PGAM5 plays in the death of hepatocytes induced by I/R. Using a PGAM5-silence mice model, we investigated the role of PGAM5 in liver I/R injury and its relevant molecular mechanisms. Our data showed that PGAM5 was highly expressed in mice with liver I/R injury. Silence of PGAM5 could decrease I/R-induced hepatocyte death in mice. In subcellular levels, the silence of PGAM5 could restore mitochondrial membrane potential, increase mitochondrial DNA copy number and transcription levels, inhibit ROS generation, and prevent I/R-induced opening of abnormal mPTP. As for the molecular mechanisms, we indicated that the silence of PGAM5 could inhibit Drp1(S616) phosphorylation, leading to a partial reduction of mitochondrial fission. In addition, Mdivi-1 could inhibit mitochondrial fission, decrease hepatocyte death, and attenuate liver I/R injury in mice. In conclusion, our data reveal the molecular mechanism of PGAM5 in driving hepatocyte death through activating mitochondrial fission in liver I/R injury.
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Affiliation(s)
- Hongwei Tang
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, 450052, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, 450052, Henan, China
| | - Qiwen Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Xu Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Jiakai Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Danfeng Guo
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, 450052, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, 450052, Henan, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, East Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, 450052, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, 450052, Henan, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, East Jianshe Road, Zhengzhou, 450052, Henan, China
- Henan Engineering Technology Research Center of Organ Transplantation, Zhengzhou, 450052, Henan, China
- ZhengZhou Engineering Laboratory of Organ Transplantation Technique and Application, Zhengzhou, 450052, Henan, China
| | - Xiaoyi Shi
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, East Jianshe Road, Zhengzhou, 450052, Henan, China.
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Zhang M, Liu Q, Meng H, Duan H, Liu X, Wu J, Gao F, Wang S, Tan R, Yuan J. Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:12. [PMID: 38185705 PMCID: PMC10772178 DOI: 10.1038/s41392-023-01688-x] [Citation(s) in RCA: 114] [Impact Index Per Article: 114.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 08/29/2023] [Accepted: 10/18/2023] [Indexed: 01/09/2024] Open
Abstract
Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of the intricate mechanisms underlying I/R injury hinders the development of effective therapeutic interventions. The Wnt signaling pathway exhibits extensive crosstalk with various other pathways, forming a network system of signaling pathways involved in I/R injury. This review article elucidates the underlying mechanisms involved in Wnt signaling, as well as the complex interplay between Wnt and other pathways, including Notch, phosphatidylinositol 3-kinase/protein kinase B, transforming growth factor-β, nuclear factor kappa, bone morphogenetic protein, N-methyl-D-aspartic acid receptor-Ca2+-Activin A, Hippo-Yes-associated protein, toll-like receptor 4/toll-interleukine-1 receptor domain-containing adapter-inducing interferon-β, and hepatocyte growth factor/mesenchymal-epithelial transition factor. In particular, we delve into their respective contributions to key pathological processes, including apoptosis, the inflammatory response, oxidative stress, extracellular matrix remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, and blood-brain barrier damage during I/R injury. Our comprehensive analysis of the mechanisms involved in Wnt signaling during I/R reveals that activation of the canonical Wnt pathway promotes organ recovery, while activation of the non-canonical Wnt pathways exacerbates injury. Moreover, we explore novel therapeutic approaches based on these mechanistic findings, incorporating evidence from animal experiments, current standards, and clinical trials. The objective of this review is to provide deeper insights into the roles of Wnt and its crosstalk signaling pathways in I/R-mediated processes and organ dysfunction, to facilitate the development of innovative therapeutic agents for I/R injury.
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Affiliation(s)
- Meng Zhang
- The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, 272067, China
| | - Qian Liu
- Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Hui Meng
- Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Hongxia Duan
- Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Xin Liu
- Second Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Jian Wu
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Fei Gao
- The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, 272067, China
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Shijun Wang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
| | - Rubin Tan
- Department of Physiology, Basic medical school, Xuzhou Medical University, Xuzhou, 221004, China.
| | - Jinxiang Yuan
- The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, 272067, China.
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Villani R, Loizzi D, Sacco AF, Mirabella L, Santoliquido M, Mongiello D, Sollitto F, Serviddio G. Prevalence and clinical relevance of liver dysfunction after thoracic surgery: a retrospective study. Sci Rep 2023; 13:23045. [PMID: 38155193 PMCID: PMC10754851 DOI: 10.1038/s41598-023-49427-0] [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: 07/02/2023] [Accepted: 12/07/2023] [Indexed: 12/30/2023] Open
Abstract
Postoperative elevation of serum aminotransferase or alkaline phosphatase levels after liver and heart surgeries has been widely reported. The prevalence and clinical significance of hypertransaminasemia/liver dysfunction after thoracic surgery remains largely unknown. Significant differences in surgical procedures between thoracic and extra-thoracic surgeries may suggest different risks of liver dysfunction. We retrospectively analyzed data from 224 consecutive patients who underwent thoracic surgery. Liver function tests were recorded the day before surgery, 12 h, 1 day, 5, and 10 days after the surgical procedure. Patients were studied to identify the frequency of hypertransaminasemia and/or hyperbilirubinemia and/or increase of INR levels. 37,5% of patients showed an increase in serum alanine aminotransferase (ALT) level after thoracic surgery, whereas an increase in gamma glutamyl transferase (GGT) serum levels of any grade was observed in 53,6% of patients. Approximately 83% of patients who experienced an increase in the serum GGT or ALT levels showed a grade 1 or 2 change. Operative time was associated with hypertransaminasemia in the univariate and multivariate analyses, whereas the use of metformin was associated with a lower risk of ALT increase.
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Affiliation(s)
- Rosanna Villani
- C.U.R.E. (University Center for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto 1, 71122, Foggia, Italy.
| | - Domenico Loizzi
- Institute of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Antonia Federica Sacco
- C.U.R.E. (University Center for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto 1, 71122, Foggia, Italy
| | - Lucia Mirabella
- Anesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Mariateresa Santoliquido
- C.U.R.E. (University Center for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto 1, 71122, Foggia, Italy
| | - Diletta Mongiello
- Institute of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Francesco Sollitto
- Institute of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gaetano Serviddio
- C.U.R.E. (University Center for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Pinto 1, 71122, Foggia, Italy
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Lin X, Zhou Y, Ye L, Wang B, Jiao Y, Yu W, Gao P, Yang L. A bibliometric and visualized analysis of hepatic ischemia-reperfusion injury (HIRI) from 2002 to 2021. Heliyon 2023; 9:e22644. [PMID: 38074868 PMCID: PMC10700868 DOI: 10.1016/j.heliyon.2023.e22644] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 10/07/2023] [Accepted: 11/15/2023] [Indexed: 03/14/2025] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is a complex pathological phenomenon dominated by the innate immune system and involves a variety of immune cells. This condition frequently occurs during hepatectomy, liver transplantation or hemorrhagic shock. HIRI represents an important factor in the poor prognosis of patients after liver surgery. However, there is still a lack of effective intervention to reduce the incidence of HIRI. In this study, we aimed to describe the overall structure of scientific research on HIRI over the past 20 years and provide valuable information and guidelines for future researchers. Bibliometric analysis was used to comprehensively review developments in HIRI and changes in our understanding of HIRI over the past two decades. We identified a total of 4267 articles on HIRI that were published over the past 20 years of which basic research was predominant. Collaboration network analysis revealed that China, the University of California Los Angeles, and Ronald W Busuttil were the most influential country, institute, and scholar, respectively. Co-occurrence cluster analysis revealed that ischemic preconditioning, liver cirrhosis, hepatic I/R injury, autophagy, acute liver failure, oxygen, donation after circulatory death, Nlrp3, remote organ, and microdialysis were the top 10 clusters. Keyword burst detection indicated that autophagy, inflammation, and early allograft dysfunction represent the current research hotspots. In summary, this is the first bibliometric analysis of HIRI research. Our timely analysis of these hotpots and research trends may provide a framework for future researchers and further promote research on the key mechanisms and therapeutic measures in this field.
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Affiliation(s)
- Xiaoqi Lin
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, China
| | - Yanyu Zhou
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, China
| | - Lina Ye
- Maternal and Child Care Service Centre, Changxing County, Zhejiang, China
| | - Baoshan Wang
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, China
| | - Yingfu Jiao
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, China
| | - Weifeng Yu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, China
| | - Po Gao
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, China
| | - Liqun Yang
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, China
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Tong L, Liu R, Yang Y, Zhao J, Ye S, Wang X, Qin Y. Ghrelin protects against ischemia/reperfusion-induced hepatic injury via inhibiting Caspase-11-mediated noncanonical pyroptosis. Transpl Immunol 2023; 80:101888. [PMID: 37453584 DOI: 10.1016/j.trim.2023.101888] [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: 09/23/2022] [Revised: 06/20/2023] [Accepted: 07/01/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND Ischemia/reperfusion (I/R) injury is a complication of liver transplantation. I/R-induced inflammatory cell death, namely, pyroptosis, that is triggered by overactive inflammasomes results in the production of proinflammatory cytokines. Hepatic I/R injury correlates with the activation of the Caspase-11-mediated pyroptosis pathway. We investigated whether ghrelin, which is a pleiotropic gut hormone, may have anti-hepatic I/R injury effects, but the mechanism by which Ghrelin ameliorates hepatic I/R -induced injury remains a mystery. METHODS Hepatic I/R injury was induced in a mouse model by clamping the left and right lobes of the liver for 90 min followed by reperfusion for 6 h, 12 h, or 24 h. As treatment, a saline with or without ghrelin was infused via the tail vain. Hepatocytes were isolated using a two-step collagenase liver perfusion method. RESULTS In our study, treatment with ghrelin protected against hepatic I/R injury as shown by decreased alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels (p < 0.001) and reduced the histological injury in liver tissues compared with untreated controls. The LDH level of primary hepatocytes was increased by hypoxia/reoxygenation (H/R), and it was then restored to normal levels by ghrelin-treatment (p < 0.05). Western blotting analysis showed that ghrelin significantly inhibited the expression of pyroptosis-related proteins, including Caspase-11, GSDMD-N, NLRP3 and HMGB1, both in vivo and in vitro (all p < 0.05) compared with the untreated controls. Immunofluorescence showed that the expression of Gasdamin D (GSDMD) in hepatocytes was increased after I/R or H/R, whereas GSDMD expression was reduced by ghrelin treatment (p < 0.05). CONCLUSIONS Our findings suggest that ghrelin ameliorated I/R-induced hepatic injury by inhibiting Caspase-11-mediated pyroptosis. Ghrelin may be a potential therapeutic option to prevent hepatic I/R injury after liver transplantation.
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Affiliation(s)
- Linge Tong
- Department of Physiology and Pathophysiology, School of Basic Medicine, Da Li University, Dali, Yunnan, China
| | - Rengui Liu
- Department of Physiology and Pathophysiology, School of Basic Medicine, Da Li University, Dali, Yunnan, China
| | - Yang Yang
- Department of Physiology and Pathophysiology, School of Basic Medicine, Da Li University, Dali, Yunnan, China
| | - Jingyao Zhao
- Department of Physiology and Pathophysiology, School of Basic Medicine, Da Li University, Dali, Yunnan, China
| | - Shengying Ye
- Department of Physiology and Pathophysiology, School of Basic Medicine, Da Li University, Dali, Yunnan, China
| | - Xinrui Wang
- Department of Physiology and Pathophysiology, School of Basic Medicine, Da Li University, Dali, Yunnan, China
| | - Yan Qin
- Department of Physiology and Pathophysiology, School of Basic Medicine, Da Li University, Dali, Yunnan, China.
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Machado IF, Palmeira CM, Rolo AP. Preservation of Mitochondrial Health in Liver Ischemia/Reperfusion Injury. Biomedicines 2023; 11:948. [PMID: 36979927 PMCID: PMC10046671 DOI: 10.3390/biomedicines11030948] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/06/2023] [Accepted: 03/16/2023] [Indexed: 03/22/2023] Open
Abstract
Liver ischemia-reperfusion injury (LIRI) is a major cause of the development of complications in different clinical settings such as liver resection and liver transplantation. Damage arising from LIRI is a major risk factor for early graft rejection and is associated with higher morbidity and mortality after surgery. Although the mechanisms leading to the injury of parenchymal and non-parenchymal liver cells are not yet fully understood, mitochondrial dysfunction is recognized as a hallmark of LIRI that exacerbates cellular injury. Mitochondria play a major role in glucose metabolism, energy production, reactive oxygen species (ROS) signaling, calcium homeostasis and cell death. The diverse roles of mitochondria make it essential to preserve mitochondrial health in order to maintain cellular activity and liver integrity during liver ischemia/reperfusion (I/R). A growing body of studies suggest that protecting mitochondria by regulating mitochondrial biogenesis, fission/fusion and mitophagy during liver I/R ameliorates LIRI. Targeting mitochondria in conditions that exacerbate mitochondrial dysfunction, such as steatosis and aging, has been successful in decreasing their susceptibility to LIRI. Studying mitochondrial dysfunction will help understand the underlying mechanisms of cellular damage during LIRI which is important for the development of new therapeutic strategies aimed at improving patient outcomes. In this review, we highlight the progress made in recent years regarding the role of mitochondria in liver I/R and discuss the impact of liver conditions on LIRI.
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Affiliation(s)
- Ivo F. Machado
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal
- IIIUC—Institute of Interdisciplinary Research, University of Coimbra, 3000 Coimbra, Portugal
| | - Carlos M. Palmeira
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal
- Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal
| | - Anabela P. Rolo
- CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal
- Department of Life Sciences, University of Coimbra, 3000 Coimbra, Portugal
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1,25-Dihydroxycholecalciferol down-regulates 3-mercaptopyruvate sulfur transferase and caspase-3 in rat model of non-alcoholic fatty liver disease. J Mol Histol 2023; 54:119-134. [PMID: 36930413 DOI: 10.1007/s10735-023-10118-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 02/27/2023] [Indexed: 03/18/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the commonest cause of liver morbidity and mortality and has multiple unclear pathogenic mechanisms. Vitamin D deficiency was associated with increased incidence and severity of NAFLD. Increased hepatic expression of 3-mercaptopyruvate sulfur transferase (MPST) and dysregulated hepatocyte apoptosis were involved in NAFLD pathogenesis. We aimed to explore the protective effect of 1,25-Dihydroxycholecalciferol (1,25-(OH)2 D3) against development of NAFLD and the possible underlying mechanisms, regarding hepatic MPST and caspase-3 expression. 60 male adult rats were divided into 4 and 12 week fed groups; each was subdivided into control, high-fat diet (HFD), and HFD + VD. Serum levels of lipid profile parameters, liver enzymes, insulin, glucose, C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and hepatic levels of malondialdehyde (MDA), total antioxidant capacity (TAC), and reactive oxygen species (ROS) were measured. BMI and HOMA-IR were calculated, and liver tissues were processed for histopathological and immunohistochemical studies. The present study found that 1,25-(OH)2 D3 significantly decreased BMI, HOMA-IR, serum levels of glucose, insulin, liver enzymes, lipid profile parameters, CRP, TNF-α, hepatic levels of MDA, ROS, hepatic expression of MPST, TNF-α, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and caspase-3; and significantly increased hepatic TAC in both HFD-fed groups. In conclusion: Administration of 1,25-(OH)2 D3 with HFD abolished the NAFLD changes associated with HFD in 4-week group, and markedly attenuated the changes in 12-week group. The anti-apoptotic effect via decrement of caspase-3 and MPST expression are novel mechanisms suggested to be implicated in the protective effect of 1,25-(OH)2 D3.
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Kim JS, Chapman WC, Lin Y. Mitochondrial Autophagy in Ischemic Aged Livers. Cells 2022; 11:cells11244083. [PMID: 36552847 PMCID: PMC9816943 DOI: 10.3390/cells11244083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 12/09/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Mitochondrial autophagy (mitophagy) is a central catabolic event for mitochondrial quality control. Defective or insufficient mitophagy, thus, can result in mitochondrial dysfunction, and ultimately cell death. There is a strong causal relationship between ischemia/reperfusion (I/R) injury and mitochondrial dysfunction following liver resection and transplantation. Compared to young patients, elderly patients poorly tolerate I/R injury. Accumulation of abnormal mitochondria after I/R is more prominent in aged livers than in young counterparts. This review highlights how altered autophagy is mechanistically involved in age-dependent hypersensitivity to reperfusion injury.
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Affiliation(s)
- Jae-Sung Kim
- Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA; (W.C.C.); (Y.L.)
- Department of Cell Biology & Physiology, Washington University in St. Louis, St. Louis, MO 63110, USA
- Correspondence:
| | - William C. Chapman
- Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA; (W.C.C.); (Y.L.)
| | - Yiing Lin
- Department of Surgery, Washington University in St. Louis, St. Louis, MO 63110, USA; (W.C.C.); (Y.L.)
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10
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Demir EA, Tutuk O, Dogan-Gocmen H, Ozyilmaz DS, Karagul MI, Kara M, Temiz M, Tumer C. CREB1 and PPAR-α/γ Pathways in Hepatic Ischemia/Reperfusion: Route for Curcumin to Hepatoprotection. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2022; 21:e133779. [PMID: 36942070 PMCID: PMC10024335 DOI: 10.5812/ijpr-133779] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/31/2022] [Accepted: 01/15/2023] [Indexed: 02/04/2023]
Abstract
Background Hepatic ischemia/reperfusion injury is a major problem that can exacerbate complications, particularly in liver transplantations. Objectives This study aimed to investigate the cellular mechanisms of ischemia/reperfusion injury and hepatoprotection by curcumin. Methods Wistar albino rats were divided into four groups as Control, Sham, I/R, and Cur+I/R. Hepatic ischemia/reperfusion was induced in I/R and Cur+I/R animals, the latter of which was also given 50 mg/kg/day of curcumin for 14 days. Liver aminotransferases and the transcription regulators of inflammation (RelA, IκB, PPAR-α, PPAR-γ, CREB1) were examined along with the histological examination. Results Hepatic ischemia/reperfusion was found to disrupt hepatic microstructure and downregulate PPAR-α, PPAR-γ, and CREB1 transcripts. Curcumin supplementation in hepatic ischemia/reperfusion recovered the structural organization and promoted the hepatocyte regeneration while increasing expressions of PPARs and CREB1. RelA and IκB were found unaltered, possibly due to the crosstalk between targeted transcripts by ischemia/reperfusion and curcumin. Conclusions In sum, PPAR-α/γ and CREB1 were involved in hepatic ischemia/reperfusion and, moreover, were detected to be stimulated by curcumin. PPAR and CREB pathways were found to provide a route to hepatoprotection for curcumin supplementation as evidenced by the microstructural improvement.
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Affiliation(s)
- Enver Ahmet Demir
- Department of Physiology, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, Turkey
- Corresponding Author: Department of Physiology, Faculty of Medicine, Hatay Mustafa Kemal University, 31040, Hatay, Turkey.
| | - Okan Tutuk
- Department of Physiology, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, Turkey
| | - Hatice Dogan-Gocmen
- Department of Physiology, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, Turkey
| | - Duygu Seren Ozyilmaz
- Department of Physiology, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, Turkey
| | - Meryem Ilkay Karagul
- Department of Histology and Embryology, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, Turkey
| | - Mikail Kara
- Department of Histology and Embryology, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, Turkey
| | - Muhyittin Temiz
- Department of General Surgery, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, Turkey
| | - Cemil Tumer
- Department of Physiology, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, Turkey
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11
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Diminazene aceturate attenuates hepatic ischemia/reperfusion injury in mice. Sci Rep 2022; 12:18158. [PMID: 36307457 PMCID: PMC9616812 DOI: 10.1038/s41598-022-21865-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 10/04/2022] [Indexed: 12/31/2022] Open
Abstract
Hepatic ischemia/reperfusion (I/R) injury is one of the leading causes of mortality following partial hepatectomy, liver transplantation, hypovolemic shock and trauma; however, effective therapeutic targets for the treatment of hepatic I/R injury are lacking. Recent studies have shown that diminazene aceturate (DIZE) has protective effects against inflammation, oxidative stress and cell death, which are the main pathogenetic mechanisms associated with hepatic I/R injury. However, the mechanistic effects DIZE exerts on hepatic I/R remain unknown. C57BL/6 male mice were pretreated with either 15 mg/kg DIZE or vehicle control (saline) and subjected to partial liver ischemia for 60 min. One day after induction of hepatic I/R, liver damage, inflammatory responses, oxidative stress and apoptosis were analyzed. By evaluating plasma alanine aminotransferase levels and histology, we found that DIZE treatment attenuated liver failure and was associated with a reduction in histologically-apparent liver damage. We also found that DIZE-treated mice had milder inflammatory responses, less reactive oxidative damage and less apoptosis following hepatic I/R compared to vehicle-treated mice. Taken together, our study demonstrates that DIZE protects against ischemic liver injury by attenuating inflammation and oxidative damage and may be a potential therapeutic agent for the prevention and treatment of ischemic liver failure.
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12
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Pretzsch E, Nieß H, Khaled NB, Bösch F, Guba M, Werner J, Angele M, Chaudry IH. Molecular Mechanisms of Ischaemia-Reperfusion Injury and Regeneration in the Liver-Shock and Surgery-Associated Changes. Int J Mol Sci 2022; 23:12942. [PMID: 36361725 PMCID: PMC9657004 DOI: 10.3390/ijms232112942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/16/2022] [Accepted: 10/20/2022] [Indexed: 09/01/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes.
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Affiliation(s)
- Elise Pretzsch
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Hanno Nieß
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany
| | - Florian Bösch
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Markus Guba
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Martin Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Irshad H. Chaudry
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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13
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Owen A, Patten D, Vigneswara V, Frampton J, Newsome PN. PDGFRα/Sca-1 Sorted Mesenchymal Stromal Cells Reduce Liver Injury in Murine Models of Hepatic Ischemia-Reperfusion Injury. Stem Cells 2022; 40:1056-1070. [PMID: 35999023 PMCID: PMC9707286 DOI: 10.1093/stmcls/sxac059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 07/06/2022] [Indexed: 11/12/2022]
Abstract
Liver transplantation is an effective therapy, but increasing demand for donor organs has led to the use of marginal donor organs with increased complication rates. Mesenchymal stromal cells (MSC) pleiotropically modulate aberrant immune-mediated responses and represent a potential therapy to target the inflammation seen post-transplant with marginal donor livers. To avoid the confounding effects of xenotransplantation seen in studies with human MSC, a PDGFRα/Sca-1 (PaS) sorted MSC population was used which was analogous to human MSC populations (LNGFR+Thy-1+VCAM-1Hi). PaS MSC are a well-described population that demonstrate MSC properties without evidence of clonal mutation during expansion. We demonstrate their anti-inflammatory properties herein through their suppression of T-lymphocyte proliferation in vitro and secretion of anti-inflammatory cytokines (IL-10 and OPG) after stimulation (P = .004 and P = .003). The MDR2-/- model of biliary injury and hepatic ischemia-reperfusion (HIR) injury models were used to replicate the non-anastomotic biliary complications seen following liver transplantation. Systemic MSC therapy in MDR2-/- mice led to reduced liver injury with an increase in restorative macrophages (5913 ± 333.9 vs 12 597 ± 665.8, P = .002, n = 7) and a change in lymphocyte ratios (3.55 ± 0.37 vs 2.59 ± 0.139, P = .023, n = 17), whereas subcutaneous administration of MSC showed no beneficial effect. MSC also reduced cell death in the HIR model assessed by Periodic acid-Schiff (PAS) staining (91.7% ± 2.8 vs 80.1% ± 4.6, P = .03). Systemically administered quantum dot-labeled MSC were tracked using single-cell resolution CryoViz imaging which demonstrated their sequestration in the lungs alongside retention/redistribution to injured liver tissue. MSC represent a potential novel therapy in marginal organ transplantation which warrants further study.
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Affiliation(s)
| | | | | | | | - Philip N Newsome
- Corresponding author: Philip N. Newsome, Centre for Liver and Gastrointestinal Research, Institute of Biomedical Research, University of Birmingham, Vincent Drive, Birmingham B15 2TT, UK.
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14
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Han J, Luo L, Wang Y, Wu S, Kasim V. Therapeutic potential and molecular mechanisms of salidroside in ischemic diseases. Front Pharmacol 2022; 13:974775. [PMID: 36060000 PMCID: PMC9437267 DOI: 10.3389/fphar.2022.974775] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 07/29/2022] [Indexed: 11/13/2022] Open
Abstract
Rhodiola is an ancient wild plant that grows in rock areas in high-altitude mountains with a widespread habitat in Asia, Europe, and America. From empirical belief to research studies, Rhodiola has undergone a long history of discovery, and has been used as traditional medicine in many countries and regions for treating high-altitude sickness, anoxia, resisting stress or fatigue, and for promoting longevity. Salidroside, a phenylpropanoid glycoside, is the main active component found in all species of Rhodiola. Salidroside could enhance cell survival and angiogenesis while suppressing oxidative stress and inflammation, and thereby has been considered a potential compound for treating ischemia and ischemic injury. In this article, we highlight the recent advances in salidroside in treating ischemic diseases, such as cerebral ischemia, ischemic heart disease, liver ischemia, ischemic acute kidney injury and lower limb ischemia. Furthermore, we also discuss the pharmacological functions and underlying molecular mechanisms. To our knowledge, this review is the first one that covers the protective effects of salidroside on different ischemia-related disease.
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Affiliation(s)
- Jingxuan Han
- The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
- State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing, China
| | - Lailiu Luo
- The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
- State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing, China
| | - Yicheng Wang
- The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
- State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing, China
| | - Shourong Wu
- The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
- State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China
- *Correspondence: Shourong Wu, ; Vivi Kasim,
| | - Vivi Kasim
- The Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
- State and Local Joint Engineering Laboratory for Vascular Implants, Chongqing, China
- The 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioengineering, Chongqing University, Chongqing, China
- *Correspondence: Shourong Wu, ; Vivi Kasim,
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15
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Kaltenmeier C, Wang R, Popp B, Geller D, Tohme S, Yazdani HO. Role of Immuno-Inflammatory Signals in Liver Ischemia-Reperfusion Injury. Cells 2022; 11:cells11142222. [PMID: 35883665 PMCID: PMC9323912 DOI: 10.3390/cells11142222] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/09/2022] [Accepted: 07/13/2022] [Indexed: 02/01/2023] Open
Abstract
Ischemia reperfusion injury (IRI) is a major obstacle in liver resection and liver transplantation. The initial step of IRI is mediated through ischemia which promotes the production of reactive oxygen species in Kupffer cells. This furthermore promotes the activation of pro-inflammatory signaling cascades, including tumor necrosis factor-alpha, IL-6, interferon, inducible nitric oxide synthase, TLR9/nuclear-factor kappa B pathway, and the production of damage-associated molecular patterns (DAMPs), such as ATP, histone, high mobility group box 1 (HMGB1), urate, mitochondrial formyl peptides and S100 proteins. With ongoing cell death of hepatocytes during the ischemic phase, DAMPs are built up and released into the circulation upon reperfusion. This promotes a cytokines/chemokine storm that attracts neutrophils and other immune cells to the site of tissue injury. The effect of IRI is further aggravated by the release of cytokines and chemokines, such as epithelial neutrophil activating protein (CXCL5), KC (CXCL1) and MIP-2 (CXCL2), the complement proteins C3a and C5a, mitochondrial-derived formyl peptides, leukotriene B4 and neutrophil extracellular traps (NETs) from migrating neutrophils. These NETs can also activate platelets and form Neutrophil-platelet microthrombi to further worsen ischemia in the liver. In this review we aim to summarize the current knowledge of mediators that promote liver IRI, and we will discuss the role of neutrophils and neutrophil extracellular traps in mediating IRI.
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Affiliation(s)
- Christof Kaltenmeier
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
| | - Ronghua Wang
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
| | - Brandon Popp
- Lake Erie College of Osteopathic Medicine, Erie, PA 16509, USA;
| | - David Geller
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
| | - Samer Tohme
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
| | - Hamza O. Yazdani
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; (C.K.); (R.W.); (D.G.); (S.T.)
- Correspondence:
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16
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Ailenberg M, Kapus A, Leung CH, Szaszi K, Williams P, diCiano-Oliveira C, Marshall JC, Rotstein OD. ACTIVATION OF THE MITOCHONDRIAL ANTIVIRAL SIGNALING PROTEIN (MAVS) FOLLOWING LIVER ISCHEMIA/REPERFUSION AND ITS EFFECT ON INFLAMMATION AND INJURY. Shock 2022; 58:78-89. [PMID: 35670454 PMCID: PMC9415233 DOI: 10.1097/shk.0000000000001949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/14/2022] [Accepted: 05/09/2022] [Indexed: 11/25/2022]
Abstract
ABSTRACT Resuscitation of trauma patients after hemorrhagic shock causes global I/R, which may contribute to organ dysfunction. Oxidative stress resulting from I/R is known to induce signaling pathways leading to the production of inflammatory molecules culminating in organ dysfunction/injury. Our recent work demonstrated that oxidative stress was able to induce activation of the mitochondrial antiviral signaling protein (MAVS), a protein known to be involved in antiviral immunity, in an in vitro model. We therefore hypothesized that the MAVS pathway might be involved in I/R-induced inflammation and injury. The present studies show that MAVS is activated in vivo by liver I/R and in vitro in RAW 264.7 cells by hypoxia/reoxygenation (H/R). We utilized both in vivo (liver I/R in MAVS knockout mice) and in vitro (MAVS siRNA in RAW 264.7 cells followed by H/R) models to study the role of MAVS activation on downstream events. In vivo , we demonstrated augmented injury and inflammation in MAVS knockout mice compared with wild-type animals; as shown by increased hepatocellular injury, induction of hepatocyte apoptosis augmented plasma TNF-α levels. Further, in vitro silencing of MAVS by specific siRNA in RAW 264.7 and exposure of the cells to H/R caused activation of mitophagy. This may represent a compensatory response to increased liver inflammation. We conclude that activation of MAVS by hypoxia/reoxygenation dampens inflammation, potentially suggesting a novel target for intervention.
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Affiliation(s)
- Menachem Ailenberg
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - Andras Kapus
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - Chung Ho Leung
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - Katalin Szaszi
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - Philip Williams
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - Caterina diCiano-Oliveira
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - John C. Marshall
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
| | - Ori D. Rotstein
- Keenan Research Centre for Biomedical Science of St. Michael's Hospital and the Departments of Surgery, St. Michael's Hospital and the University of Toronto
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17
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Histone deacetylase 2 inhibitor valproic acid attenuates bisphenol A-induced liver pathology in male mice. Sci Rep 2022; 12:10258. [PMID: 35715448 PMCID: PMC9205966 DOI: 10.1038/s41598-022-12937-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 05/18/2022] [Indexed: 12/02/2022] Open
Abstract
Accumulating evidence indicates the role of endocrine disruptor bisphenol A (BPA) in many pathological conditions. Histone deacetylase (HDAC) inhibition has potential for the treatment of many diseases/abnormalities. Using a mouse BPA exposure model, this study investigated the hepatoprotective effects of the Food and Drug Administration–approved HDAC2 inhibitor valproic acid (VPA) against BPA-induced liver pathology. We randomly divided 30 adult male Swiss albino mice (8 weeks old; N = 6) into five groups: group 1, no treatment (sham control (SC)); group 2, only oral sterile corn oil (vehicle control (VC)); group 3, 4 mg/kg/day of oral BPA (single dose (BPA group)); group 4, 0.4% oral VPA (VPA group); and group 5, oral BPA + VPA (BPA + VPA group). At the age of 10 weeks, the mice were euthanized for biochemical and histological examinations. BPA promoted a significant decrease in the body weight (BW), an increase in the liver weight, and a significant increase in the levels of liver damage markers aspartate aminotransferase and alanine aminotransferase in the BPA group compared to SC, as well as pathological changes in liver tissue. We also found an increase in the rate of apoptosis among hepatocytes. In addition, BPA significantly increased the levels of oxidative stress indices, malondialdehyde, and protein carbonylation but decreased the levels of reduced glutathione (GSH) in the BPA group compared to SC. In contrast, treatment with the HDAC2 inhibitor VPA significantly attenuated liver pathology, oxidative stress, and apoptosis and also enhanced GSH levels in VPA group and BPA + VPA group. The HDAC2 inhibitor VPA protects mice against BPA-induced liver pathology, likely by inhibiting oxidative stress and enhancing the levels of antioxidant-reduced GSH.
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18
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Shi S, Bonaccorsi-Riani E, Schurink I, van den Bosch T, Doukas M, Lila KA, Roest HP, Xhema D, Gianello P, de Jonge J, Verstegen MMA, van der Laan LJW. Liver Ischemia and Reperfusion Induce Periportal Expression of Necroptosis Executor pMLKL Which Is Associated With Early Allograft Dysfunction After Transplantation. Front Immunol 2022; 13:890353. [PMID: 35655777 PMCID: PMC9152120 DOI: 10.3389/fimmu.2022.890353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 04/13/2022] [Indexed: 11/29/2022] Open
Abstract
Background Early allograft dysfunction (EAD) following liver transplantation (LT) remains a major threat to the survival of liver grafts and recipients. In animal models, it is shown that hepatic ischemia-reperfusion injury (IRI) triggers phosphorylation of Mixed Lineage Kinase domain-like protein (pMLKL) inducing necroptotic cell death. However, the clinical implication of pMLKL-mediated cell death in human hepatic IRI remains largely unexplored. In this study, we aimed to investigate the expression of pMLKL in human liver grafts and its association with EAD after LT. Methods The expression of pMLKL was determined by immunohistochemistry in liver biopsies obtained from both human and rat LT. Human liver biopsies were obtained at the end of preservation (T0) and ~1 hour after reperfusion (T1). The positivity of pMLKL was quantified electronically and compared in rat and human livers and post-LT outcomes. Multiplex immunofluorescence staining was performed to characterize the pMLKL-expressing cells. Results In the rat LT model, significant pMLKL expression was observed in livers after IRI as compared to livers of sham-operation animals. Similarly, the pMLKL score was highest after IRI in human liver grafts (in T1 biopsies). Both in rats and humans, the pMLKL expression is mostly observed in the portal triads. In grafts who developed EAD after LT (n=24), the pMLKL score at T1 was significantly higher as compared to non-EAD grafts (n=40). ROC curve revealed a high predictive value of pMLKL score at T1 (AUC 0.70) and the ratio of pMLKL score at T1 and T0 (pMLKL-index, AUC 0.82) for EAD. Liver grafts with a high pMLKL index (>1.64) had significantly higher levels of serum ALT, AST, and LDH 24 hours after LT compared to grafts with a low pMLKL index. Multivariate logistical regression analysis identified the pMLKL-index (Odds ratio=1.3, 95% CI 1.1-1.7) as a predictor of EAD development. Immunohistochemistry on serial sections and multiplex staining identified the periportal pMLKL-positive cells as portal fibroblasts, fibrocytes, and a minority of cholangiocytes. Conclusion Periportal pMLKL expression increased significantly after IRI in both rat and human LT. The histological score of pMLKL is predictive of post-transplant EAD and is associated with early liver injury after LT. Periportal non-parenchymal cells (i.e. fibroblasts) appear most susceptible to pMLKL-mediated cell death during hepatic IRI.
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Affiliation(s)
- Shaojun Shi
- Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Eliano Bonaccorsi-Riani
- Abdominal Transplant Unit, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.,Pôle de Chirurgie Expérimentale et Transplantation Institute de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Ivo Schurink
- Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Thierry van den Bosch
- Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Michael Doukas
- Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Karishma A Lila
- Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, Netherlands
| | - Henk P Roest
- Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Daela Xhema
- Pôle de Chirurgie Expérimentale et Transplantation Institute de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Pierre Gianello
- Pôle de Chirurgie Expérimentale et Transplantation Institute de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Jeroen de Jonge
- Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Monique M A Verstegen
- Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, Netherlands
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Zhao M, Shang Z, Cai J, Wu C, Xu Y, Zeng L, Cai H, Xu M, Fan Y, Li Y, Gao W, Xu W, Zu L. Development and Validation of Predictive Model—HASBLAD Score—For Major Adverse Cardiovascular Events During Perioperative Period of Non-cardiac Surgery: A Single Center Experience in China. Front Cardiovasc Med 2022; 9:774191. [PMID: 35615561 PMCID: PMC9124933 DOI: 10.3389/fcvm.2022.774191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 04/15/2022] [Indexed: 11/27/2022] Open
Abstract
Background Major adverse cardiovascular events (MACEs) represent a significant reason of morbidity and mortality in non-cardiac surgery during perioperative period. The prevention of perioperative MACEs has always been one of the hotspots in the research field. Current existing models have not been validated in Chinese population, and have become increasingly unable to adapt to current clinical needs. Objectives To establish and validate several simple bedside tools for predicting MACEs during perioperative period of non-cardiac surgery in Chinese hospitalized patients. Design We used a nested case-control study to establish our prediction models. A nomogram along with a risk score were developed using logistic regression analysis. An internal cohort was used to evaluate the performance of discrimination and calibration of these predictive models including the revised cardiac risk index (RCRI) score recommended by current guidelines. Setting Peking University Third Hospital between January 2010 and December 2020. Patients Two hundred and fifty three patients with MACEs and 1,012 patients without were included in the training set from January 2010 to December 2019 while 38,897 patients were included in the validation set from January 2020 and December 2020, of whom 112 patients had MACEs. Main Outcome Measures The MACEs included the composite outcomes of cardiac death, non-fatal myocardial infarction, non-fatal congestive cardiac failure or hemodynamically significant ventricular arrhythmia, and Takotsubo cardiomyopathy. Results Seven predictors, including Hemoglobin, CARDIAC diseases, Aspartate aminotransferase (AST), high Blood pressure, Leukocyte count, general Anesthesia, and Diabetes mellitus (HASBLAD), were selected in the final model. The nomogram and HASBLAD score all achieved satisfactory prediction performance in the training set (C statistic, 0.781 vs. 0.768) and the validation set (C statistic, 0.865 vs. 0.843). Good calibration was observed for the probability of MACEs in the training set and the validation set. The two predictive models both had excellent discrimination that performed better than RCRI in the validation set (C statistic, 0.660, P < 0.05 vs. nomogram and HASBLAD score). Conclusion The nomogram and HASBLAD score could be useful bedside tools for predicting perioperative MACEs of non-cardiac surgery in Chinese hospitalized patients.
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20
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Chen Y, He Y, Wu X, Xu X, Gong J, Chen Y, Gong J. Rubicon promotes the M2 polarization of Kupffer cells via LC3-associated phagocytosis-mediated clearance to improve liver transplantation. Cell Immunol 2022; 378:104556. [DOI: 10.1016/j.cellimm.2022.104556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 11/03/2022]
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Liver ischaemia-reperfusion injury: a new understanding of the role of innate immunity. Nat Rev Gastroenterol Hepatol 2022; 19:239-256. [PMID: 34837066 DOI: 10.1038/s41575-021-00549-8] [Citation(s) in RCA: 177] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/29/2021] [Indexed: 02/08/2023]
Abstract
Liver ischaemia-reperfusion injury (LIRI), a local sterile inflammatory response driven by innate immunity, is one of the primary causes of early organ dysfunction and failure after liver transplantation. Cellular damage resulting from LIRI is an important risk factor not only for graft dysfunction but also for acute and even chronic rejection and exacerbates the shortage of donor organs for life-saving liver transplantation. Hepatocytes, liver sinusoidal endothelial cells and Kupffer cells, along with extrahepatic monocyte-derived macrophages, neutrophils and platelets, are all involved in LIRI. However, the mechanisms underlying the responses of these cells in the acute phase of LIRI and how these responses are orchestrated to control and resolve inflammation and achieve homeostatic tissue repair are not well understood. Technological advances allow the tracking of cells to better appreciate the role of hepatic macrophages and platelets (such as their origin and immunomodulatory and tissue-remodelling functions) and hepatic neutrophils (such as their selective recruitment, anti-inflammatory and tissue-repairing functions, and formation of extracellular traps and reverse migration) in LIRI. In this Review, we summarize the role of macrophages, platelets and neutrophils in LIRI, highlight unanswered questions, and discuss prospects for innovative therapeutic regimens against LIRI in transplant recipients.
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Chen Z, Lin R, Zhuo H, Xu F, Liu X. Intravenous immunoglobulin is effective in alleviating hepatic ischemia-reperfusion injury: a rat model study. Mol Biol Rep 2022; 49:341-349. [PMID: 34727292 DOI: 10.1007/s11033-021-06879-9] [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: 08/03/2021] [Accepted: 10/22/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Hepatic ischemia-reperfusion injury (I/R) is an important factor affecting the prognosis of patients undergoing liver surgery. This study aimed to explore the value of intravenous immunoglobulin (IVIG) in hepatic I/R and its mechanism in a rat model. MATERIALS AND METHODS Forty eight adult male Sprague-Dawley (SD) rats were divided into six groups randomly: (1-2) treated with normal saline (NS) without ischemia or reperfusion; (3-4) treated with NS + 30 min ischemia; (5-6) treated with IVIG + 30 min ischemia. Rats of group 1/3/5 were euthanized at 12 h after operation (sham + NS + 12 h, I/R + NS + 12 h, I/R + IVIG + 12 h group) while group 2/4/6 were euthanized at 24 h (sham + NS + 24 h, I/R + NS + 24 h, I/R + IVIG + 24 h group). Interleukin 10 (IL-10), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) were quantified as well as serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Hepatic pathological changes were observed while nuclear factor kappa B p65 (NF-κB p65), Inhibitory Subunit of NF Kappa B Alpha (IKB-alpha) and cleaved caspase-3 were detected. CONCLUSION ALT, AST, IL-6, TNF-alpha, NF-κB p65 and cleaved caspase-3 were increased by I/R whereas IL-10 and IKB-alpha were decreased. However, IVIG pretreatment reduced ALT, AST, IL-6, TNF-alpha, NF-κB p65 and cleaved caspase-3, but increased IL-10 and IKB-alpha. IVIG treatment attenuates the infiltration of inflammatory cell and cell apoptosis which were observed in I/R groups. IVIG may alleviate hepatic I/R in rats by inhibiting the classical NF-κB signaling pathway, reducing IL-6, TNF-alpha, promoting IL-10, and inhibiting cell apoptosis.
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Affiliation(s)
- Zeming Chen
- Shantou University Medical College, Shantou, China
| | - Runzhui Lin
- Shantou University Medical College, Shantou, China
| | - Hua Zhuo
- Shantou University Medical College, Shantou, China
| | - Fengjie Xu
- Shantou University Medical College, Shantou, China
| | - Xingmu Liu
- Second Affiliated Hospital of Shantou University Medical College, Shantou, China
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Congestive Hepatopathy Secondary to Right Ventricular Hypertrophy Related to Monocrotaline-Induced Pulmonary Arterial Hypertension. Int J Mol Sci 2021; 22:ijms222111891. [PMID: 34769319 PMCID: PMC8585108 DOI: 10.3390/ijms222111891] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 10/21/2021] [Accepted: 10/25/2021] [Indexed: 12/22/2022] Open
Abstract
Heart dysfunction and liver disease often coexist. Among the types of cardiohepatic syndrome, Type 2 is characterized by the chronic impairment of cardiac function, leading to chronic liver injury, referred to as congestive hepatopathy (CH). In this study, we aimed to establish a rat model of CH secondary to right ventricular hypertrophy (RVH) related to monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Fifty male Wistar rats were divided into four groups and randomly assigned to control and experimental groups. Three experimental groups were submitted to intraperitoneal MCT inoculation (60 mg/kg) and were under its effect for 15, 30 and 37 days. The animals were then sacrificed, obtaining cardiac and hepatic tissues for anatomopathological and morphometric analysis. At macroscopic examination, the livers in the MCT groups presented a nutmeg-like appearance. PAH produced marked RVH and dilatation in the MCT groups, characterized by a significant increase in right ventricular free wall thickness (RVFWT) and chamber area. At histological evaluation, centrilobular congestion was the earliest manifestation, with preservation of the hepatocytes. Centrilobular hemorrhagic necrosis was observed in the groups exposed to prolonged MCT. Sinusoidal dilatation was markedly increased in the MCT groups, quantified by the Sinusoidal Lumen Ratio (SLR). The Congestive Hepatic Fibrosis Score and the Centrilobular Fibrosis Ratio (CFR) were also significantly increased in the MCT30 group. Hepatic atrophy, steatosis, apoptotic bodies and, rarely, hydropic swelling were also observed. SLR correlated strongly with CFR and RVFWT, and CFR correlated moderately with RVFWT. Our rat model was able to cause CH, related to monocrotaline-induced PAH and RVH; it was feasible, reproducible, and safe.
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Valade G, Libert N, Martinaud C, Vicaut E, Banzet S, Peltzer J. Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock. Front Immunol 2021; 12:749659. [PMID: 34659252 PMCID: PMC8511792 DOI: 10.3389/fimmu.2021.749659] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/06/2021] [Indexed: 12/28/2022] Open
Abstract
Severe trauma is the principal cause of death among young people worldwide. Hemorrhagic shock is the leading cause of death after severe trauma. Traumatic hemorrhagic shock (THS) is a complex phenomenon associating an absolute hypovolemia secondary to a sudden and significant extravascular blood loss, tissue injury, and, eventually, hypoxemia. These phenomena are responsible of secondary injuries such as coagulopathy, endotheliopathy, microcirculation failure, inflammation, and immune activation. Collectively, these dysfunctions lead to secondary organ failures and multi-organ failure (MOF). The development of MOF after severe trauma is one of the leading causes of morbidity and mortality, where immunological dysfunction plays a central role. Damage-associated molecular patterns induce an early and exaggerated activation of innate immunity and a suppression of adaptive immunity. Severe complications are associated with a prolonged and dysregulated immune–inflammatory state. The current challenge in the management of THS patients is preventing organ injury, which currently has no etiological treatment available. Modulating the immune response is a potential therapeutic strategy for preventing the complications of THS. Mesenchymal stromal cells (MSCs) are multipotent cells found in a large number of adult tissues and used in clinical practice as therapeutic agents for immunomodulation and tissue repair. There is growing evidence that their efficiency is mainly attributed to the secretion of a wide range of bioactive molecules and extracellular vesicles (EVs). Indeed, different experimental studies revealed that MSC-derived EVs (MSC-EVs) could modulate local and systemic deleterious immune response. Therefore, these new cell-free therapeutic products, easily stored and available immediately, represent a tremendous opportunity in the emergency context of shock. In this review, the pathophysiological environment of THS and, in particular, the crosstalk between the immune system and organ function are described. The potential therapeutic benefits of MSCs or their EVs in treating THS are discussed based on the current knowledge. Understanding the key mechanisms of immune deregulation leading to organ damage is a crucial element in order to optimize the preparation of EVs and potentiate their therapeutic effect.
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Affiliation(s)
- Guillaume Valade
- Institut de Recherche Biomédicale des Armées (IRBA), Inserm UMRS-MD-1197, Clamart, France
| | - Nicolas Libert
- Service d'Anesthésie-Réanimation, Hôpital d'instruction des armées Percy, Clamart, France
| | - Christophe Martinaud
- Unité de Médicaments de Thérapie Innovante, Centre de Transfusion Sanguine des Armées, Clamart, France
| | - Eric Vicaut
- Laboratoire d'Etude de la Microcirculation, Université de Paris, UMRS 942 INSERM, Paris, France
| | - Sébastien Banzet
- Institut de Recherche Biomédicale des Armées (IRBA), Inserm UMRS-MD-1197, Clamart, France
| | - Juliette Peltzer
- Institut de Recherche Biomédicale des Armées (IRBA), Inserm UMRS-MD-1197, Clamart, France
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Haga S, Kanno A, Morita N, Jin S, Matoba K, Ozawa T, Ozaki M. Poly(ADP-ribose) Polymerase (PARP) is Critically Involved in Liver Ischemia/reperfusion-injury. J Surg Res 2021; 270:124-138. [PMID: 34656890 DOI: 10.1016/j.jss.2021.09.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 08/27/2021] [Accepted: 09/14/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Poly(ADP-ribose) polymerase (PARP) is a DNA-repairing enzyme activated by extreme genomic stress, and therefore is potently activated in the remnant liver suffering from ischemia after surgical resection. However, the impact of PARP on post-ischemic liver injury has not been elucidated yet. MATERIALS AND METHODS We investigated the impact of PARP on murine hepatocyte/liver injury induced by hypoxia/ischemia, respectively. RESULTS PJ34, a specific inhibitor of PARP, markedly protected against hypoxia/reoxygenation (H/R)-induced cell death, though z-VAD-fmk, a pan-caspase inhibitor similarly showed the protective effect. PJ34 did not affect H/R-induced caspase activity or caspase-mediated cell death. z-VAD-fmk also did not affect the production of PAR (i.e., PARP activity). Therefore, PARP- and caspase-mediated cell death occurred in a mechanism independent of each other in H/R. H/R immediately induced activation of PARP and cell death afterwards, both of which were suppressed by PJ34 or Trolox, an antioxidant. This suggests that H/R-induced cell death occurred redox-dependently through PARP activation. H/R and OS induced nuclear translocation of apoptosis inducing factor (AIF, a marker of parthanatos) and RIP1-RIP3 interaction (a marker of necroptosis), both of which were suppressed by PJ34. H/R induced PARP-mediated parthanatos and necroptosis redox-dependently. In mouse experiments, PJ34 significantly reduced serum levels of AST, ALT & LDH and areas of hepatic necrosis after liver ischemia/reperfusion, similar to z-VAD-fmk or Trolox. CONCLUSION PARP, activated by ischemic damage and/or oxidative stress, may play a critical role in post-ischemic liver injury by inducing programmed necrosis (parthanatos and necroptosis). PARP inhibition may be one of the promising strategies against post-ischemic liver injury.
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Affiliation(s)
- Sanae Haga
- Department of Biological Response and Regulation, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Akira Kanno
- Department of Environmental Applied Chemistry, University of Toyama, Toyama, Toyama, Japan
| | - Naoki Morita
- Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo, Hokkaido, Japan
| | - Shigeki Jin
- Department of Forensic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Kotaro Matoba
- Department of Forensic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Takeaki Ozawa
- Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan
| | - Michitaka Ozaki
- Department of Biological Response and Regulation, Hokkaido University, Sapporo, Hokkaido, Japan; Laboratory of Molecular and Functional Bio-Imaging, Hokkaido University, Sapporo, Hokkaido, Japan.
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Madić V, Petrović A, Jušković M, Jugović D, Djordjević L, Stojanović G, Vasiljević P. Polyherbal mixture ameliorates hyperglycemia, hyperlipidemia and histopathological changes of pancreas, kidney and liver in a rat model of type 1 diabetes. JOURNAL OF ETHNOPHARMACOLOGY 2021; 265:113210. [PMID: 32795501 DOI: 10.1016/j.jep.2020.113210] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/07/2020] [Accepted: 07/20/2020] [Indexed: 05/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE One of the commonly prescribed 'anti-diabetic' polyherbal mixtures by European herbalists is made of Rubus fruticosus and Vaccinium myrtillus leaves, Potentilla erecta roots, Geum urbanum aerial parts and Phaseolus vulgaris pods. AIM OF THE STUDY This study aimed to evaluate the phytochemical composition, antioxidant capacity, potential toxicity, hypoglycemic, hypolipidemic, nephroprotective and hepatoprotective activities of this polyherbal mixture decoction. MATERIALS AND METHODS The phytochemical composition was evaluated using HPLC-UV. The antioxidant activity was assessed using the DPPH test. Potential toxicity was evaluated using the acute and sub-chronic oral toxicity method. Diabetes was induced in Wistar female rats with a single intraperitoneal injection of alloxan monohydrate (150 mg/kg). The animals whose blood glucose was >20 mmol/L for 14 consecutive days were considered diabetic. For the next 14 days, D-10 and D-20 groups were treated with the polyherbal mixture (10 and 20 g of dry plant material/kg, respectively). I and M were control groups treated with insulin glargine (13 IU/kg) and metformin (150 mg/kg), respectively. Healthy control (HC) and diabetic control (DC) groups were treated with water. The blood glucose level was measured on days 14, 21 and 28. Lipid profile analysis was done on day 28. Pancreas, kidney and liver histopathology was evaluated using the H&E and Masson's trichrome staining. The liver tissue was additionally tested for PAS-positive cells. RESULTS The HPLC-UV analysis revealed the presence of quinic, gallic and caftaric acid, arbutin, rutin, trifolin, astragalin, hyperoside, isoquercetin and quercitrin. The antioxidant activity of the extract was higher than the reference's one (p < 0.01). Treatment with the polyherbal mixture (10 and 20 g/kg) has shown no toxic effects. No major decline in blood sugar was recorded in I and M groups compared to the DC one (22.86 ± 2.58, 28.5 ± 0.42 and 27.82 ± 0.9 mmol/L, respectively). The polyherbal mixture lowered the blood glucose level to the normal value (8.64 ± 4.09, 5.26 ± 1.3 and 6.76 ± 1.54 mmol/L in D-10, D-20 and HC groups, respectively). Furthermore, it decreased the levels of total cholesterol, triglycerides, VLDL, LDL, atherogenic and cardiovascular risk indices (p < 0.001) compared to the DC group. In addition, the extract restored histopathological changes of the pancreas, kidneys and liver to the healthy animal level. CONCLUSION Treatment with the polyherbal mixture extract was more effective than the standard drugs (insulin and metformin) in the amelioration of hyperglycemia, hyperlipidemia, and histopathological changes of the pancreas, kidney and liver tissue.
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Affiliation(s)
- Višnja Madić
- Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia.
| | - Aleksandra Petrović
- Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia.
| | - Marina Jušković
- Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia.
| | - Dragana Jugović
- Laboratory for Cytogenetics and Immunology, Clinical Center of Niš, Bulevar Dr. Zorana Đinđića 48, 18000, Niš, Serbia.
| | - Ljubiša Djordjević
- Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia.
| | - Gordana Stojanović
- Department of Chemistry, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia.
| | - Perica Vasiljević
- Department of Biology and Ecology, Faculty of Sciences and Mathematics, University of Niš, Višegradska 33, 18000, Niš, Serbia.
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A Mouse Model of Acute Liver Injury by Warm, Partial Ischemia-Reperfusion for Testing the Efficacy of Virus-Derived Therapeutics. Methods Mol Biol 2021; 2225:275-292. [PMID: 33108669 DOI: 10.1007/978-1-0716-1012-1_16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Ischemia-reperfusion injury (IRI) drives early and long-term damage to organs as well as compounding damage from acute transplant rejection and surgical trauma. IRI initiates an aggressive and prolonged inflammation leading to tissue injury, organ failure, and death. However, there are few effective therapeutic interventions for IRI. The destructive inflammatory cell activity in IRI is part of an aberrant innate immune response that triggers multiple pathways. Hence, immune-modulating treatments to control pathways triggered by IRI hold great therapeutic potential. Viruses, especially large DNA viruses, have evolved highly effective immune-modulating proteins for the purpose of immune evasion and to protect the virus from the host immune defenses. A number of these immune-modulating proteins have proven therapeutically effective in preclinical models, many with function targeting pathways known to be involved in IRI. The use of virus-derived immune-modulating proteins thus represents a promising source for new treatments to target ischemia-reperfusion injury. Laboratory small animal models of IRI are well established and are able to reproduce many aspects of ischemia-reperfusion injury seen in humans. This chapter will discuss the methods used to perform the IRI procedure in mice, as well as clinically relevant diagnostic tests to evaluate liver injury and approaches for assessing histological damage while testing novel immune modulating protein treatments.
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Maeda Y, Kikuchi R, Kawagoe J, Tsuji T, Koyama N, Yamaguchi K, Nakamura H, Aoshiba K. Anti-cancer strategy targeting the energy metabolism of tumor cells surviving a low-nutrient acidic microenvironment. Mol Metab 2020; 42:101093. [PMID: 33007425 PMCID: PMC7578269 DOI: 10.1016/j.molmet.2020.101093] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/17/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Tumor cells experience hypoxia, acidosis, and hypoglycemia. Metabolic adaptation to glucose shortage is essential to maintain tumor cells' survival because of their high glucose requirement. This study evaluated the hypothesis that acidosis might promote tumor survival during glucose shortage and if so, explored a novel drug targeting metabolic vulnerability to glucose shortage. METHODS Cell survival and bioenergetics metabolism were assessed in lung cancer cell lines. Our in-house small-molecule compounds were screened to identify those that kill cancer cells under low-glucose conditions. Cytotoxicity against non-cancerous cells was also assessed. Tumor growth was evaluated in vivo using a mouse engraft model. RESULTS Acidosis limited the cellular consumption of glucose and ATP, causing tumor cells to enter a metabolically dormant but energetically economic state, which promoted tumor cell survival during glucose deficiency. We identified ESI-09, a previously known exchange protein directly activated by cAMP (EAPC) inhibitor, as an anti-cancer compound that inhibited cancer cells under low-glucose conditions even when associated with acidosis. Bioenergetic studies showed that independent of EPAC inhibition, ESI-09 was a safer mitochondrial uncoupler than a classical uncoupler and created a futile cycle of mitochondrial respiration, leading to decreased ATP production, increased ATP dissipation, and fuel scavenging. Accordingly, ESI-09 exhibited more cytotoxic effects under low-glucose conditions than under normal glucose conditions. ESI-09 was also more effective than actively proliferating cells on quiescent glucose-restricted cells. Cisplatin showed opposite effects. ESI-09 inhibited tumor growth in lung cancer engraft mice. CONCLUSIONS This study highlights the acidosis-induced promotion of tumor survival during glucose shortage and demonstrates that ESI-09 is a novel potent anti-cancer mitochondrial uncoupler that targets a metabolic vulnerability to glucose shortage even when associated with acidosis. The higher cytotoxicity under lower-than-normal glucose conditions suggests that ESI-09 is safer than conventional chemotherapy, can target the metabolic vulnerability of tumor cells to low-glucose stress, and is applicable to many cancer cell types.
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Affiliation(s)
- Yuki Maeda
- Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuou, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan
| | - Ryota Kikuchi
- Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuou, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan; Department of Respiratory Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Junichiro Kawagoe
- Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuou, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan; Department of Respiratory Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Takao Tsuji
- Department of Medicine, Otsuki Municipal Hospital, 1255 Hanasaki, Otsuki-chou, Otsuki-shi, Yamanashi, 401-0015, Japan
| | - Nobuyuki Koyama
- Department of Clinical Oncology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuou, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan
| | - Kazuhiro Yamaguchi
- Department of Respiratory Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Hiroyuki Nakamura
- Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuou, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan
| | - Kazutetsu Aoshiba
- Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuou, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan.
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Baidya R, Crawford DHG, Gautheron J, Wang H, Bridle KR. Necroptosis in Hepatosteatotic Ischaemia-Reperfusion Injury. Int J Mol Sci 2020; 21:ijms21165931. [PMID: 32824744 PMCID: PMC7460692 DOI: 10.3390/ijms21165931] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/12/2020] [Accepted: 08/12/2020] [Indexed: 02/07/2023] Open
Abstract
While liver transplantation remains the sole treatment option for patients with end-stage liver disease, there are numerous limitations to liver transplantation including the scarcity of donor livers and a rise in livers that are unsuitable to transplant such as those with excess steatosis. Fatty livers are susceptible to ischaemia-reperfusion (IR) injury during transplantation and IR injury results in primary graft non-function, graft failure and mortality. Recent studies have described new cell death pathways which differ from the traditional apoptotic pathway. Necroptosis, a regulated form of cell death, has been associated with hepatic IR injury. Receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL) are thought to be instrumental in the execution of necroptosis. The study of hepatic necroptosis and potential therapeutic approaches to attenuate IR injury will be a key factor in improving our knowledge regarding liver transplantation with fatty donor livers. In this review, we focus on the effect of hepatic steatosis during liver transplantation as well as molecular mechanisms of necroptosis and its involvement during liver IR injury. We also discuss the immune responses triggered during necroptosis and examine the utility of necroptosis inhibitors as potential therapeutic approaches to alleviate IR injury.
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Affiliation(s)
- Raji Baidya
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland QLD 4006, Australia; (R.B.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Brisbane, Queensland QLD 4120, Australia;
| | - Darrell H. G. Crawford
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland QLD 4006, Australia; (R.B.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Brisbane, Queensland QLD 4120, Australia;
| | - Jérémie Gautheron
- Sorbonne University, Inserm, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France;
- Institute of Cardiometabolism and Nutrition (ICAN), 75013 Paris, France
| | - Haolu Wang
- Gallipoli Medical Research Institute, Brisbane, Queensland QLD 4120, Australia;
- Diamantina Institute, The University of Queensland, Brisbane, Queensland QLD 4102, Australia
| | - Kim R. Bridle
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland QLD 4006, Australia; (R.B.); (D.H.G.C.)
- Gallipoli Medical Research Institute, Brisbane, Queensland QLD 4120, Australia;
- Correspondence: ; Tel.: +61-7-3346-0698
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Inhaled Argon Impedes Hepatic Regeneration after Ischemia/Reperfusion Injury in Rats. Int J Mol Sci 2020; 21:ijms21155457. [PMID: 32751707 PMCID: PMC7432339 DOI: 10.3390/ijms21155457] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/20/2020] [Accepted: 07/28/2020] [Indexed: 11/16/2022] Open
Abstract
Organoprotective effects of noble gases are subject of current research. One important field of interest is the effect of noble gases on hepatic regenerative capacity. For the noble gas argon, promising studies demonstrated remarkable experimental effects in neuronal and renal cells. The aim of this study was to investigate the effects of argon on the regenerative capacity of the liver after ischemia/reperfusion injury (IRI). Male, Sprague-Dawley rats underwent hepatic IRI by clamping of the hepatic artery. Expression of hepatoproliferative genes (HGF, IL-1β, IL-6, TNF), cell cycle markers (BrdU, TUNEL, Ki-67), and liver enzymes (ALT, AST, Bilirubin, LDH) were assessed 3, 36, and 96 h after IRI. Expression of IL-1β and IL-6 was significantly higher after argon inhalation after 36 h (IL-1β 5.0 vs. 8.7 fold, p = 0.001; IL-6 9.6 vs. 19.1 fold, p = 0.05). Ki-67 was higher in the control group compared to the argon group after 36 h (214.0 vs. 38.7 positive cells/1000 hepatocytes, p = 0.045). Serum levels of AST and ALT did not differ significantly between groups. Our data indicate that argon inhalation has detrimental effects on liver regeneration after IRI as measured by elevated levels of the proinflammatory cytokines IL-1β and IL-6 after 36 h. In line with these results, Ki-67 is decreased in the argon group, indicating a negative effect on liver regeneration in argon inhalation.
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Chitosan protects liver against ischemia-reperfusion injury via regulating Bcl-2/Bax, TNF-α and TGF-β expression. Int J Biol Macromol 2020; 164:1565-1574. [PMID: 32735924 DOI: 10.1016/j.ijbiomac.2020.07.212] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/15/2020] [Accepted: 07/26/2020] [Indexed: 01/20/2023]
Abstract
The study aimed to investigate the potential attenuation effect of chitosan in liver ischemia/reperfusion injury (I/R), and its relevant protective mechanisms. Chitosan (200 mg/kg) has been administered orally for 30 days, later animals underwent liver 45 min ischemia and reperfusion for 60 min. Following treatment with chitosan, the levels of serum aminotransferases and lactate dehydrogenase were significantly reduced. Similarly, hepatic (GSH, SOD, CAT, GST and GPx) were enhanced, and the level of tissue malondialdehyde (MDA) was decreased. In addition, inflammatory cytokinesis (TNF-α and TGF-β) have recorded a significant decrease in their mRNA expression and protein levels using qPCR and ELISA respectively. Marked reduction of apoptosis has been indicated by the elevation in BCL2, and decreasing in BAX, Caspace-3 and Cytochrome-c expression levels, which furthermore confirmed by DNA fragmentation assay. The enhancement of the previous parameters resulted in a marked improvement in the liver architectures after chitosan administration. In conclusion, chitosan has proved its efficiency as an anti-inflammatory and antioxidant agent through its inhibitory effect of cytokines and reducing ROS respectively. In addition, chitosan could modulate the changes in histological structure and alleviate apoptosis induced by liver I/R, which recommend it as an efficient agent for protection against liver I/R injury.
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Kim D, Choi JW, Han S, Gwak MS, Kim GS, Jeon SY, Ryu S, Hahm TS, Ko JS. Ischemic Preconditioning Protects Against Hepatic Ischemia-Reperfusion Injury Under Propofol Anesthesia in Rats. Transplant Proc 2020; 52:2964-2969. [PMID: 32586662 DOI: 10.1016/j.transproceed.2020.05.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 02/19/2020] [Accepted: 05/12/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Propofol is widely used in general anesthesia, and it has been reported to protect various organs against ischemia-reperfusion injury (IRI), including liver. To evaluate the hepatoprotective effects of ischemic preconditioning (IP) under propofol anesthesia, we investigated the possible underlying mechanisms in rats. METHODS Male Sprague-Dawley rats were randomly assigned to 3 groups: sham group (n = 5), non-IP group (n = 9; 45 minutes of hepatic ischemia followed by 2 hours of reperfusion), and IP group (n = 9; IP applied as 10 minutes of hepatic ischemia followed by 15 minutes of reperfusion before 45 minutes of ischemia). Anesthesia was maintained with intravenous (IV) infusion of propofol (800 μg/kg/min). Liver enzymes, histopathological changes, and cytokine expression were examined. RESULTS The IP group showed significantly lower liver enzyme levels (aspartate aminotransferase, P = .045; alanine aminotransferase, P = .006) and reduced the histologic grades of hepatic injury 2 hours after reperfusion (P = .004) compared to the non-IP group. Lactate dehydrogenase activity (P < .001) and interleukin-6 mRNA levels were significantly higher in the non-IP group than in the sham and IP groups (P = .002, both groups). CONCLUSIONS Our results demonstrate that IP under propofol anesthesia significantly attenuated hepatic IRI. The principal mechanism of the protective effects appeared to involve reduced expression of the IL-6 pro-inflammatory cytokine and subsequent reduction of the degree of necrosis.
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Affiliation(s)
- Doyeon Kim
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Won Choi
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sangbin Han
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mi Sook Gwak
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Gaab Soo Kim
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Su Yeon Jeon
- Department of Laboratory Animal Research, Samsung Biomedical Research Institute, Seoul, Korea
| | - Sun Ryu
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Soo Hahm
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Justin Sangwook Ko
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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Owen A, Newsome PN. Mesenchymal Stromal Cells, a New Player in Reducing Complications From Liver Transplantation? Front Immunol 2020; 11:1306. [PMID: 32636850 PMCID: PMC7318292 DOI: 10.3389/fimmu.2020.01306] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 05/22/2020] [Indexed: 12/12/2022] Open
Abstract
In response to the global burden of liver disease there has been a commensurate increase in the demand for liver transplantation. However, due to a paucity of donor organs many centers have moved toward the routine use of marginal allografts, which can be associated with a greater risk of complications and poorer clinical outcomes. Mesenchymal stromal cells (MSC) are a multi-potent progenitor cell population that have been utilized to modulate aberrant immune responses in acute and chronic inflammatory conditions. MSC exert an immunomodulatory effect on innate and adaptive immune systems through the release of both paracrine soluble factors and extracellular vesicles. Through these routes MSC can switch the regulatory function of the immune system through effects on macrophages and T regulatory cells enabling a switch of phenotype from injury to restoration. A key benefit seems to be their ability to tailor their response to the inflammatory environment without compromising the host ability to fight infection. With over 200 clinical trials registered to examine MSC therapy in liver disease and an increasing number of trials of MSC therapy in solid organ transplant recipients, there is increasing consideration for their use in liver transplantation. In this review we critically appraise the potential role of MSC therapy in the context of liver transplantation, including their ability to modulate reperfusion injury, their role in the reduction of medium term complications in the biliary tree and their potential to enhance tolerance in transplanted organs.
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Affiliation(s)
- Andrew Owen
- National Institute for Health Research Birmingham, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Department of Anesthesia and Critical Care, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Philip N Newsome
- National Institute for Health Research Birmingham, Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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Abstract
The human liver is an organ with a diverse array of immunologic functions. Its unique anatomic position that leads to it receiving all the mesenteric venous blood, combined with its unique micro anatomy, allows it to serve as a sentinel for the body's immune system. Hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells express key molecules that recruit and activate innate and adaptive immunity. Additionally, a diverse array of lymphoid and myeloid immune cells resides within and traffics to the liver in specific circumstances. Derangement of these trafficking mechanisms underlies the pathophysiology of autoimmune liver diseases, nonalcoholic steatohepatitis, and liver transplantation. Here, we review these pathways and interactions along with potential targets that have been identified to be exploited for therapeutic purposes.
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35
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Nakamura K, Kageyama S, Kaldas FM, Hirao H, Ito T, Kadono K, Dery KJ, Kojima H, Gjertson DW, Sosa RA, Kujawski M, Busuttil RW, Reed EF, Kupiec-Weglinski JW. Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury. J Clin Invest 2020; 130:2689-2704. [PMID: 32027621 PMCID: PMC7190917 DOI: 10.1172/jci133142] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 01/30/2020] [Indexed: 12/16/2022] Open
Abstract
Although CEACAM1 (CC1) glycoprotein resides at the interface of immune liver injury and metabolic homeostasis, its role in orthotopic liver transplantation (OLT) remains elusive. We aimed to determine whether/how CEACAM1 signaling may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. In the mouse, donor liver CC1 null mutation augmented IRI-OLT (CC1-KO→WT) by enhancing ROS expression and HMGB1 translocation during cold storage, data supported by in vitro studies where hepatic flush from CC1-deficient livers enhanced macrophage activation in bone marrow-derived macrophage cultures. Although hepatic CC1 deficiency augmented cold stress-triggered ASK1/p-p38 upregulation, adjunctive ASK1 inhibition alleviated IRI and improved OLT survival by suppressing p-p38 upregulation, ROS induction, and HMGB1 translocation (CC1-KO→WT), whereas ASK1 silencing (siRNA) promoted cytoprotection in cold-stressed and damage-prone CC1-deficient hepatocyte cultures. Consistent with mouse data, CEACAM1 expression in 60 human donor liver biopsies correlated negatively with activation of the ASK1/p-p38 axis, whereas low CC1 levels associated with increased ROS and HMGB1 translocation, enhanced innate and adaptive immune responses, and inferior early OLT function. Notably, reduced donor liver CEACAM1 expression was identified as one of the independent predictors for early allograft dysfunction (EAD) in human OLT patients. Thus, as a checkpoint regulator of IR stress and sterile inflammation, CEACAM1 may be considered as a denominator of donor hepatic tissue quality, and a target for therapeutic modulation in OLT recipients.
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Affiliation(s)
- Kojiro Nakamura
- Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Liver Transplant Center
| | - Shoichi Kageyama
- Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Liver Transplant Center
| | - Fady M. Kaldas
- Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Liver Transplant Center
| | - Hirofumi Hirao
- Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Liver Transplant Center
| | - Takahiro Ito
- Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Liver Transplant Center
| | - Kentaro Kadono
- Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Liver Transplant Center
| | - Kenneth J. Dery
- Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Liver Transplant Center
| | - Hidenobu Kojima
- Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Liver Transplant Center
| | - David W. Gjertson
- Department of Biostatistics, UCLA School of Public Health
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Rebecca A. Sosa
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Maciej Kujawski
- Department of Molecular Immunology, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Ronald W. Busuttil
- Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Liver Transplant Center
| | - Elaine F. Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Jerzy W. Kupiec-Weglinski
- Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Liver Transplant Center
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36
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Inhibition of Frizzled-2 by small interfering RNA protects rat hepatic BRL-3A cells against cytotoxicity and apoptosis induced by Hypoxia/Reoxygenation. GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:107-116. [PMID: 31964521 DOI: 10.1016/j.gastrohep.2019.02.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 02/12/2019] [Accepted: 02/22/2019] [Indexed: 01/30/2023]
Abstract
Frizzled-2 plays an important role in maintaining normal hepatic cell functionality. This study aimed to investigate the role of inhibition of Frizzled-2 in protecting rat liver BRL-3A cells from Hypoxia/Reoxygenation (H/R). In vitro H/R hepatic cell model was established by culturing BRL-3A cells under H/R condition. Frizzled-2 siRNA was transfected into BRL-3A cells to inhibit Frizzled-2 signaling. Wnt5a and Frizzled-2 were significantly increased in BRL-3A cells upon H/R treatment. H/R treatment induced cell cytotoxicity, the early apoptosis rate and the intracellular Ca2+ level in BRL-3A cells while silencing frizzled-2 gene decreased the H/R induced cell cytotoxicity, apoptosis and intracellular Ca2+ level. In vivo mice study further showed the up-regulation of Frizzled-2/Wnt 5 pathway and cleaved Caspase-3 expression in liver tissues under ischemia and reperfusion injury (IRI). In summary, inhibition of Frizzled-2 by its siRNA may protects BRL-3A cells by attenuating the H/R induced cell cytotoxicity and apoptosis.
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Ziemann C, Roller J, Malter MM, Keller K, Kollmar O, Glanemann M, Menger MD, Sperling J. Intra-arterial EmboCept S® and DC Bead® effectively inhibit tumor growth of colorectal rat liver metastases. BMC Cancer 2019; 19:938. [PMID: 31601175 PMCID: PMC6785845 DOI: 10.1186/s12885-019-6135-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 09/04/2019] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Intra-arterial therapy with embolics is established for the treatment of malignancies of the liver. However, there are no studies comparing the different effects of various embolics used in clinical practice. Herein, we analyzed the effect of 3 different embolics on tumor growth in a rat model of colorectal liver metastases. METHODS Eight days after subcapsular implantation of 5 × 105 colorectal cancer cells (CC531) in the left liver lobe of WAG/Rij rats were randomized into 4 groups (n = 8) and underwent intra-arterial hepatic therapy. Animals received either EmboCept S®, DC Bead® or Lipiodol® Ultra-Fluid. Animals of the control group received a comparable amount of saline. Tumor growth was measured on day 8 and 11 using a three-dimensional 40 MHz ultrasound device. On day 11 tumor and liver tissue were removed for histological and immunohistochemical analyses. RESULTS On day 11 animals of the control group showed a tumor growth of ~ 60% compared to day 8. Application of Lipiodol Ultra-Fluid® did not significantly influence tumor growth (~ 40%). In contrast, treatment with EmboCept S® or DC Bead® completely inhibited tumor growth. Of interest, application of EmboCept S® did not only completely inhibit tumor growth but even decreased tumor size. Immunohistochemical analysis showed a significant increase of necrotic areas within the tumors after application of EmboCept S® and DC Bead® compared to Lipiodol® Ultra-Fluid. CONCLUSION The present study demonstrates that an intra-arterial therapy with EmboCept S® and DC Bead®, but not Lipiodol® Ultra-Fluid, results in a complete inhibition of rat colorectal liver metastatic growth.
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Affiliation(s)
- Christian Ziemann
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany.
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany.
- Present address: Department of Cardiovascular Surgery, University Heart Center, University Medical Center, University of Freiburg, Hugstetter Str. 55, 79104, Freiburg, Germany.
| | - Jonas Roller
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany
| | - Markus M Malter
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Kira Keller
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Otto Kollmar
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
- Present address: Department of General and Visceral Surgery, Helios Dr. Horst Schmidt Kliniken, Wiesbaden, Germany
| | - Matthias Glanemann
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany
| | - Michael D Menger
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Jens Sperling
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
- Present address: Department of General and Visceral Surgery, University Medical Center Göttingen, Göttingen, Germany
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Evaluation with endothelial nitric oxide synthase (eNOS) immunoreactivity of the protective role of astaxanthin on hepatorenal injury of remote organs caused by ischaemia reperfusion of the lower extremities. GASTROENTEROLOGY REVIEW 2019; 15:161-172. [PMID: 32550950 PMCID: PMC7294969 DOI: 10.5114/pg.2019.88620] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 08/09/2019] [Indexed: 02/07/2023]
Abstract
Introduction Ischemia and following reperfusion triggers local and systemic damage with the involvement of free oxygen radicals and inflammatory mediators. Although blood flow saves extremity from necrosis,multi organ dysfunction may progress and cause death of the patient. Aim The study aims to examine the effect of astaxanthin (AST) on the prevention of remote tissue injury resulting from lower extremity ischaemia–reperfusion (I/R). To elucidate the potential hepatoprotective and renoprotective effects of AST, in addition to histopathological findings, the intrahepatic and intrarenal kinetics of endothelial nitric oxide synthase (eNOS) during I/R were determined by using the immunohistochemical method. Material and methods Twenty-eight male Wistar albino rats were divided into four groups. For the control group, only the anaesthesia procedure (2 h) was conducted without I/R. In the I/R group, 2 h of reperfusion was conducted following ischaemia under anaesthesia. For the I/R group + AST, 7 days prior to ischaemia, 125 mg/kg AST was given with gavage, and 2 h of ischaemia and 2 h of reperfusion were conducted under anaesthesia. Following necropsy, liver and kidney tissue samples were fixed in 10% buffered formalin for 48 h for histopathological and immunohistochemical investigation. Results The histological analysis revealed that severe I/R hepatorenal injury such as inflammatory cell infiltration, dilatation in sinusoids and lumen of tubuli, congestion in glomerular capillaries, degeneration in hepatocyte and epithelial cells of tubuli, and necrosis was ameliorated by AST. Immunohistochemical studies showed that the I/R-induced elevation in eNOS expression was reduced by AST treatment. Conclusions In the case of acute lower extremity I/R, AST decreased the ischaemic injury in liver and renal tissues by protecting the microcirculation and providing a cytoprotective effect with vasodilatation.
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Necroptosis signaling in liver diseases: An update. Pharmacol Res 2019; 148:104439. [PMID: 31476369 DOI: 10.1016/j.phrs.2019.104439] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/11/2019] [Accepted: 08/29/2019] [Indexed: 02/07/2023]
Abstract
The apoptosis alternate cell death pathways are extensively studied in recent years and their significance has been well recognized. With identification of newer cell death pathways, the therapeutic opportunities to modulate cell death have indeed further extended. Necroptosis, among other apoptosis alternate pathways, has been immensely studied recently in different hepatic disease models. Receptor-interacting protein 1 (RIPK1), RIPK3 and mixed lineage kinase domain like (MLKL) seemed to be the key players to mediate necroptosis pathway. Initially, necroptosis seemed to be following the typical pathway. But recently diverse pathways and outcomes have been observed. With recent studies reporting diverse outcomes, the necroptosis signalling has become a lot more interesting and intricate. The typical RIPK1 signalling followed by RIPK3 and MLKL might not always be strictly followed. Although, necroptosis signalling has been intensively investigated in various disease conditions; however, there is still a need to further elaborate and understand the unique scaffolding and kinase properties and other signalling interactions of necroptosis signalling molecules.
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40
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Shi S, Verstegen MMA, Mezzanotte L, de Jonge J, Löwik CWGM, van der Laan LJW. Necroptotic Cell Death in Liver Transplantation and Underlying Diseases: Mechanisms and Clinical Perspective. Liver Transpl 2019; 25:1091-1104. [PMID: 31077562 PMCID: PMC6617733 DOI: 10.1002/lt.25488] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 04/22/2019] [Indexed: 12/13/2022]
Abstract
Cell death is a natural process for the turnover of aged cells, but it can also arise as a result of pathological conditions. Cell death is recognized as a key feature in both acute and chronic hepatobiliary diseases caused by drug, alcohol, and fat uptake; by viral infection; or after surgical intervention. In the case of chronic disease, cell death can lead to (chronic) secondary inflammation, cirrhosis, and the progression to liver cancer. In liver transplantation, graft preservation and ischemia/reperfusion injury are associated with acute cell death. In both cases, so-called programmed cell death modalities are involved. Several distinct types of programmed cell death have been described of which apoptosis and necroptosis are the most well known. Parenchymal liver cells, including hepatocytes and cholangiocytes, are susceptible to both apoptosis and necroptosis, which are triggered by distinct signal transduction pathways. Apoptosis is dependent on a proteolytic cascade of caspase enzymes, whereas necroptosis induction is caspase-independent. Moreover, different from the "silent" apoptotic cell death, necroptosis can cause a secondary inflammatory cascade, so-called necroinflammation, triggered by the release of various damage-associated molecular patterns (DAMPs). These DAMPs activate the innate immune system, leading to both local and systemic inflammatory responses, which can even cause remote organ failure. Therapeutic targeting of necroptosis by pharmacological inhibitors, such as necrostatin-1, shows variable effects in different disease models.
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Affiliation(s)
- Shaojun Shi
- Department of SurgeryErasmus MC ‐ University Medical CenterRotterdamthe Netherlands
| | | | - Laura Mezzanotte
- Department of RadiologyErasmus MC ‐ University Medical CenterRotterdamthe Netherlands
| | - Jeroen de Jonge
- Department of SurgeryErasmus MC ‐ University Medical CenterRotterdamthe Netherlands
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Yaron JR, Chen H, Ambadapadi S, Zhang L, Tafoya AM, Munk BH, Wakefield DN, Fuentes J, Marques BJ, Harripersaud K, Bartee MY, Davids JA, Zheng D, Rand K, Dixon L, Moyer RW, Clapp WL, Lucas AR. Serp-2, a virus-derived apoptosis and inflammasome inhibitor, attenuates liver ischemia-reperfusion injury in mice. J Inflamm (Lond) 2019; 16:12. [PMID: 31160886 PMCID: PMC6542089 DOI: 10.1186/s12950-019-0215-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 05/17/2019] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Ischemia-reperfusion injury (IRI) is an antigen-independent, innate immune response to arterial occlusion and ischemia with subsequent paradoxical exacerbation after reperfusion. IRI remains a critical problem after vessel occlusion and infarction or during harvest and surgery in transplants. After transplant, liver IRI (LIRI) contributes to increased acute and chronic rejection and graft loss. Tissue loss during LIRI has been attributed to local macrophage activation and invasion with excessive inflammation together with hepatocyte apoptosis and necrosis. Inflammatory and apoptotic signaling are key targets for reducing post-ischemic liver injury.Myxomavirus is a rabbit-specific leporipoxvirus that encodes a suite of immune suppressing proteins, often with extensive function in other mammalian species. Serp-2 is a cross-class serine protease inhibitor (serpin) which inhibits the inflammasome effector protease caspase-1 as well as the apoptotic proteases granzyme B and caspases 8 and 10. In prior work, Serp-2 reduced inflammatory cell invasion after angioplasty injury and after aortic transplantation in rodents. In this report, we explore the potential for therapeutic treatment with Serp-2 in a mouse model of LIRI. METHODS Wildtype (C57BL/6 J) mice were subjected to warm, partial (70%) hepatic ischemia for 90 min followed by treatment with saline or Serp-2 or M-T7, 100 ng/g/day given by intraperitoneal injection on alternate days for 5 days. M-T7 is a Myxomavirus-derived inhibitor of chemokine-GAG interactions and was used in this study for comparative analysis of an unrelated viral protein with an alternative immunomodulating mechanism of action. Survival, serum ALT levels and histopathology were assessed 24 h and 10 days post-LIRI. RESULTS Serp-2 treatment significantly improved survival to 85.7% percent versus saline-treated wildtype mice (p = 0.0135), while M-T7 treatment did not significantly improve survival (p = 0.2584). Liver viability was preserved by Serp-2 treatment with a significant reduction in serum ALT levels (p = 0.0343) and infarct scar thickness (p = 0.0016), but with no significant improvement with M-T7 treatment. Suzuki scoring by pathologists blinded with respect to treatment group indicated that Serp-2 significantly reduced hepatocyte necrosis (p = 0.0057) and improved overall pathology score (p = 0.0046) compared to saline. Immunohistochemistry revealed that Serp-2 treatment reduced macrophage infiltration into the infarcted liver tissue (p = 0.0197). CONCLUSIONS Treatment with Serp-2, a virus-derived inflammasome and apoptotic pathway inhibitor, improves survival after liver ischemia-reperfusion injury in mouse models. Treatment with a cross-class immune modulator provides a promising new approach designed to reduce ischemia-reperfusion injury, improving survival and reducing chronic transplant damage.
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Affiliation(s)
- Jordan R. Yaron
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ USA
| | - Hao Chen
- The Department of Tumor Surgery, Second Hospital of Lanzhou University and The Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou, China
| | - Sriram Ambadapadi
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ USA
| | - Liqiang Zhang
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ USA
| | - Amanda M. Tafoya
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ USA
| | - Barbara H. Munk
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ USA
| | | | - Jorge Fuentes
- Divisions of Cardiovascular Medicine and Rheumatology, Department of Medicine, University of Florida, Gainesville, FL USA
| | - Bruno J. Marques
- Divisions of Cardiovascular Medicine and Rheumatology, Department of Medicine, University of Florida, Gainesville, FL USA
| | - Krishna Harripersaud
- Divisions of Cardiovascular Medicine and Rheumatology, Department of Medicine, University of Florida, Gainesville, FL USA
| | - Mee Yong Bartee
- Divisions of Cardiovascular Medicine and Rheumatology, Department of Medicine, University of Florida, Gainesville, FL USA
| | - Jennifer A. Davids
- Divisions of Cardiovascular Medicine and Rheumatology, Department of Medicine, University of Florida, Gainesville, FL USA
| | - Donghang Zheng
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL USA
| | - Kenneth Rand
- Department of Pathology, University of Florida, Gainesville, FL USA
| | - Lisa Dixon
- Department of Pathology, University of Florida, Gainesville, FL USA
| | - Richard W. Moyer
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL USA
| | - William L. Clapp
- Department of Pathology, University of Florida, Gainesville, FL USA
| | - Alexandra R. Lucas
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ USA
- Divisions of Cardiovascular Medicine and Rheumatology, Department of Medicine, University of Florida, Gainesville, FL USA
- Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL USA
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Takahashi T, Yoshioka M, Uchinami H, Nakagawa Y, Otsuka N, Motoyama S, Yamamoto Y. Hepatic Stellate Cells Play a Functional Role in Exacerbating Ischemia-Reperfusion Injury in Rat Liver. Eur Surg Res 2019; 60:74-85. [PMID: 31132769 DOI: 10.1159/000499750] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 03/20/2019] [Indexed: 11/19/2022]
Abstract
PURPOSE The involvement of hepatic stellate cells (HSCs) with ischemia-reperfusion (I/R) injury in rat liver was examined using gliotoxin, which is known to induce HSC apoptosis. METHODS Male Sprague-Dawley rats were used. HSC was represented by a glial fibrillary acidic protein (GFAP)-positive cell. Liver ischemia was produced by cross-clamping the hepatoduodenal ligament. The degree of I/R injury was evaluated by a release of aminotransferases. Sinusoidal diameter and sinusoidal perfusion rates were examined using intravital fluorescence microscopy. RESULTS Gliotoxin significantly decreased the number of GFAP-positive cells 48 h after dosing (2.50 ± 0.19% [mean ± SD] in the nontreated group vs. 1.91 ± 0.46% in the gliotoxin-treated group). Liver damage was significantly suppressed by the pretreatment with gliotoxin. Sinusoidal diameters in zone 3 were wider in the gliotoxin group (10.25 ± 0.35 µm) than in the nontreated group (8.21 ± 0.50 µm). The sinusoidal perfusion rate was maintained as well in the gliotoxin group as in normal livers, even after I/R. CONCLUSIONS Pretreatment with gliotoxin significantly reduced the number of HSCs in the liver and further suppressed liver injury following I/R. It is strongly suggested that HSCs play a functional role in exacerbating the degree of I/R injury of the liver.
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Affiliation(s)
- Tomokazu Takahashi
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Masato Yoshioka
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan,
| | - Hiroshi Uchinami
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Yasuhiko Nakagawa
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Naohiko Otsuka
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Satoru Motoyama
- Department of Comprehensive Cancer Control, Akita University Graduate School of Medicine, Akita, Japan
| | - Yuzo Yamamoto
- Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan
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Evodiamine alleviates kidney ischemia reperfusion injury in rats: A biochemical and histopathological study. J Cell Biochem 2019; 120:17159-17166. [DOI: 10.1002/jcb.28976] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 03/14/2019] [Accepted: 03/22/2019] [Indexed: 12/12/2022]
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Kolachala VL, Palle SK, Shen M, Shenoi A, Shayakhmetov DM, Gupta NA. Influence of Fat on Differential Receptor Interacting Serine/Threonine Protein Kinase 1 Activity Leading to Apoptotic Cell Death in Murine Liver Ischemia Reperfusion Injury Through Caspase 8. Hepatol Commun 2019; 3:925-942. [PMID: 31334443 PMCID: PMC6601319 DOI: 10.1002/hep4.1352] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 03/11/2019] [Indexed: 12/14/2022] Open
Abstract
Current understanding is that receptor interacting serine/threonine protein kinase 1 (RIPK1) can lead to two distinct forms of cell death: RIPK3‐mediated necroptosis or caspase 8 (Casp8)‐mediated apoptosis. Here, we report that RIPK1 signaling is indispensable for protection from hepatocellular injury in a steatotic liver undergoing ischemia reperfusion injury (IRI) but not in the lean liver. In lean liver IRI, RIPK1‐mediated cell death is operational, leading to protection in RIP1 kinase‐dead knock‐in (RIPK1K45A) mice and necrostatin‐1s (Nec1s)‐treated lean wild‐type (WT) mice. However, when fed a high‐fat diet (HFD), RIPK1K45A‐treated and Nec1s‐treated WT mice undergoing IRI demonstrate exacerbated hepatocellular injury along with decreased RIPK1 ubiquitylation. Furthermore, we demonstrate that HFD‐fed RIPK3–/–/Casp8–/– mice show protection from IRI, but HFD‐fed RIPK3–/–/Casp8–/+ mice do not. We also show that blockade of RIPK1 leads to increased Casp8 activity and decreases mitochondrial viability. Conclusion: Although more studies are required, we provide important proof of concept for RIPK1 inhibition leading to distinctive outcomes in lean and steatotic liver undergoing IRI. Considering the rising incidence of nonalcoholic fatty liver disease (NAFLD) in the general population, it will be imperative to address this critical difference when treating patients with RIPK1 inhibitors. This study also presents a new target for drug therapy to prevent hepatocellular injury in NAFLD.
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Affiliation(s)
| | - Sirish K Palle
- Department of Pediatrics Emory University School of Medicine Atlanta GA
| | - Ming Shen
- Department of Pediatrics Emory University School of Medicine Atlanta GA
| | - Asha Shenoi
- Department of Pediatrics Emory University School of Medicine Atlanta GA
| | | | - Nitika A Gupta
- Department of Pediatrics Emory University School of Medicine Atlanta GA.,Transplant Services Children's Healthcare of Atlanta Atlanta GA
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Joung JY, Cho JH, Kim YH, Choi SH, Son CG. A literature review for the mechanisms of stress-induced liver injury. Brain Behav 2019; 9:e01235. [PMID: 30761781 PMCID: PMC6422711 DOI: 10.1002/brb3.1235] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 01/15/2019] [Accepted: 01/18/2019] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Experimental studies and clinical observations have shown that stress can damage hepatic tissue both directly and indirectly. Many studies have partially revealed the contributors of stress-induced liver injury; however, the whole process has not yet been uncovered. This review aims to summarize the mechanisms that have been proposed to be involved. METHODS A literature search was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed) in its entirety up to March 2018, and analyzed the animal-derived mechanistic studies on stress-induced liver injury. RESULTS The liver is the organ that meets and filters a mass of alien material, and then maintains immune tolerance under physiological conditions. Under stress conditions, however, immune tolerance is interrupted, which results in the induction of inflammation in the liver. Contributors to this process can be categorized as follows: hypoxia-reoxygenation, over-activation of Kupffer cells and oxidative stress, influx of gut-derived lipopolysaccharide and norepinephrine, and over-production of stress hormones and activation of the sympathetic nerve. CONCLUSIONS Psychological stress is associated with a variety of pathological conditions resulting in liver injury through multiple systems, including the sympathetic nervous and adrenocortical system. Mechanistic understanding of this phenomenon is important for the clinical practice of managing patients with hepatic disorders and should be explored further in the future.
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Affiliation(s)
- Jin-Yong Joung
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University, Daejeon, Korea
| | - Jung-Hyo Cho
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University, Daejeon, Korea
| | - Yun-Hee Kim
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine (KIOM), Daejeon, Korea
| | - Seung-Hoon Choi
- Department of Life Convergence, Graduate School of Dankook University, Yongin, Korea
| | - Chang-Gue Son
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Daejeon University, Daejeon, Korea
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Glycyrrhizin attenuates hepatic ischemia-reperfusion injury by suppressing HMGB1-dependent GSDMD-mediated kupffer cells pyroptosis. Int Immunopharmacol 2019; 68:145-155. [PMID: 30634142 DOI: 10.1016/j.intimp.2019.01.002] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 12/20/2018] [Accepted: 01/02/2019] [Indexed: 12/11/2022]
Abstract
Gasdermin D (GSDMD), a genetic substrate for inflammatory caspases, plays a central role in pyroptosis of macrophages and release of interleukin‑1β (IL-1β), but was mainly referred to microbial infection. High mobility group box-1 (HMGB1), served as an alarm molecule during various pathological process, has been widely recognized to be involved in liver ischemia-reperfusion (I/R). Glycyrrhizin, a natural anti-inflammatory and antiviral triterpene in clinical use, was recently referred to have ability to prevent I/R induced liver injury by inhibiting HMGB1 expression and activity. However, the mechanisms responsible for damage amelioration subsequently to HMGB1 inhibition during liver I/R remain enigmatic. This study was designed to explore the functional role and molecular mechanism of glycyrrhizin in the regulation of I/R induced liver injury. We found that liver I/R promotes GSDMD-mediated pyroptotic cell death of Kupffer cells, which was inhibited by glycyrrhizin. Interestingly, endogenous HMGB1, not exogenous one, was involved in hypoxia-reoxygenation (H/R) induced pyroptosis. Moreover, GSDMD knockdown protects kupffer cells against H/R induced pyroptosis in vitro. Here, we report, for the first time, that glycyrrhizin attenuated tissue damage and kupffer cells pyroptosis during liver ischemia-reperfusion injury (LIRI) and identify a previously unrecognized HMGB1- dependent GSDMD- mediated signaling pathway in the mechanism of kupffer cells pyroptosis induced by H/R. Our findings provide the first demonstration of GSDMD-determined pyroptotic cell death responsible for I/R induced release of IL-1β and this would provide a mandate to better understand the unconventional mechanisms of cytokine release in the sterile innate immune system.
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Lin L, Wang Q, Lu J, Lv S, Jiang S. Protective effects of tilapia fish oil and liposomes on ischemia reperfusion injury of rat liver. J Food Biochem 2018. [DOI: 10.1111/jfbc.12665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Affiliation(s)
- Lin Lin
- School of Food Science and Engineering Hefei University of Technology Hefei China
- Key Laboratory for Agricultural Products Processing of Anhui Province Hefei China
| | - Qianqian Wang
- School of Food Science and Engineering Hefei University of Technology Hefei China
| | - Jianfeng Lu
- School of Food Science and Engineering Hefei University of Technology Hefei China
- Key Laboratory for Agricultural Products Processing of Anhui Province Hefei China
| | - Shun Lv
- School of Food Science and Engineering Hefei University of Technology Hefei China
- Key Laboratory for Agricultural Products Processing of Anhui Province Hefei China
| | - Shaotong Jiang
- School of Food Science and Engineering Hefei University of Technology Hefei China
- Key Laboratory for Agricultural Products Processing of Anhui Province Hefei China
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NLRP3 Inflammasome and IL-33: Novel Players in Sterile Liver Inflammation. Int J Mol Sci 2018; 19:ijms19092732. [PMID: 30213101 PMCID: PMC6163521 DOI: 10.3390/ijms19092732] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 09/09/2018] [Accepted: 09/10/2018] [Indexed: 12/11/2022] Open
Abstract
In sterile liver inflammation, danger signals are released in response to tissue injury to alert the immune system; e.g., by activation of the NLRP3 inflammasome. Recently, IL-33 has been identified as a novel type of danger signal or “alarmin”, which is released from damaged and necrotic cells. IL-33 is a pleiotropic cytokine that targets a broad range of immune cells and exhibits pro- and anti-inflammatory properties dependent on the disease. This review summarizes the immunomodulatory roles of the NLRP3 inflammasome and IL-33 in sterile liver inflammation and highlights potential therapeutic strategies targeting these pathways in liver disease.
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49
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Xing Y, Li J, Li SP, Xi J, Ma N, Liu L, Wang JS, Cai JZ. MiR-27a-5p regulates apoptosis of liver ischemia-reperfusion injury in mice by targeting Bach1. J Cell Biochem 2018; 119:10376-10383. [PMID: 30145824 DOI: 10.1002/jcb.27383] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Accepted: 07/03/2018] [Indexed: 12/20/2022]
Abstract
Ischemia-reperfusion (I/R) injury causes cellular dysfunction and a series of immune or apoptotic reactions. Bach1 is a mammalian transcription factor that represses Hmox1, which encodes heme oxygenase-1 (HO-1) that can degrade heme into free iron, carbon monoxide, and biliverdin, to play an important role in antioxidant, anti-inflammatory, and antiapoptotic activities. MicroRNAs (miRNAs) can be found in a variety of eukaryotic cells and viruses, a class of noncoding small RNAs that are encoded by endogenous genes. The aims of this study were to determine whether miR-27a-5p targets Bach1 and regulates cellular death; the dual-luciferase reporter assay was used to detect this and the results showed that miR-27a-5p significantly decreased the luciferase activity of the Bach1 3'-untranslated region. MiR-27a-5p was increased in mice during hepatic I/R and Bach1 was decreased. By transfecting the AML12 cells with the mimic, inhibitor miR-27a-5p in hypoxia/reoxygenation (H/R) models showed that overexpression of miR-27a-5p decreased Bach1 messenger RNA, upregulated HO-1 expression, and promoted antiapoptotic Bcl-2 and downregulated proapoptotic caspase-3 gene expression. In contrast, the miR-27a-5p inhibitor yielded the opposite results. Meanwhile, transfection with Bach1 small interference RNA obviously upregulated the protein levels of HO-1 and resulted in an increase in Bcl-2 and a decrease in caspase-3 protein levels. Thus, we can conclude that miR-27a-5p is relevant to liver I/R injury and overexpression of miR-27a-5p may alleviate apoptosis in H/R injury by targeting Bach1 in vitro.
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Affiliation(s)
- Yu Xing
- Department of General Surgery, Tianjin Third Central Hospital, Tianjin, China
| | - Jing Li
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Shi-Peng Li
- Department of General Surgery, Jiaozuo People's Hospital, Xinxiang Medical University, Jiaozuo, China
| | - Jiri Xi
- Department of Liver Transplantion, Oriental Organ Transplant Center, Tianjin First Central Hospital, Tianjin, China
| | - Ning Ma
- Department of Liver Transplantion, Oriental Organ Transplant Center, Tianjin First Central Hospital, Tianjin, China
| | - Lei Liu
- Department of Liver Transplantion, Oriental Organ Transplant Center, Tianjin First Central Hospital, Tianjin, China
| | - Jin-Shan Wang
- Department of Liver Transplantion, Oriental Organ Transplant Center, Tianjin First Central Hospital, Tianjin, China
| | - Jin-Zhen Cai
- Department of Liver Transplantion, Oriental Organ Transplant Center, Tianjin First Central Hospital, Tianjin, China
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50
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Wang W, Xiao Q, Hu XY, Liu ZZ, Zhang XJ, Xia ZP, Ye QF, Niu Y. Mild Hypothermia Pretreatment Attenuates Liver Ischemia Reperfusion Injury Through Inhibiting c-Jun NH2-terminal Kinase Phosphorylation in Rats. Transplant Proc 2018; 50:259-266. [PMID: 29407320 DOI: 10.1016/j.transproceed.2017.12.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 11/22/2017] [Accepted: 12/12/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Mild hypothermia is known to be protected against ischemia reperfusion (IR) injury. But the exact mechanisms of protection have not yet been fully understood and its usage has been limited. Mild hypothermia pretreatment (MHP) is used to investigate the mechanisms of the protective effects against liver IR injury. METHODS Anesthetized male Sprague-Dawley rats were randomly divided into five groups including the normal group (N), sham group (S), MHP group, normothermia pretreatment (NP) + IR group, and the MHP + IR group. In the pretreatment groups, mild hypothermia (32.2 ± 0.3°C) and normothermia (37 ± 0.5°C) pretreatment were applied for 2 hours, respectively. Then the IR groups suffered partial (70%) hepatic ischemia for 1 hour and reperfusion for 6 hours. At last, hepatic injury, apoptosis, and protein expression were assessed. RESULTS Levels of serum alanine transaminase, hepatic injury, hepatocyte apoptosis, and c-Jun N-terminal kinase (JNK) phosphorylation were significantly higher in the IR groups. But when compared to NP, all these changes induced by IR were markedly attenuated by MHP. Serum alanine transaminase levels were 383.4 ± 13.1U/L in the MHP + IR group and 951.3 ± 39.4 U/L in the NP + IR group. The histologic score of liver injury in the MHP + IR group was 4.83 ± 1.17, whereas in the NP + IR group it was 10.5 ± 1.05. The proportion of apoptotic cells in the MHP + IR group was 11.58 ± 0.60, but in the NP + IR group, it was 44.95 ± 1.61. The phosphorylation of JNK was also significantly reduced in the MHP + IR group. All these differences are statistically significant (P < .05). CONCLUSIONS MHP could markedly reduce liver IR injury, and these protective effects may be mainly exerted via inhibition of JNK phosphorylation.
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Affiliation(s)
- W Wang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Q Xiao
- The Third Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha, China
| | - X-Y Hu
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Z-Z Liu
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - X-J Zhang
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Z-P Xia
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China
| | - Q-F Ye
- Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, China; The Third Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha, China.
| | - Y Niu
- The Third Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha, China
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