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Yan F, Zhang Q, Mutembei BM, Wang C, Alhajeri ZA, Pandit K, Zhang F, Zhang K, Yu Z, Fung KM, Elgenaid SN, Parrack P, Ali W, Hostetler CA, Milam AN, Nave B, Squires R, Martins PN, Battula NR, Potter S, Pan C, Chen Y, Tang Q. Comprehensive Evaluation of Human Donor Liver Viability with Polarization-Sensitive Optical Coherence Tomography. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.03.31.25321497. [PMID: 40236439 PMCID: PMC11998830 DOI: 10.1101/2025.03.31.25321497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Human liver transplantation is severely constrained by a critical shortage of donor livers, with approximately one quarter of patients on the waiting list dying due to the scarcity of viable organs. Current liver viability assessments, which rely on invasive pathological methods, are hampered by limited sampling from biopsies, particularly in marginal livers from extended criteria donors (ECD) intended to expand the donor pool. Consequently, there is a pressing need for more comprehensive and non-invasive evaluation techniques to meet the escalating demand for liver transplants. In this study, we propose the use of polarization-sensitive optical coherence tomography (PS-OCT) to perform a thorough viability evaluation across the entire surface of donor livers. PS-OCT imaging was conducted on multiple regions, achieving near-complete coverage of the liver surface, and the findings were cross-validated with histopathological evaluations. The analysis of hepatic parameters derived from pathology highlighted tissue heterogeneity. Leveraging machine learning and texture analysis, we quantified hepatic steatosis, fibrosis, inflammation, and necrosis, and established strong correlations (≥ 80%) between PS-OCT quantifications and pathological assessments. PS-OCT offers a non-invasive assessment of liver viability by quantifying hepatic parenchymal parameters across the entire donor liver, significantly complementing current pathological analysis. These results suggest that PS-OCT provides a robust, non-invasive approach to assessing donor liver viability, which could potentially decrease the discard rate of higher risk livers, thereby expanding the donor pool and reducing the inadvertent use of those livers unsuitable for transplantation.
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Liu J, Yin D, Zhang W, Wang X, James TD, Li P, Tang B. A multifunctional "three-in-one" fluorescent theranostic system for hepatic ischemia-reperfusion injury. Chem Sci 2024; 15:19820-19833. [PMID: 39568886 PMCID: PMC11575585 DOI: 10.1039/d4sc04962d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 11/01/2024] [Indexed: 11/22/2024] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is the main cause of postoperative liver dysfunction and liver failure. Traditional separation of HIRI diagnosis and therapy confers several disadvantages, including the inability to visualize the therapeutic and asynchronous action. However, developing a versatile material with integrated diagnosis and treatment for HIRI remains a great challenge. Given that hypochlorous acid (HOCl) plays a crucial oxidative role in HIRI, we developed a single-component multifunctional fluorescent theranostic platform (MB-Gly) with a "three-in-one" molecular design incorporating a near-infrared fluorophore methylene blue, glycine and a HOCl-response unit, which could not only provide real-time visualization of HIRI but also boost targeted drug delivery. Using MB-Gly, we were able to achieve real-time and dynamic monitoring of HOCl during HIRI in hepatocytes and mouse livers and reduce the liver damage in hepatocytes and mice. RNA sequencing illustrated the therapeutic role of MB-Gly associated with changes in gene expression related to apoptosis, oxidative stress, metabolism and inflammation. To the best of our knowledge, this is the first multifunctional fluorescent theranostic system for HIRI reported to date. Our smart "three-in-one" approach shines light on the etiology and pathogenesis of HIRI, providing profound insights into the development of potential therapeutic targets.
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Affiliation(s)
- Jihong Liu
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
- Key Laboratory for Advanced Materials, Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Shanghai Key Laboratory of Functional Materials Chemistry, Institute of Fine Chemicals, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology Shanghai 200237 People's Republic of China
| | - Dongni Yin
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
| | - Wen Zhang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
| | - Xin Wang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
| | - Tony D James
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
- Department of Chemistry, University of Bath Bath BA2 7AY UK
- School of Chemistry and Chemical Engineering, Henan Normal University Xinxiang 453007 People's Republic of China
| | - Ping Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
- College of Chemistry and Chemical Engineering, Northwest Normal University Lanzhou 730070 People's Republic of China
| | - Bo Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University China
- Laoshan Laboratory Qingdao 266237 People's Republic of China
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You Y, Qian Z, Jiang Y, Chen L, Wu D, Liu L, Zhang F, Ning X, Zhang Y, Xiao J. Insights into the pathogenesis of gestational and hepatic diseases: the impact of ferroptosis. Front Cell Dev Biol 2024; 12:1482838. [PMID: 39600338 PMCID: PMC11588751 DOI: 10.3389/fcell.2024.1482838] [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: 08/20/2024] [Accepted: 10/30/2024] [Indexed: 11/29/2024] Open
Abstract
Ferroptosis, a distinct form of non-apoptotic cell death characterized by iron dependency and lipid peroxidation, is increasingly linked to various pathological conditions in pregnancy and liver diseases. It plays a critical role throughout pregnancy, influencing processes such as embryogenesis, implantation, and the maintenance of gestation. A growing body of evidence indicates that disruptions in these processes can precipitate pregnancy-related disorders, including pre-eclampsia (PE), gestational diabetes mellitus (GDM), and intrahepatic cholestasis of pregnancy (ICP). Notably, while ICP is primarily associated with elevated maternal serum bile acid levels, its precise etiology remains elusive. Oxidative stress induced by bile acid accumulation is believed to be a significant factor in ICP pathogenesis. Similarly, the liver's susceptibility to oxidative damage underscores the importance of lipid metabolism dysregulation and impaired iron homeostasis in the progression of liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cholestatic liver injury, autoimmune hepatitis (AIH), acute liver injury, viral hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). This review discusses the shared signaling mechanisms of ferroptosis in gestational and hepatic diseases, and explores recent advances in understanding the mechanisms of ferroptosis and its potential role in the pathogenesis of gestational and hepatic disorders, with the aim of identifying viable therapeutic targets.
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Affiliation(s)
- Yilan You
- Departments of Obstetrics and Gynecology, Wuxi Maternal and Child Healthcare Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Zhiwen Qian
- Departments of Obstetrics and Gynecology, Wuxi Maternal and Child Healthcare Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Ying Jiang
- Departments of Obstetrics and Gynecology, Wuxi Maternity and Child Healthcare Hospital, Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Lingyan Chen
- Departments of Obstetrics and Gynecology, Wuxi Maternal and Child Healthcare Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Danping Wu
- Departments of Obstetrics and Gynecology, Wuxi Maternity and Child Healthcare Hospital, Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Lu Liu
- Departments of Obstetrics and Gynecology, Wuxi Maternity and Child Healthcare Hospital, Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Feng Zhang
- Departments of Obstetrics and Gynecology, Wuxi Maternal and Child Healthcare Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Xin Ning
- Departments of Obstetrics and Gynecology, Wuxi Maternity and Child Healthcare Hospital, Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Yan Zhang
- Departments of Obstetrics and Gynecology, Wuxi Maternal and Child Healthcare Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
- Departments of Obstetrics and Gynecology, Wuxi Maternity and Child Healthcare Hospital, Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, China
| | - Jianping Xiao
- Departments of Obstetrics and Gynecology, Wuxi Maternal and Child Healthcare Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
- Departments of Obstetrics and Gynecology, Wuxi Maternity and Child Healthcare Hospital, Women’s Hospital of Jiangnan University, Jiangnan University, Wuxi, China
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Chen C, Feng D, Wang Y, Yao T, Mackowiak B, Gao B. Necrotic Liver Lesion Resolution: Another Mode of Liver Regeneration. Semin Liver Dis 2024; 44:333-342. [PMID: 38955211 DOI: 10.1055/a-2358-9505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/04/2024]
Abstract
The liver has the great ability to regenerate after partial resection or injury, and the mechanisms underlying liver regeneration have been extensively investigated. Interestingly, acute liver injuries triggered by various etiologies are associated with the formation of necrotic lesions, and such necrotic lesions are also rapidly resolved. However, how necrotic liver lesions are repaired has not been carefully investigated until recently. In this review, we briefly summarize the spatiotemporal process of necrotic liver lesion resolution in several liver injury models including immune-mediated liver injury and drug-induced liver injury. The roles of liver nonparenchymal cells and infiltrating immune cells in controlling necrotic liver lesion resolution are discussed, which may help identify potential therapies for acute liver injury and failure.
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Affiliation(s)
- Cheng Chen
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Yang Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Tiantian Yao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Bryan Mackowiak
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
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Jain R, Ajenu EO, Lopera Higuita M, Hafiz EOA, Muzikansky A, Romfh P, Tessier SN. Real-time monitoring of mitochondrial oxygenation during machine perfusion using resonance Raman spectroscopy predicts organ function. Sci Rep 2024; 14:7328. [PMID: 38538723 PMCID: PMC10973340 DOI: 10.1038/s41598-024-57773-w] [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: 12/11/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024] Open
Abstract
Organ transplantation is a life-saving procedure affecting over 100,000 people on the transplant waitlist. Ischemia reperfusion injury (IRI) is a major challenge in the field as it can cause post-transplantation complications and limit the use of organs from extended criteria donors. Machine perfusion technology has the potential to mitigate IRI; however, it currently fails to achieve its full potential due to a lack of highly sensitive and specific assays to assess organ quality during perfusion. We developed a real-time and non-invasive method of assessing organs during perfusion based on mitochondrial function and injury using resonance Raman spectroscopy. It uses a 441 nm laser and a high-resolution spectrometer to quantify the oxidation state of mitochondrial cytochromes during perfusion. This index of mitochondrial oxidation, or 3RMR, was used to understand differences in mitochondrial recovery of cold ischemic rodent livers during machine perfusion at normothermic temperatures with an acellular versus cellular perfusate. Measurement of the mitochondrial oxidation revealed that there was no difference in 3RMR of fresh livers as a function of normothermic perfusion when comparing acellular versus cellular-based perfusates. However, following 24 h of static cold storage, 3RMR returned to baseline faster with a cellular-based perfusate, yet 3RMR progressively increased during perfusion, indicating injury may develop over time. Thus, this study emphasizes the need for further refinement of a reoxygenation strategy during normothermic machine perfusion that considers cold ischemia durations, gradual recovery/rewarming, and risk of hemolysis.
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Affiliation(s)
- Rohil Jain
- Center for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA
- Shriners Children's Hospital, Boston, MA, USA
| | - Emmanuella O Ajenu
- Center for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA
- Shriners Children's Hospital, Boston, MA, USA
| | - Manuela Lopera Higuita
- Center for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA
- Shriners Children's Hospital, Boston, MA, USA
| | - Ehab O A Hafiz
- Department of Electron Microscopy Research, Clinical Laboratory Division, Theodor Bilharz Research Institute, Giza, Egypt
| | - Alona Muzikansky
- Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA
| | | | - Shannon N Tessier
- Center for Engineering in Medicine and Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA.
- Shriners Children's Hospital, Boston, MA, USA.
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Wu S, Cheng C, Zhu W, Yang J, He BB, Li S, Wang X, Guo H, Chen D, Guo YM. Whole transcriptome analysis reveals that immune infiltration- lncRNAs are related to cellular apoptosis in liver transplantation. Front Immunol 2023; 14:1152742. [PMID: 37081883 PMCID: PMC10110847 DOI: 10.3389/fimmu.2023.1152742] [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: 01/31/2023] [Accepted: 03/20/2023] [Indexed: 04/22/2023] Open
Abstract
Introduction In most instances, liver transplantation (LT) is the only available treatment for end-stage liver diseases. However, LT could also induce serious liver diseases or injury, and the underlying mechanisms of LT-induced complications remain largely unknown, especially the mechanisms of the dysfunction of the immune system mediated by long noncoding RNAs (lncRNAs). Methods In this study, we globally analyzed the proportion of immune cells by using the transcriptome sequencing data (RNA-seq) of needle-core liver biopsies from pre- and post-transplantation recipients. Dysregulated lncRNAs were found to be correlated with the altered fractions of immune cells. We finally explored the potential targets of dysregulated lncRNAs and analyzed their functions in LT. Results We found that in the samples, some immune cells changed significantly after LT, including CD4 T cells, NK cells and mast cells. The proportion of macrophages in different polarization states also changed significantly, with M0 macrophages increasing and M2 macrophages decreasing. Through weighted gene co-expression network analysis (WGCNA), 7 gene expression modules related to LT were identified. These modules were related to changes in the proportion of different immune cells. The functions of these modules represent the response modes of different functional genes after LT. Among these modules, MEtan and MEyellow modules were primarily enriched in apoptosis and inflammatory pathways. Twelve immunity-related lncRNAs were identified for the first time, and the regulatory network co-changing with immune cells was also identified. The co-expressed genes of these lncRNAs were highly enriched in apoptosis-related pathways. Many apoptosis-related genes were found to be up-regulated after LT. Discussion In summary, we speculated that the expression and regulation of these apoptotic genes may be related to the changes in the proportion of immune cells. Some of these lncRNAs and apoptosis-related genes have been reported to be related to cell proliferation and apoptosis. They are also potential biomarkers or therapeutic targets.
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Affiliation(s)
- Shile Wu
- Soochow University, Suzhou, Jiangsu, China
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
| | - Chao Cheng
- Center for Genome Analysis, Wuhan Ruixing Biotechnology Co., Ltd, Wuhan, China
| | - Wenjun Zhu
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
| | - Jinyu Yang
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
| | - Bei-bei He
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
| | - Song Li
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
| | - Xinsheng Wang
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
| | - Hao Guo
- Center for Genome Analysis, Wuhan Ruixing Biotechnology Co., Ltd, Wuhan, China
| | - Dong Chen
- Center for Genome Analysis, Wuhan Ruixing Biotechnology Co., Ltd, Wuhan, China
- *Correspondence: Ya-min Guo, ; Dong Chen,
| | - Ya-min Guo
- General Surgery Department, Qinghai Provincial People’s Hospital, Xining, Qinghai, China
- *Correspondence: Ya-min Guo, ; Dong Chen,
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Hui B, Shu Y, Yang D, Wang Z, Zhang L, Lei N, Yang Z. Sinomenine pretreatment alleviates hepatic ischemia/reperfusion injury through activating Nrf-2/HO-1 pathway. Immun Inflamm Dis 2022; 10:e700. [PMID: 36169257 PMCID: PMC9517062 DOI: 10.1002/iid3.700] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 08/19/2022] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION Ischemia-reperfusion (IR) injury is induced by an interrupted blood flow and succeeding blood restoration, which is common in the operation of liver transplantation. Serious IR injury is a major reason leading to transplant failure. Hepatic IR is featured by excessive inflammatory response, oxidative stress, and apoptosis. Sinomenine (SIN) is derived from the herb Sinomeniumacutum and shows properties of anti-inflammation and antiapoptosis in multiple IR-induced organ injuries. However, the effect of SIN in hepatic IR has not been investigated. METHODS This study aims to investigate impacts of SIN on hepatic IR and the involved signaling pathway. An in vivo rat model of syngeneic orthotopic liver transplantation was constructed to induce the hepatic IR injury. RESULTS Results showed that SIN pretreatment provided a significant prevention against IR-induced hepatic injury as manifested by the downregulated activities of serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, the alleviatedoxidative stress as shown by increased activities of serum superoxide dismutase and glutathione peroxidase, and decreased serum level of malondialdehyde, the suppressed inflammatory responses as shown by downregulated serum tumor necrosis factor-α, interleukin (IL)-6, IL-8 levels, and upregulated IL-10 level, as well as attenuated apoptosis as shown by decreased protein expression of cleaved caspase-3 and -9. In line with these results, SIN pretreatment also alleviatedthe hepatic histopathological changes in IR rats and induced Nrf-2/HO-1 activation. The use of brusatol, a selective inhibitor for Nrf-2, effectively reversed SIN-induced above effects. CONCLUSIONS Altogether, our results demonstrate that SIN might be a useful therapeutic drug for preventing hepatic IR-induced injury during clinical liver transplantation.
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Affiliation(s)
- Bo Hui
- Department of General Surgery Unit‐4The Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Yantao Shu
- Department of General Surgery Unit‐4The Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Dandan Yang
- Department of General Surgery Unit‐4The Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Zhidong Wang
- Department of General Surgery Unit‐4The Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Li Zhang
- Department of General Surgery Unit‐4The Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Nina Lei
- Department of General Surgery Unit‐4The Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Zhengan Yang
- Department of General Surgery Unit‐4The Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
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Transcriptomic Hallmarks of Ischemia-Reperfusion Injury. Cells 2021; 10:cells10071838. [PMID: 34360008 PMCID: PMC8305649 DOI: 10.3390/cells10071838] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/07/2021] [Accepted: 07/09/2021] [Indexed: 12/15/2022] Open
Abstract
Ischemia reperfusion injury (IRI) is associated with a broad array of life-threatening medical conditions including myocardial infarct, cerebral stroke, and organ transplant. Although the pathobiology and clinical manifestations of IRI are well reviewed by previous publications, IRI-related transcriptomic alterations are less studied. This study aimed to reveal a transcriptomic hallmark for IRI by using the RNA-sequencing data provided by several studies on non-human preclinical experimental models. In this regard, we focused on the transcriptional responses of IRI in an acute time-point up to 48 h. We compiled a list of highly reported genes in the current literature that are affected in the context of IRI. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and found many of the up-regulated genes to be involved in cell survival, cell surface signaling, response to oxidative stress, and inflammatory response, while down-regulated genes were predominantly involved in ion transport. Furthermore, by GO analysis, we found that multiple inflammatory and stress response processes were affected after IRI. Tumor necrosis factor alpha (TNF) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways were also highlighted in the Kyoto Encyclopedia of Genes and Genomes enrichment analysis. In the last section, we discuss the treatment approaches and their efficacy for IRI by comparing RNA sequencing data from therapeutic interventions with the results of our cross-comparison of differentially expressed genes and pathways across IRI.
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Belon AR, Tannuri ACA, de Albuquerque Rangel Moreira D, Figueiredo JL, da Silva AM, Serafini S, Guimarães RR, Faria CS, de Alexandre AS, Gonçalves JO, Paes VR, Tannuri U. Impact of Three Methods of Ischemic Preconditioning on Ischemia-Reperfusion Injury in a Pig Model of Liver Transplantation. J INVEST SURG 2021; 35:900-909. [PMID: 34180750 DOI: 10.1080/08941939.2021.1933274] [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: 12/11/2022]
Abstract
BACKGROUND Ischemic preconditioning (IPC), either direct (DIPC) or remote (RIPC), is a procedure aimed at reducing the harmful effects of ischemia-reperfusion (I/R) injury. OBJECTIVES To assess the local and systemic effects of DIPC, RIPC, and both combined, in the pig liver transplant model. MATERIALS AND METHODS Twenty-four pigs underwent orthotopic liver transplantation and were divided into 4 groups: control, direct donor preconditioning, indirect preconditioning at the recipient, and direct donor with indirect recipient preconditioning. The recorded parameters were: donor and recipient weight, graft-to-recipient weight ratio (GRWR), surgery time, warm and cold ischemia time, and intraoperative hemodynamic values. Blood samples were collected before native liver removal (BL) and at 0 h, 1 h, 3 h, 6 h, 12 h, 18 h, and 24 h post-reperfusion for the biochemical tests: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), creatinine, BUN (blood urea nitrogen), lactate, total and direct bilirubin. Histopathological examination of liver, gut, kidney, and lung fragments were performed, as well as molecular analyses for expression of the apoptosis-related BAX (pro-apoptotic) and Bcl-XL (anti-apoptotic) genes, eNOS (endothelial nitric oxide synthase) gene, and IL-6 gene related to inflammatory ischemia-reperfusion injury, using real-time polymerase chain reaction (RT-PCR). RESULTS There were no differences between the groups regarding biochemical and histopathological parameters. We found a reduced ratio between the expression of the BAX gene and Bcl-XL in the livers of animals with IPC versus the control group. CONCLUSIONS DIPC, RIPC or a combination of both, produce beneficial effects at the molecular level without biochemical or histological changes.
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Affiliation(s)
- Alessandro Rodrigo Belon
- Laboratory of Experimental Surgery (LIM26), Department of Surgery, University of Sao Paulo Medical School, Sao Paulo, Brazil.,Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Ana Cristina Aoun Tannuri
- Laboratory of Experimental Surgery (LIM26), Department of Surgery, University of Sao Paulo Medical School, Sao Paulo, Brazil.,Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Daniel de Albuquerque Rangel Moreira
- Laboratory of Experimental Surgery (LIM26), Department of Surgery, University of Sao Paulo Medical School, Sao Paulo, Brazil.,Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Jose Luiz Figueiredo
- Laboratory of Experimental Surgery (LIM26), Department of Surgery, University of Sao Paulo Medical School, Sao Paulo, Brazil.,Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Alessandra Matheus da Silva
- Laboratory of Experimental Surgery (LIM26), Department of Surgery, University of Sao Paulo Medical School, Sao Paulo, Brazil.,Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Suellen Serafini
- Laboratory of Experimental Surgery (LIM26), Department of Surgery, University of Sao Paulo Medical School, Sao Paulo, Brazil.,Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Raimundo Renato Guimarães
- Laboratory of Experimental Surgery (LIM26), Department of Surgery, University of Sao Paulo Medical School, Sao Paulo, Brazil.,Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Caroline Silverio Faria
- Laboratory of Experimental Surgery (LIM26), Department of Surgery, University of Sao Paulo Medical School, Sao Paulo, Brazil.,Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Alcione Sanches de Alexandre
- Laboratory of Experimental Surgery (LIM26), Department of Surgery, University of Sao Paulo Medical School, Sao Paulo, Brazil.,Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Josiane Oliveira Gonçalves
- Laboratory of Experimental Surgery (LIM26), Department of Surgery, University of Sao Paulo Medical School, Sao Paulo, Brazil.,Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Vitor Ribeiro Paes
- Laboratory of Experimental Surgery (LIM26), Department of Surgery, University of Sao Paulo Medical School, Sao Paulo, Brazil.,Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Uenis Tannuri
- Laboratory of Experimental Surgery (LIM26), Department of Surgery, University of Sao Paulo Medical School, Sao Paulo, Brazil.,Pediatric Surgery Division, Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), University of Sao Paulo Medical School, Sao Paulo, Brazil
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Gu XX, Xu XX, Liao HH, Wu RN, Huang WM, Cheng LX, Lu YW, Mo J. Dexmedetomidine hydrochloride inhibits hepatocyte apoptosis and inflammation by activating the lncRNA TUG1/miR-194/SIRT1 signaling pathway. J Inflamm (Lond) 2021; 18:20. [PMID: 34039367 PMCID: PMC8157629 DOI: 10.1186/s12950-021-00287-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 05/06/2021] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Liver injury seriously threatens the health of people. Meanwhile, dexmedetomidine hydrochloride (DEX) can protect against liver injury. However, the mechanism by which Dex mediates the progression of liver injury remains unclear. Thus, this study aimed to investigate the function of DEX in oxygen and glucose deprivation (OGD)-treated hepatocytes and its underlying mechanism. METHODS In order to investigate the function of DEX in liver injury, WRL-68 cells were treated with OGD. Cell viability was measured by MTT assay. Cell apoptosis was detected by flow cytometry. Inflammatory cytokines levels were measured by ELISA assay. The interaction between miR-194 and TUG1 or SIRT1 was detected by dual-luciferase reporter. Gene and protein levels were measured by qPCR or western blotting. RESULTS DEX notably reversed OGD-induced inflammation and apoptosis in WRL-68 cell. Meanwhile, the effect of OGD on TUG1, SIRT1 and miR-194 expression in WRL-68 cells was reversed by DEX treatment. However, TUG1 knockdown or miR-194 overexpression reversed the function of DEX in OGD-treated WRL-68 cells. Moreover, TUG1 could promote the expression of SIRT1 by sponging miR-194. Furthermore, knockdown of TUG1 promoted OGD-induced cell growth inhibition and inflammatory responses, while miR-194 inhibitor or SIRT1 overexpression partially reversed this phenomenon. CONCLUSIONS DEX could suppress OGD-induced hepatocyte apoptosis and inflammation by mediation of TUG1/miR-194/SIRT1 axis. Therefore, this study might provide a scientific basis for the application of DEX on liver injury treatment.
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Affiliation(s)
- Xiao-Xia Gu
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, No.57, South People's Avenue, Xiashan District, 524001, Zhanjiang, Guangdong Province, P.R. China
| | - Xiao-Xia Xu
- Operating room, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong Province, P.R. China
| | - Hui-Hua Liao
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, No.57, South People's Avenue, Xiashan District, 524001, Zhanjiang, Guangdong Province, P.R. China
| | - Ruo-Na Wu
- Operating room, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong Province, P.R. China
| | - Wei-Ming Huang
- Department of Thyroid and Breast Surgery, Affiliated Hospital of Guangdong Medical University, 524001, Zhanjiang, Guangdong Province, P.R. China
| | - Li-Xia Cheng
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, No.57, South People's Avenue, Xiashan District, 524001, Zhanjiang, Guangdong Province, P.R. China
| | - Yi-Wen Lu
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, No.57, South People's Avenue, Xiashan District, 524001, Zhanjiang, Guangdong Province, P.R. China
| | - Jian Mo
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, No.57, South People's Avenue, Xiashan District, 524001, Zhanjiang, Guangdong Province, P.R. China.
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Chen L, Ma K, Fan H, Wang X, Cao T. Exogenous hydrogen sulfide protects against hepatic ischemia/reperfusion injury by inhibiting endoplasmic reticulum stress and cell apoptosis. Exp Ther Med 2021; 22:799. [PMID: 34093755 PMCID: PMC8170662 DOI: 10.3892/etm.2021.10231] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 05/05/2021] [Indexed: 12/11/2022] Open
Abstract
The aim of the present study was to explore the effect of exogenous hydrogen sulphide (H2S) on endoplasmic reticulum (ER) stress (ERS) in a rat model of hepatic ischemia/reperfusion (I/R) injury. A total of 48 Sprague-Dawley rats were randomly divided into four groups (n=12/group) as follows: Sham, I/R, I/R preceded by NaHS (I/R-NaHS) and I/R preceded by L-C-propargylglycine (PAG), a H2S inhibitor (I/R-PAG). With the exception of the sham group, the rats in the other groups were subjected to 30 min hepatic warm ischemia followed by reperfusion for 6 or 12 h. Hepatic function was evaluated by serum concentrations of alanine aminotransferase (ALT). Apoptosis of hepatic cells was assessed by TUNEL staining and measurement of caspase-12 expression. The expression levels of ERS-associated proteins and mRNAs of pancreatic ER eukaryotic translation initiation factor-2a kinase (PERK), activating transcription factor-6 (ATF6), glucose-regulated protein (GRP) 78, TNF-receptor-associated factor (TRAF)-2, C/EBP homologous protein (CHOP) and caspase-12 were also measured by western blotting and reverse transcription-quantitative PCR. The serum concentrations of ALT in the I/R and I/R-PAG groups were found to be significantly higher compared with those in the sham and I/R-NaHS groups after 6 h of reperfusion; in addition, the ALT level returned to normal in the I/R group, while it increased further in the I/R-PAG group after 12 h of reperfusion. A higher cell apoptosis rate was observed in the I/R and I/R-PAG groups and the highest cell apoptosis rate was observed in the I/R-PAG group; correspondingly, the expression of caspase-12 was increased in the I/R and I/R-PAG groups. H2S appeared to significantly attenuate hepatic I/R-induced ERS response, as indicated by the decreased expression of ATF6, PERK, GRP78, TRAF2 and CHOP. Endogenous H2S may serve a hepatoprotective function after I/R, and inhibition of endogenous H2S results in aggravation of I/R damage. Exogenous H2S was shown to inhibit ERS-related gene expression, leading to suppression of inflammatory reaction and improvement of I/R damage. Therefore, exogenous H2S has therapeutic potential to alleviate hepatic I/R injury.
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Affiliation(s)
- Liang Chen
- Department of General Surgery, Affiliated Huadu Hospital of Southern Medical University (People's Hospital of Huadu District), Guangzhou, Guangdong 510800, P.R. China
| | - Keqiang Ma
- Department of General Surgery, Affiliated Huadu Hospital of Southern Medical University (People's Hospital of Huadu District), Guangzhou, Guangdong 510800, P.R. China
| | - Haining Fan
- Department of Hepatopancreatobiliary Surgery, the Affiliated Hospital of Qinghai University, Xining, Qinghai 810001, P.R. China
| | - Xiaolong Wang
- Department of General Surgery, Affiliated Huadu Hospital of Southern Medical University (People's Hospital of Huadu District), Guangzhou, Guangdong 510800, P.R. China
| | - Tiansheng Cao
- Department of General Surgery, Affiliated Huadu Hospital of Southern Medical University (People's Hospital of Huadu District), Guangzhou, Guangdong 510800, P.R. China
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12
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Ueda J, Mamada Y, Taniai N, Yoshioka M, Hirakata A, Kawano Y, Shimizu T, Kanda T, Takata H, Kondo R, Kaneya Y, Aoki Y, Yoshida H. Massage of the Hepatoduodenal Ligament Recovers Portal Vein Flow Immediately After the Pringle Maneuver in Hepatectomy. World J Surg 2021; 44:3086-3092. [PMID: 32394011 DOI: 10.1007/s00268-020-05570-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND The Pringle maneuver is often used in liver surgery to minimize bleeding during liver transection. Many authors have demonstrated that intermittent use of the Pringle maneuver is safe and effective when performed appropriately. However, some studies have reported that the Pringle maneuver is a significant risk factor for portal vein thrombosis. In this study, we evaluated the effectiveness of portal vein flow after the Pringle maneuver and the impact that massaging the hepatoduodenal ligament after the Pringle maneuver has on portal vein flow. MATERIALS AND METHODS Patients treated with the Pringle maneuver for hepatectomies performed to treat hepatic disease at our hospital between August 2014 and March 2019 were included in the study (N = 101). We divided these patients into two groups, a massage group and nonmassage group. We measured portal vein blood flow with ultrasonography before and after clamping of the hepatoduodenal ligament. We also evaluated laboratory data after the hepatectomy. RESULTS Portal vein flow was significantly lower after the Pringle maneuver than before clamping of the hepatoduodenal ligament. The portal vein flow after the Pringle maneuver was improved following massage of the hepatoduodenal ligament. After hepatectomy, serum prothrombin time was significantly higher and serum C-reactive protein was significantly lower in the massage group than in the nonmassage group. CONCLUSION Massaging the hepatoduodenal ligament after the Pringle maneuver is recommended in order to quickly recover portal vein flow during hepatectomy and to improve coagulability.
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Affiliation(s)
- Junji Ueda
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-5-1, Bunkyo-ku Sendagi, Tokyo, 113-8603, Japan. .,Department of Gastrointestinal Surgery, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari Inzai, Chiba, 270-1694, Japan. .,Department of Gastrointestinal Surgery, Nippon Medical School Musashi Kosugi Hospital, 1-396 Kosugi Nakahara-ku, Kawasaki, 211-8533, Japan. .,Department of Surgery, Nippon Medical School Tamanagayama Hospital, 1-7-1, Nagayama, Tama-City, Tokyo, 206-8512, Japan.
| | - Yasuhiro Mamada
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-5-1, Bunkyo-ku Sendagi, Tokyo, 113-8603, Japan
| | - Nobuhiko Taniai
- Department of Gastrointestinal Surgery, Nippon Medical School Musashi Kosugi Hospital, 1-396 Kosugi Nakahara-ku, Kawasaki, 211-8533, Japan
| | - Masato Yoshioka
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-5-1, Bunkyo-ku Sendagi, Tokyo, 113-8603, Japan
| | - Atsushi Hirakata
- Department of Gastrointestinal Surgery, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari Inzai, Chiba, 270-1694, Japan
| | - Youichi Kawano
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-5-1, Bunkyo-ku Sendagi, Tokyo, 113-8603, Japan
| | - Tetsuya Shimizu
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-5-1, Bunkyo-ku Sendagi, Tokyo, 113-8603, Japan
| | - Tomohiro Kanda
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-5-1, Bunkyo-ku Sendagi, Tokyo, 113-8603, Japan
| | - Hideyuki Takata
- Department of Gastrointestinal Surgery, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari Inzai, Chiba, 270-1694, Japan
| | - Ryota Kondo
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-5-1, Bunkyo-ku Sendagi, Tokyo, 113-8603, Japan
| | - Yohei Kaneya
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-5-1, Bunkyo-ku Sendagi, Tokyo, 113-8603, Japan
| | - Yuto Aoki
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-5-1, Bunkyo-ku Sendagi, Tokyo, 113-8603, Japan
| | - Hiroshi Yoshida
- Department of Gastrointestinal Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-5-1, Bunkyo-ku Sendagi, Tokyo, 113-8603, Japan
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Yan B, Luo J, Kaltenmeier C, Du Q, Stolz DB, Loughran P, Yan Y, Cui X, Geller DA. Interferon Regulatory Factor-1 (IRF1) activates autophagy to promote liver ischemia/reperfusion injury by inhibiting β-catenin in mice. PLoS One 2020; 15:e0239119. [PMID: 33137133 PMCID: PMC7605671 DOI: 10.1371/journal.pone.0239119] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 07/27/2020] [Indexed: 01/08/2023] Open
Abstract
Autophagy is an important factor in liver ischemia-reperfusion injury. In the current study we investigate the function of interferon regulatory factor-1 (IRF1) in regulating autophagy to promote hepatic ischemia reperfusion injury (IR). The high expression of IRF1 during hepatic IR exhibited increased liver damage and was associated with activation of autophagy shown by Western blot markers, as well as immunofluorescent staining for autophagosomes. These effects were diminished by IRF1 deficiency in IRF1 knock out (KO) mice. Moreover, the autophagy inhibitor 3-MA decreased IR-induced liver necrosis and markedly abrogated the rise in liver injury tests (AST/ALT). β-catenin expression decreased during liver IR and was increased in the IRF1 KO mice. Immunoprecipitation assay showed the binding between IRF1 and β-catenin. Overexpression of IRF1 induced autophagy and also inhibited the expression of β-catenin. β-catenin inhibitor increased autophagy while β-catenin agonist suppressed autophagy in primary mouse hepatocytes. These results indicate that IRF1 induced autophagy aggravates hepatic IR injury in part by inhibiting β-catenin and suggests that targeting IRF1 may be an effective strategy in reducing hepatic IR injury.
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Affiliation(s)
- Bing Yan
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
| | - Jing Luo
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Christof Kaltenmeier
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Qiang Du
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Donna B. Stolz
- Center for Biologic Imaging, University of Pittsburgh Medical School, Pittsburgh, PA, United States of America
| | - Patricia Loughran
- Center for Biologic Imaging, University of Pittsburgh Medical School, Pittsburgh, PA, United States of America
| | - Yihe Yan
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Xiao Cui
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - David A. Geller
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
- * E-mail:
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AntagomiR-199a Enhances the Liver Protective Effect of Hypoxia-Preconditioned BM-MSCs in a Rat Model of Reduced-Size Liver Transplantation. Transplantation 2020; 104:61-71. [PMID: 31449185 DOI: 10.1097/tp.0000000000002928] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Reduced-size liver transplantation (LT) was invented to overcome the shortage of donor livers; however, it has proven to be more susceptible to ischemia-reperfusion injury. Bone marrow-derived mesenchymal stem cell infusion has been shown to be protective following LT. Optimization of MSC infusion has been performed, among which hypoxia preconditioning and miRNA modulation have shown promise. MiR-199a inhibition was reported to induce angioneogenesis; however, whether mir-199a inhibition enhances the protective effect of Bone marrow-derived mesenchymal stem cells in LT remains unknown. In this study, we combined antagomiR-199a with hypoxia-preconditioned MSC (H-MSC) infusion to discuss their effect and mechanism in a rat model of reduced-size LT. METHODS A reduced-size LT model was constructed and H-MSCs were intraportally injected during operation. AgomiR-199a and antagomir-199a were injected through the caudal vein once a day after LT. The level of apoptosis and proinflammatory cytokines were measured. An anti-vascular endothelial growth factor (VEGF) antibody was injected to further explore the underlying mechanism. RESULTS AntagomiR-199a plus H-MSC not only significantly decreased ALT and AST 72 h after LT but also ameliorated the level of apoptosis and inhibited inflammatory reactions. On the contrary, agomir-199a reduced the protective effect of the H-MSC infusion. In terms of mechanism, the liver protective effect of miR-199a inhibition was abolished by treatment with a VEGF-neutralizing antibody. CONCLUSIONS AntagomiR-199a enhanced the protective effect of H-MSCs infusion via activation of the hypoxia induction factor 1α/VEGF axis.
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15
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Wang X, Liu Z, Shen L. [Isoflurane preconditioning inhibits caspase-11-related noncanonical pyroptosis pathway to alleviate hepatic ischemia-reperfusion injury in mice]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:670-675. [PMID: 32897214 DOI: 10.12122/j.issn.1673-4254.2020.05.09] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE To study the protective effect of isoflurane preconditioning on hepatic ischemia-reperfusion (I/R) injury mediated by the noncanonical pyroptosis pathway. METHODS Thirty C57BL/6 mice were randomly divided into sham-operated group, isoflurane group and I/R group, and in the latter two groups, hepatic I/R injury was induced by clamping the portal vein for 30 min. In isoflurane group, the mice were pretreated with 1.4% isoflurane 30 min before the surgery. The protective effect of isoflurane preconditioning against hepatic I/R injury was evaluated by assessing the pathological score of HE staining of the liver tissue and serum ALT and AST levels. Serum IL-1β and IL-18 levels and the protein expression of GSDMS were detected by ELISA and Western blotting to evaluate the inhibitory effect of isoflurane preconditioning on pyroptosis. Western blotting and immunofluroescence were used to detect the protein expression of caspase-11 in the liver tissues to evaluate the inhibitory effect of isoflurane preconditioning on noncanonical pyroptosis pathway. RESULTS The Suzuki's score of the liver tissue was significantly higher in I/R group than in the sham group (P < 0.05), while the score in the isoflurane group was significantly lower than that in the I/R group (P < 0.05). Serum ALT and AST levels significantly increased in the sham group (P < 0.05), and were significantly lower in isoflurane group than in I/R group (P < 0.05). The serum levels of IL-1β and IL-18 were significantly higher in I/R group than in sham group (P < 0.05), and were significantly lower in isoflurane group than in I/R group (P < 0.05). The expression of GSDMD in the I/R group was significantly higher than that in sham group, and was significantly lower in isoflurane group than in I/R group (P < 0.05). The hepatic expression of caspase-11 was significantly higher in I/R group than in sham group (P < 0.05), and was significantly lower in isoflurane group than in I/R group (P < 0.05). CONCLUSIONS Isoflurane preconditioning has protective effect against hepatic I/R injury, which is related to the inhibition of the noncanonical pyroptosis pathway.
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Affiliation(s)
- Xiaoying Wang
- Department of Pathology, School of Basic Medical Science, Kunming Medical University, Kunming 650500, China
| | - Zuojin Liu
- Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Lijuan Shen
- Department of Pathology, School of Basic Medical Science, Kunming Medical University, Kunming 650500, China
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16
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Zhang S, Zhang Q, Wang F, Guo X, Liu T, Zhao Y, Gu B, Chen H, Li Y. Hydroxychloroquine inhibiting neutrophil extracellular trap formation alleviates hepatic ischemia/reperfusion injury by blocking TLR9 in mice. Clin Immunol 2020; 216:108461. [PMID: 32437924 DOI: 10.1016/j.clim.2020.108461] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/21/2020] [Accepted: 05/07/2020] [Indexed: 01/30/2023]
Abstract
Hepatic ischemia/reperfusion (I/R) injury may arise after partial hepatectomy and liver transplantation. Neutrophil extracellular traps (NETs) were involved in hepatic I/R injury. This study tested the hypothesis that blocking NETs formation could be a potential therapeutic target against hepatic I/R injury. NETs were excessively formed within liver and in serum of I/R mice models and were testified to be an independent contributor to hepatic I/R injury. Hydroxychloroquine (HCQ) alleviated hepatic I/R injury by inhibiting NETs formation in SCID and c57BL/6 mice models. In vitro, HCQ inhibited neutrophils to form NETs at a concentration of 100 μg/ml. CpG-ODN reversed the effect of HCQ inhibiting NETs formation. HCQ inhibited PAD4 and Rac2 expressions by blocking TLR9. NETs are essential contributors to hepatic I/R injury. HCQ blocking TLR9 protects against hepatic I/R injury by inhibiting NETs formation, which may suggest utility of HCQ or other TLR9 agonists for preventing hepatic I/R injury in clinical practices.
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Affiliation(s)
- Sigong Zhang
- Department of Rheumatology, Lanzhou University Second Hospital, Key Laboratory of Digestive System Tumors of Gansu Province, China
| | - Qiuyue Zhang
- the Second Clinical Medical College, Lanzhou University, China
| | - Furong Wang
- Department of Pathology, Lanzhou University Second Hospital, China
| | - Xuehui Guo
- Gansu Emergency Medical Aid Center, China
| | - Tao Liu
- Lanzhou University Second Hospital, Key Laboratory of Digestive System Tumors of Gansu Province, China
| | - Yang Zhao
- Lanzhou University Second Hospital, Key Laboratory of Digestive System Tumors of Gansu Province, China
| | - Baohong Gu
- the Second Clinical Medical College, Lanzhou University, China
| | - Hao Chen
- Lanzhou University Second Hospital, Key Laboratory of Digestive System Tumors of Gansu Province, China
| | - Yumin Li
- Lanzhou University Second Hospital, Key Laboratory of Digestive System Tumors of Gansu Province, China.
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Li CX, Yang XX, Wang HW, Li XC, Ng KTP, Lo CM, Man K. FTY720 Suppresses Liver Tumor Growth and Metastasis by Reducing Circulating Regulating T Cells and Enhancing the Anti-Tumor Effect of Rapamycin. Onco Targets Ther 2020; 13:4743-4754. [PMID: 32547103 PMCID: PMC7262652 DOI: 10.2147/ott.s234394] [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: 10/12/2019] [Accepted: 02/25/2020] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND In this study, we aimed to study the effect of FTY720 treatment in reducing circulating Tregs level and then suppressing liver tumor metastasis after hepatectomy and I/R injury in animal models. Furthermore, we also investigated the synergistic anti-tumor effect of FTY720 combined with rapamycin on hepatocellular carcinoma. METHODS The effect of FTY720 on suppressing Tregs mobilization and tumor metastasis after hepatectomy was investigated in an orthotopic liver tumor rat model with hepatectomy and hepatic ischemia/reperfusion (I/R) injury. The synergistic anti-tumor effect of FTY720 combined with rapamycin was further explored both in in vitro functional study and in orthotopic liver tumor mouse model. RESULTS In rat model, hepatic I/R promoted tumor metastasis and increased circulating Tregs after hepatectomy. The treatment of FTY720 reduced liver tumor metastasis and the number of circulating Tregs. Furthermore, FTY720 enhanced the anti-tumor capacity of rapamycin by inhibiting tumor cell proliferation and migration in vitro and reducing tumor growth in vivo through suppressing hepatic stellate cell activation and tumor angiogenesis. CONCLUSION FTY720 suppressed liver tumor growth and metastasis by reducing the population of circulating Tregs and enhancing the anti-tumor effect of rapamycin. It was suggested that FTY720 single or combined with rapamycin might provide novel insight for suppressing tumor growth and metastasis for HCC patients.
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Affiliation(s)
- Chang Xian Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Nanjing, Jiangsu Province, People’s Republic of China
| | - Xin Xiang Yang
- Department of Surgery, The University of Hong Kong, Hong Kong, People’s Republic of China
| | - Hong Wei Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Nanjing, Jiangsu Province, People’s Republic of China
| | - Xiang Cheng Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Nanjing, Jiangsu Province, People’s Republic of China
| | - Kevin Tak-Pan Ng
- Department of Surgery, The University of Hong Kong, Hong Kong, People’s Republic of China
| | - Chung Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong, People’s Republic of China
| | - Kwan Man
- Department of Surgery, The University of Hong Kong, Hong Kong, People’s Republic of China
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Amiri M, Toosi MN, Moazzami B, Jafarian A, Shahsavari H, Javaherian M, Dashti H, Fakhar N, Karimi M, Khani F. Factors Associated With Length of Hospital Stay Following Liver Transplant Surgery. EXP CLIN TRANSPLANT 2020; 18:313-319. [PMID: 32133943 DOI: 10.6002/ect.2019.0077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Length of stay is considered an important surrogate for transplant survival rate and resource utilization. Therefore, in the present study, our aim was to determine factors affecting length of hospital stay. MATERIALS AND METHODS We retrospectively analyzed records of patients who underwent liver transplant at the Tehran University of Medical Sciences Liver Transplantation Center from March 2014 to March 2016. RESULTS For our final analyses, there were 161 adult recipients, including 106 males (65.8%) and 55 females (34.1%). Univariate analyses showed that body mass index, Modelfor End-Stage Liver Disease score, duration of surgery, number of administered packed red blood cells and fibrinogen during surgery, reoperation, retransplant, bacterial infection, pleural effusion, ascites, renal failure that required dialysis, and wound infection were risk factors for length of hospital stay. After multivariate linear regression analysis, only body mass index (β = 0.016; P = .028), Model for End-Stage Liver Disease score (β = 0.017; P = .002), surgical duration (β = 0.002; P = .001), reoperation (β = 0.016; P < .001), presence of pleural effusion (β = 0.212; P = .042), and management of bacterial infection (β = 0.21; P = .03) and psychiatric problems after liver transplant (β = 0.213; P = .025) were independent risk factors for length of hospital stay. CONCLUSIONS The present study showed that multiple preoperative, intraoperative, and postoperative variables could have an impact on length of hospitalization. Therefore, methods for assessing these factors could improve patient outcomes and resource savings in liver transplant centers.
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Affiliation(s)
- Mahmoud Amiri
- >From the Department of Medical-Surgical Nursing, School of Nursing and Midwifery, University of Medical Sciences, Tehran, Iran
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Li S, Li H, Xu X, Saw PE, Zhang L. Nanocarrier-mediated antioxidant delivery for liver diseases. Theranostics 2020; 10:1262-1280. [PMID: 31938064 PMCID: PMC6956819 DOI: 10.7150/thno.38834] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 10/30/2019] [Indexed: 12/12/2022] Open
Abstract
Liver is the principal detoxifying organ and metabolizes various compounds that produce free radicals (FR) constantly. To maintain the oxidative/antioxidative balance in the liver, antioxidants would scavenge FR by preventing tissue damage through FR formation, scavenging, or by enhancing their decomposition. The disruption of this balance therefore leads to oxidative stress and in turn leads to the onset of various diseases. Supplying the liver with exogeneous antioxidants is an effective way to recreate the oxidative/antioxidative balance in the liver homeostasis. Nevertheless, due to the short half-life and instability of antioxidants in circulation, the methodology for delivering antioxidants to the liver needs to be improved. Nanocarrier mediated delivery of antioxidants proved to be an ingenious way to safely and efficiently deliver a high payload of antioxidants into the liver for circumventing liver diseases. The objective of this review is to provide an overview of the role of reactive oxygen species (oxidant) and ROS scavengers (antioxidant) in liver diseases. Subsequently, current nanocarrier mediated antioxidant delivery methods for liver diseases are discussed.
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Affiliation(s)
- Senlin Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Huiru Li
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Xiaoding Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Phei Er Saw
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Lei Zhang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
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Kaymaz B, Coban G, Goksel F, Toman H, Golge UH, Komurcu E. Tavşan modelinde ekstremite iskemi-reperfüzyon hasarına ozon tedavisinin etkisi. FAMILY PRACTICE AND PALLIATIVE CARE 2019. [DOI: 10.22391/fppc.596783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Identification of Key Transcription Factors AP-1 and AP-1-Dependent miRNAs Forming a Co-Regulatory Network Controlling PTEN in Liver Ischemia/Reperfusion Injury. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8962682. [PMID: 31781649 PMCID: PMC6875376 DOI: 10.1155/2019/8962682] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 07/07/2019] [Accepted: 07/18/2019] [Indexed: 11/18/2022]
Abstract
Liver ischemia/reperfusion (I/R) injury is a complex and common clinical disease with limited therapeutic options. The aim of our study was to discover the candidate target genes in liver I/R injury and to further elucidate the potential regulatory mechanisms, especially the ones involving transcription factors and miRNAs. The analysis of mouse data set GSE10657 from Gene Expression Omnibus database (GEO) revealed 203 differentially expressed genes (DEGs) including 19 transcription factors (TFs). Functional and pathway enrichment analyses were conducted to explore their biological functions. We further obtained the targets of TFs and miRNAs, to form our TF-mRNA/TF-miRNA-mRNA co-regulatory network. In our network, we found that the important subunits of activator protein 1 (AP-1) including JUN, FOS and ATF3, were hub genes in liver I/R injury. AP-1 target genes were activated in our mouse models. AP-1 could transcriptionally activate phosphatase and tensin homolog (PTEN) while AP-1-dependent miRNAs countered this effect. In conclusion, this study suggested that AP-1, together with AP-1-dependent miRNAs formed a co-regulatory network enabling AP-1 target genes to be tightly controlled, which will complete the mechanism of liver ischemia/reperfusion injury and provide direction for finding potential therapeutic targets.
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Baker MA, Nandivada P, Mitchell PD, Fell GL, Pan A, Cho BS, De La Flor DJ, Anez-Bustillos L, Dao DT, Nosé V, Puder M. Omega-3 fatty acids are protective in hepatic ischemia reperfusion injury in the absence of GPR120 signaling. J Pediatr Surg 2019; 54:2392-2397. [PMID: 31036368 PMCID: PMC6790164 DOI: 10.1016/j.jpedsurg.2019.04.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/13/2019] [Accepted: 04/08/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND A single dose of IV fish oil (FO) before hepatic ischemia reperfusion injury (HIRI) increases hepatocyte proliferation and reduces necrosis in wild type (WT) mice. It has been suggested that the GPR120 receptor on Kupffer cells mediates FO's ability to reduce HIRI. The purpose of this study was to determine whether GPR120 is required for FO to reduce HIRI. METHODS Sixty-four (n = 8/group) adult male WT (C57BL/6) and GPR120 knockout (KO) mice received IV FO (1 g/kg) or saline 1 h prior to HIRI or sham operation. Mice were euthanized 24 h postoperatively for analysis of hepatic histology, NFκB activity, and serum alanine transaminase (ALT) levels. RESULTS FO pretreated livers had less necrosis after HIRI than saline pretreated livers in both WT (mean ± SEM 25.9 ± 7.3% less, P = 0.007) and KO (36.6 ± 7.3% less, P < 0.0001) mice. There was no significant difference in percent necrosis between WT-FO and KO-FO groups. Sham groups demonstrated minimal necrosis (0-1.9%). Mean [95% CI] ALT after HIRI was significantly higher (P = 0.04) in WT-Saline mice (1604 U/L [751-3427]) compared to WT-FO (321 U/L [150-686]) but was not significantly higher in KO-Saline mice compared to KO-FO. There were no differences in ALT between WT-FO and KO-FO mice who underwent HIRI or between groups who underwent sham surgery. There were no differences in NFκB or IKKβ activation among groups as measured by Western blot analysis. CONCLUSIONS IV FO pretreatment was able to reduce HIRI in GPR120 KO mice, suggesting the hepatoprotective effects of FO are not mediated by GPR120 alone.
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Affiliation(s)
- Meredith A. Baker
- Vascular Biology Program and Department of Surgery, Boston Children’s Hospital
| | - Prathima Nandivada
- Vascular Biology Program and Department of Surgery, Boston Children’s Hospital
| | - Paul D. Mitchell
- Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital
| | - Gillian L. Fell
- Vascular Biology Program and Department of Surgery, Boston Children’s Hospital
| | - Amy Pan
- Vascular Biology Program and Department of Surgery, Boston Children’s Hospital
| | - Bennet S. Cho
- Vascular Biology Program and Department of Surgery, Boston Children’s Hospital
| | - Denis J. De La Flor
- Vascular Biology Program and Department of Surgery, Boston Children’s Hospital
| | | | - Duy T. Dao
- Vascular Biology Program and Department of Surgery, Boston Children’s Hospital
| | - Vania Nosé
- Department of Pathology, Massachusetts General Hospital
| | - Mark Puder
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital.
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Yang L, Jiang L, Jiang D, Liu B, Jin S. The protective effects of salvianolic acid A against hepatic ischemia-reperfusion injury via inhibiting expression of toll-like receptor 4 in rats. Arch Med Sci 2019; 15:1599-1607. [PMID: 31749890 PMCID: PMC6855152 DOI: 10.5114/aoms.2019.87412] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 05/22/2017] [Indexed: 01/29/2023] Open
Abstract
INTRODUCTION Ischemia-reperfusion injury (IRI) is a serious complication of hepatectomy and liver transplantation. The aim of this study was to evaluate the protective effects of salvianolic acid-A (Sal-A) against IRI-induced hepatocellular injury. MATERIAL AND METHODS Forty rats were randomly divided into the following four groups: (1) sham group, (2) IR group, (3) Sal-A(10) group and (4) Sal-A(20) group. After 90 min of ischemia and 6 h of reperfusion, serum alanine aminotransferease (ALT) and apartate aminotransferase (AST) levels were measured; the amounts of malondialdehyde (MDA) and superoxide dismutase (SOD) in the liver tissue were determined; the expression of Bcl-2 and caspase-3 was detected and the severity of apoptosis, inflammation and pathological alterations were evaluated. Also apoptosis and mRNA and protein levels of TLR4 (toll-like receptor 4) were tested. RESULTS The serum aminotransferases, hepatic MDA concentration, and apoptotic cells in the IR group were significantly higher than in the sham group (p < 0.01), whereas the Sal-A group values were lower than in the IR group (p < 0.05). Compared with the IR group, the Sal-A groups had significantly higher Bcl-2 expression and downregulated cleaved caspase-3 expression in liver tissue. Moreover, increased mRNA and protein levels of TLR4 in IR rats and Sal-A could improve the increased mRNA and protein levels of TLR4. CONCLUSIONS Sal-A had a synergistically protective effect on the liver tissue against IRI that might be due to decreased oxidative stress, inflammation, hepatocellular apoptosis and include, at least in part, the regulation of TLR4.
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Affiliation(s)
- Long Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, China
| | - Lu Jiang
- Dalian Medical University, Dalian, China
- Department of General Surgery, The Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, China
| | - Dongdong Jiang
- Dalian Medical University, Dalian, China
- Department of General Surgery, The Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, China
| | - Baiying Liu
- Dalian Medical University, Dalian, China
- Department of General Surgery, The Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, China
| | - Shi Jin
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
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Rampes S, Ma D. Hepatic ischemia-reperfusion injury in liver transplant setting: mechanisms and protective strategies. J Biomed Res 2019; 33:221-234. [PMID: 32383437 DOI: 10.7555/jbr.32.20180087] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatic ischemia-reperfusion injury is a major cause of liver transplant failure, and is of increasing significance due to increased use of expanded criteria livers for transplantation. This review summarizes the mechanisms and protective strategies for hepatic ischemia-reperfusion injury in the context of liver transplantation. Pharmacological therapies, the use of pre-and post-conditioning and machine perfusion are discussed as protective strategies. The use of machine perfusion offers significant potential in the reconditioning of liver grafts and the prevention of hepatic ischemia-reperfusion injury, and is an exciting and active area of research, which needs more study clinically.
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Affiliation(s)
- Sanketh Rampes
- Faculty of Life Sciences & Medicine, King's College London, London SE1 1U, UK
| | - Daqing Ma
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London SW10 9NH, UK
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Aloia TP, Cogliati B, Monteiro JM, Goldberg AC, de Oliveira Salvalaggio PR. Recovery of the Cholangiocytes After Ischemia and Reperfusion Injury: Ultra-Structural, Hystological and Molecular Assessment in Rats. J Clin Exp Hepatol 2018; 8:380-389. [PMID: 30563999 PMCID: PMC6286446 DOI: 10.1016/j.jceh.2018.01.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 01/31/2018] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Ischemia-reperfusion (I/R) injury of the liver is a common area of interest to transplant and hepatic surgery. Nevertheless, most of the current knowledge of I/R of the liver derives from the hepatocyte and little is known of what happens to the cholangiocytes. Herein, we assess the sequence of early events involved in the I/R injury of the cholangiocytes. METHODS Sixty Wistar rats were randomized in a SHAM group and I/R group. Serum biochemistry, histopathology, immunohistochemistry, transmission electron microscopy (TEM) and laser capture microdissection (LCM) were used for group comparison. RESULTS There was peak of alkaline phosphatase 24 h after IR injury, and an increase of aspartate aminotransferase and alanine aminotransferase after 6 h of reperfusion, followed by a return to normal levels 24 h after injury. The I/R group presented the liver parenchyma with hepatocellular degeneration up to 6 h, followed by hepatocellular necrosis at 24 h. TEM showed cholangiocyte injury, including a progressive nuclear degeneration and cell membrane rupture, beginning at 6 h and peaking at 24 h after reperfusion. Cytokeratin-18 and caspase-3-positive areas were observed in the I/R group, peaking at 24-h reperfusion. Anti-apoptotic genes Bcl-2 and Bcl-xl activity were expressed from 6 through 24 h after reperfusion. BAX expression showed an increase for 24 h. CONCLUSIONS I/R injury to the cholangiocyte occurs from 6 through 24 h after reperfusion and a combination of TEM, immunohistochemistry and LCM allows a better isolation of the cholangiocyte and a proper investigation of the events related to the I/R injury. Apoptosis is certainly involved in the I/R process, particularly mediated by BAX.
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Key Words
- ALKP, alkaline phosphatase
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- BIL, bilirubin
- CK18, cytokeratin-18
- GGT, gamma-glutamyl transferase
- HPC, hepatic progenitor cells
- I/R, ischemia–reperfusion
- LCM, laser capture microdissection
- PCNA, proliferating cell nuclear antigen
- TEM, transmission electron microscopy
- VEGF, vascular endothelial growth factor
- apoptosis
- cholangiocytes
- ischemia–reperfusion
- rats
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Affiliation(s)
- Thiago P.A. Aloia
- Experimental Research Center, Hospital Israelita Albert Einstein, 05651-901 São Paulo, Brazil,Address for correspondence: Thiago P.A. Aloia, Instituto de Ensino e Pesquisa Albert Einstein, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627 – bl A, 2SS, 05651-901 São Paulo, Brazil. Tel.: +55 11 2151 1431.
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo (USP), 05508-270 Sao Paulo, Brazil
| | - Janaina M. Monteiro
- Experimental Research Center, Hospital Israelita Albert Einstein, 05651-901 São Paulo, Brazil
| | - Anna C.K. Goldberg
- Experimental Research Center, Hospital Israelita Albert Einstein, 05651-901 São Paulo, Brazil
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Ning X, Yan X, Wang Y, Wang R, Fan X, Zhong Z, Ye Q. Parkin deficiency elevates hepatic ischemia/reperfusion injury accompanying decreased mitochondrial autophagy, increased apoptosis, impaired DNA damage repair and altered cell cycle distribution. Mol Med Rep 2018; 18:5663-5668. [PMID: 30387846 DOI: 10.3892/mmr.2018.9606] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 03/13/2017] [Indexed: 11/05/2022] Open
Affiliation(s)
- Xiao‑Jie Ning
- Hubei Key Laboratory of Medical Technology on Transplantation, Institute of Hepatobiliary Diseases, Zhongnan Hospital of Wuhan University, Transplant Center of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Xiong Yan
- Hubei Key Laboratory of Medical Technology on Transplantation, Institute of Hepatobiliary Diseases, Zhongnan Hospital of Wuhan University, Transplant Center of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yan‑Feng Wang
- Hubei Key Laboratory of Medical Technology on Transplantation, Institute of Hepatobiliary Diseases, Zhongnan Hospital of Wuhan University, Transplant Center of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Ren Wang
- Hubei Key Laboratory of Medical Technology on Transplantation, Institute of Hepatobiliary Diseases, Zhongnan Hospital of Wuhan University, Transplant Center of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Xiao‑Li Fan
- Hubei Key Laboratory of Medical Technology on Transplantation, Institute of Hepatobiliary Diseases, Zhongnan Hospital of Wuhan University, Transplant Center of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Zi‑Biao Zhong
- Hubei Key Laboratory of Medical Technology on Transplantation, Institute of Hepatobiliary Diseases, Zhongnan Hospital of Wuhan University, Transplant Center of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Qi‑Fa Ye
- Hubei Key Laboratory of Medical Technology on Transplantation, Institute of Hepatobiliary Diseases, Zhongnan Hospital of Wuhan University, Transplant Center of Wuhan University, Wuhan, Hubei 430071, P.R. China
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The hepatoprotective effect of Aloe vera on ischemia-reperfusion injury in rats. North Clin Istanb 2018; 6:203-209. [PMID: 31650105 PMCID: PMC6790936 DOI: 10.14744/nci.2018.82957] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 10/02/2018] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE: Aloe vera is known for its antioxidant properties. In this experimental study, we aimed to investigate the efficacy of Aloe vera in ischemia-reperfusion (I/R) liver injury in rats. METHODS: Male Wistar Albino rats were divided into three groups, where the sham group (n=7) underwent no medication or surgical procedures, the I/R group (n=7) was the control group that received 45 minutes of applied abdominal aorta ischemia and rats were sacrificed 24 hours after reperfusion, and the I/R+AV group (n=7) was the treatment group that was given Aloe vera (30 mg/kg) every day followed by gastric lavage for a month before applying ischemia and performing sacrifice as in the previous group. Before sacrifice, all the liver tissues were removed. Tissues were examined for histopathological investigation, iNOS immunoreactivity and tissue biochemistry, malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities. RESULTS: The SOD, CAT, and GSH-Px levels of the I/R+AV group were not significantly different from the sham group (p>0.05) but were significantly higher when compared to the I/R group. MDA levels of liver tissues were significantly lower (p<0.05) in the I/R+AV group as compared to the I/R group. Disrupted hepatic cords, sinusoidal dilatation, hemorrhage, cytoplasmic vacuolization of hepatocytes, and intensive iNOS immunoreactivity were detected in the I/R group. Decreased histopathological change score and iNOS immunoreactivity score were noticed in the I/R+AV group as compared to the I/R group. CONCLUSION: It was found that Aloe vera showed a hepatoprotective effect against I/R injury. Further research is required to determine the effective dose, administration method, and effects of Aloe vera for liver transplantation.
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Cheng Y, Wei GQ, Cai QC, Jiang Y, Wu AP. Prognostic Value of Model for End-Stage Liver Disease Incorporating with Serum Sodium Score for Development of Acute Kidney Injury after Liver Transplantation. Chin Med J (Engl) 2018; 131:1314-1320. [PMID: 29786044 PMCID: PMC5987502 DOI: 10.4103/0366-6999.232798] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background Contribution of model for end-stage liver disease incorporating with serum sodium (MELD-Na) score in predicting acute kidney injury (AKI) after orthotopic liver transplantation (OLT) is yet to be identified. This study assessed the prognostic value of MELD-Na score for the development of AKI following OLT. Methods Preoperative and surgery-related variables of 321 adult end-stage liver disease patients who underwent OLT in Fuzhou General Hospital were collected. Postoperative AKI was defined and staged in accordance with the clinical practice guidelines developed by Kidney Disease: Improving Global Outcomes. Univariate and multivariate analysis was performed to determine the risk factors for AKI following OLT. The discriminating power of MELD/MELD-Na score on AKI outcome was evaluated by receiver operating characteristic (ROC) curve. Spearman's correlation analysis was used for identifying the correlated relationship between MELD/MELD-Na score and the severity levels of AKI. Results The prevalence of AKI following OLT was in 206 out of 321 patients (64.2%). Three risk factors for AKI post-OLT were presented, preoperative calculated MELD score (odds ratio [OR] = 1.048, P = 0.021), intraoperative volume of red cell suspension transfusion (OR = 1.001, P = 0.002), and preoperative liver cirrhosis (OR = 2.015, P = 0.012). Two areas under ROC curve (AUCs) of MELD/MELD-Na score predicting AKI were 0.688 and 0.672, respectively; the difference between two AUCs was not significant (Z = 1.952, P = 0.051). The Spearman's correlation coefficients between MELD/MELD-Na score and the severity levels of AKI were 0.406 and 0.385 (P = 0.001, 0.001), respectively. Conclusions We demonstrated that preoperative MELD score, intraoperative volume of red cell suspension transfusion and preoperative liver cirrhosis were risk factors for AKI following OLT. Furthermore, we preliminarily validated that MELD score seemed to have a stronger power discriminating AKI post-OLT than that of novel MELD-Na score.
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Affiliation(s)
- Yuan Cheng
- Department of Hepatobiliary Surgery, Fuzhou General Hospital, Fuzhou, Fujian 350025, China
| | - Guo-Qing Wei
- Department of Hepatobiliary Surgery, Fuzhou General Hospital, Fuzhou, Fujian 350025, China
| | - Qiu-Cheng Cai
- Department of Hepatobiliary Surgery, Fuzhou General Hospital, Fuzhou, Fujian 350025, China
| | - Yi Jiang
- Department of Hepatobiliary Surgery, Fuzhou General Hospital, Fuzhou, Fujian 350025, China
| | - Ai-Ping Wu
- Department of Comparative Medicine, Fuzhou General Hospital, Fuzhou, Fujian 350025, China
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Magyar Z, Varga G, Mester A, Ghanem S, Somogyi V, Tanczos B, Deak A, Bidiga L, Peto K, Nemeth N. Is the early or delayed remote ischemic preconditioning the more effective from a microcirculatory and histological point of view in a rat model of partial liver ischemia-reperfusion? Acta Cir Bras 2018; 33:597-608. [DOI: 10.1590/s0102-865020180070000005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 06/09/2018] [Indexed: 01/19/2023] Open
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Remote Ischemic Preconditioning Is Efficient in Reducing Hepatic Ischemia-Reperfusion Injury in a Growing Rat Model and Does Not Promote Histologic Lesions in Distant Organs. Transplant Proc 2018; 50:3840-3844. [PMID: 30385044 DOI: 10.1016/j.transproceed.2018.04.034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 03/30/2018] [Accepted: 04/12/2018] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Ischemic preconditioning (IPC) was developed to diminish ischemia-reperfusion injury (IRI). There are two main ways of performing it: direct ischemic-preconditioning (DIP) and remote ischemic-preconditioning (RIP). The objectives of this study were to investigate local and systemic effects of DIP and RIP in liver IRI. METHODS Thirty-two weaning rats (50-70 g body weight; 21 days old) were divided into 4 groups: control (C); ischemia followed by reperfusion (IR); DIP followed by ischemia and reperfusion; and RIP followed by ischemia and reperfusion. In the IR group, the vascular pedicles of medial and left lateral liver lobes were clamped for 60 minutes and then unclamped. In the DIP group, a 10-minute cycle of ischemia followed by a 10-minute reperfusion of the same lobes was performed before 60 minutes of ischemia. In the RIP group, three 5-minute cycles of clamping and unclamping of the femoral vessels were performed before liver ischemia. The animals were euthanized 24 hours after the surgical procedures. RESULTS The serum levels of liver enzymes were significantly lower in the RIP group compared to the control and IR groups and to the DIP group. The scores of histologic hepatic lesions were significantly lower in RIP animals than those of IR animals (P = .002) and similar to the C group animals. The Bax/BCl-xl relation was lower in the DIP group than that in the RIP group (P = .045) and no differences were observed in histologic analyses of kidney, lung, intestine, and heart. CONCLUSION In young animals, the beneficial effects of RIP are more evident than those of DIP.
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Baker MA, Nandivada P, Mitchell PD, Fell GL, Pan A, Anez-Bustillos L, Dao DT, Gura KM, Nosé V, Puder M. Pretreatment with intravenous fish oil reduces hepatic ischemia reperfusion injury in a murine model. Surgery 2018; 163:1035-1039. [PMID: 29358007 DOI: 10.1016/j.surg.2017.10.071] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 09/23/2017] [Accepted: 10/31/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Ischemia reperfusion injury is a barrier to liver surgery and transplantation, particularly for steatotic livers. The purpose of this study was to determine if pretreatment with a single dose of intravenous fish oil decreases hepatic ischemia reperfusion injury and improves recovery of injured livers. METHODS Sixty adult male C57BL/6 mice received 1 g/kg intravenous fish oil (Omegaven, Fresenius Kabi) or isovolumetric 0.9% NaCl (saline) via tail vein 1 hour before 30 minutes of 70% hepatic ischemia. Animals were killed 4, 8, or 24 hours postreperfusion, and livers were harvested for histologic analysis. RESULTS Four hours postreperfusion, saline-treated livers demonstrated marked ischemia diffusely around the central veins, while intravenous fish oil-treated livers demonstrated only patchy necrosis with intervening normal parenchyma. Eight hours postreperfusion, all livers demonstrated pale areas of cell loss with surrounding regenerating hepatocytes. Ki67 staining confirmed 14.4/10 high-powered field (95% confidence interval, 3.2-25.6) more regenerating hepatocytes around areas of necrosis in intravenous fish oil-treated livers. Twenty-four hours postreperfusion, all livers demonstrated patchy areas of necrosis, with an 89% (95% confidence interval, 85-92) decrease in the area of necrosis in intravenous fish oil-treated livers. CONCLUSION Intravenous fish oil treatment prior to hepatic ischemia reperfusion injury decreased the area of hepatic necrosis and increased hepatocyte regeneration compared to saline treatment in a mouse model.
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Affiliation(s)
- Meredith A Baker
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, MA, USA
| | - Prathima Nandivada
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, MA, USA
| | - Paul D Mitchell
- Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA
| | - Gillian L Fell
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, MA, USA
| | - Amy Pan
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, MA, USA
| | - Lorenzo Anez-Bustillos
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, MA, USA
| | - Duy T Dao
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, MA, USA
| | - Kathleen M Gura
- Department of Pharmacy, Boston Children's Hospital, Boston, MA, USA
| | - Vania Nosé
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Mark Puder
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, MA, USA.
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Elnaggar AS, Guarrera JV. The Marginal Liver Donor and Organ Preservation Strategies. LIVER ANESTHESIOLOGY AND CRITICAL CARE MEDICINE 2018:207-220. [DOI: 10.1007/978-3-319-64298-7_17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Isoglycyrrhizinate Magnesium Enhances Hepatoprotective Effect of FK506 on Ischemia-Reperfusion Injury Through HMGB1 Inhibition in a Rat Model of Liver Transplantation. Transplantation 2017; 101:2862-2872. [PMID: 28885495 DOI: 10.1097/tp.0000000000001941] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Ischemia-reperfusion injury after liver transplantation (LT) impairs graft function and affects prognosis of recipients. Isoglycyrrhizinate magnesium (Iso) is a hepatoprotective drug usually used after liver injury. In this study, we intended to explore whether Iso alone have protective effect after ischemia-reperfusion injury in a rat model of liver transplantation. We also aimed to study whether Iso could enhance the hepatoprotective effect of FK506 (tacrolimus) and underlying mechanism. METHODS Rats after LT were treated with different concentration of FK506 with or without, Iso or lower-dose FK506 plus Iso. Alanine transaminase, aspartate transaminase, and albumin level were measured after 48 hours, 72 hours, and 7 days. A cell ischemic/reperfusion model was established to further study the mechanism of hepatoprotective effect of FK506 and Iso. RESULTS Iso treatment alone had no effect on liver grafts after LT, but lower-dose FK506 + Iso was better for maintenance of liver function than lower-dose FK506 alone at 48 hours, 72 hours, and 7 days after LT. In terms of mechanism, FK506 induced autophagy which resulted in significantly reduced apoptosis and maintained proliferative potential. However, autophagy induced by FK506 also lead to high-mobility group box (HMGB) 1 release from nuclei, resulting in hepatocyte injury through triggering of p38 phosphorylation and chemokine release. Iso effectively inhibited the release of HMGB1 and downstream inflammatory cytokines. CONCLUSIONS Iso could inhibit release of HMGB1 by FK506 and enhance the hepatoprotective effect of FK506 in rat LT. Combining Iso with FK506 would be promising for the patients after LT.
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Song P, Zhang J, Zhang Y, Shu Z, Xu P, He L, Yang C, Zhang J, Wang H, Li Y, Li Q. Hepatic recruitment of CD11b+Ly6C+ inflammatory monocytes promotes hepatic ischemia/reperfusion injury. Int J Mol Med 2017; 41:935-945. [PMID: 29251315 PMCID: PMC5752159 DOI: 10.3892/ijmm.2017.3315] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 11/24/2017] [Indexed: 01/09/2023] Open
Abstract
Monocytes infiltrate damaged liver tissue during noninfectious liver injury and often have dual roles, perpetuating inflammation and promoting resolution of inflammation and fibrosis. However, how monocyte subsets distribute and are differentially recruited in the liver remain unclear. In the current study, the subpopulations of infiltrating monocytes were examined following liver ischemia/reperfusion (I/R) injury in mice using flow cytometry. CD11b+Ly6C high (Ly6Chi) cells (inflammatory monocytes) and CD11b+Ly6C low cells (reparative monocytes) were recruited into the liver following I/R injury. Treatment with clodronate-loaded liposomes, which transiently deplete systemic macrophages, alleviated hepatic damage. Mice genetically deficient in C-C motif chemokine ligand 2 (CCL2), or its receptor C-C chemokine receptor 2 (CCR2), exhibited diminished hepatic damage compared with wild-type mice following I/R, by controlling intrahepatic inflammatory Ly6Chi monocyte accumulation. In addition, the CCR2 specific inhibitor RS504393 alleviated hepatic I/R injury. The results suggest that the CCR2/ CCL2 axis an important role in monocyte infiltration and may represent a novel target for the treatment of liver I/R injury.
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Affiliation(s)
- Peng Song
- Department of Vascular Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430033 P.R. China
| | - Junbin Zhang
- Department of Emergency Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430033 P.R. China
| | - Yunwei Zhang
- Department of Emergency Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430033 P.R. China
| | - Zhiping Shu
- Department of Nuclear Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430033 P.R. China
| | - Peng Xu
- Department of Emergency Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430033 P.R. China
| | - Long He
- Department of Clinical Laboratory, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430033 P.R. China
| | - Chao Yang
- Department of Vascular Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430033 P.R. China
| | - Jinxiang Zhang
- Department of Emergency Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430033 P.R. China
| | - Hui Wang
- Department of Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430033 P.R. China
| | - Yiqing Li
- Department of Vascular Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430033 P.R. China
| | - Qin Li
- Department of Vascular Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430033 P.R. China
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Abstract
Liver transplantation is the most effective treatment for selected patients with hepatocellular carcinoma. However, cancer recurrence, posttransplantation, remains to be the critical issue that affects the long-term outcome of hepatocellular carcinoma recipients. In addition to tumor biology itself, increasing evidence demonstrates that acute-phase liver graft injury is a result of hepatic ischemia reperfusion injury (which is an inevitable consequence during liver transplantation) and may promote cancer recurrence at late phase posttransplantation. The liver grafts from living donors, donors after cardiac death, and steatotic donors have been considered as promising sources of organs for liver transplantation and are associated with high incidence of liver graft injury. The acute-phase liver graft injury will trigger a series of inflammatory cascades, which may not only activate the cell signaling pathways regulating the tumor cell invasion and migration but also mobilize the circulating progenitor and immune cells to facilitate tumor recurrence and metastasis. The injured liver graft may also provide the favorable microenvironment for tumor cell growth, migration, and invasion through the disturbance of microcirculatory barrier function, induction of hypoxia and angiogenesis. This review aims to summarize the latest findings about the role and mechanisms of liver graft injury resulted from hepatic ischemia reperfusion injury on tumor recurrence posttransplantation, both in clinical and animal cohorts.
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LIU XB, LO CM, CHENG Q, NG KTP, SHAO Y, LI CX, CHUNG SK, NG IOL, YU J, MAN K. Oval Cells Contribute to Fibrogenesis of Marginal Liver Grafts under Stepwise Regulation of Aldose Reductase and Notch Signaling. Am J Cancer Res 2017; 7:4879-4893. [PMID: 29187911 PMCID: PMC5706107 DOI: 10.7150/thno.20085] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 07/29/2017] [Indexed: 12/18/2022] Open
Abstract
Background and Aims: Expanded donor criteria poses increased risk for late phase complications such as fibrosis that lead to graft dysfunction in liver transplantation. There remains a need to elucidate the precise mechanisms of post-transplant liver damage in order to improve the long-term outcomes of marginal liver grafts. In this study, we aimed to examine the role of oval cells in fibrogenic development of marginal liver grafts and explore the underlying mechanisms. Methods: Using an orthotopic rat liver transplantation model and human post-transplant liver biopsy tissues, the dynamics of oval cells in marginal liver grafts was evaluated by the platform integrating immuno-labeling techniques and ultrastructure examination. Underlying mechanisms were further explored in oval cells and an Aldose reductase (AR) knockout mouse model simulating marginal graft injury. Results: We demonstrated that activation of aldose reductase initiated oval cell proliferation in small-for-size fatty grafts during ductular reaction at the early phase after transplantation. These proliferative oval cells subsequently showed prevailing biliary differentiation and exhibited features of mesenchymal transition including dynamically co-expressing epithelial and mesenchymal markers, developing microstructures for extra-cellular matrix degradation (podosomes) or cell migration (filopodia and blebs), and acquiring the capacity in collagen production. Mechanistic studies further indicated that transition of oval cell-derived biliary cells toward mesenchymal phenotype ensued fibrogenesis in marginal grafts under the regulation of notch signaling pathway. Conclusions: Oval cell activation and their subsequent lineage commitment contribute to post-transplant fibrogenesis of small-for-size fatty liver grafts. Interventions targeting oval cell dynamics may serve as potential strategies to refine current clinical management.
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Atef Y, El-Fayoumi HM, Abdel-Mottaleb Y, Mahmoud MF. Effect of cardamonin on hepatic ischemia reperfusion induced in rats: Role of nitric oxide. Eur J Pharmacol 2017; 815:446-453. [PMID: 28966130 DOI: 10.1016/j.ejphar.2017.09.037] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 09/13/2017] [Accepted: 09/26/2017] [Indexed: 02/07/2023]
Abstract
Ischemia reperfusion (I/R) injury is a cellular damage in a hypoxic organ following the restoration of oxygen delivery. It may occur during organ transplantation, trauma and hepatectomies. Nitric oxide (NO) effects during hepatic I/R are complicated. The iNOS-derived NO has a deleterious effect, whereas eNOS-derived NO has a protective effect in liver I/R. Cardamonin (CDN) is an anti-inflammatory molecule and a novel iNOS inhibitor, and Nω-Nitro-L-arginine (L-NNA) is a NOS inhibitor. L-Arginine is a precursor of NOS. This study was designed to investigate the possible protective effects of CDN on hepatic I/R and the role of NO. Wistar rats were randomly divided into 5 groups (Sham, I/R, CDN, L-NNA and L-arginine). Liver ischemia was induced for 45min then reperfusion was allowed for 1h. L-Arginine and CDN ameliorated the deleterious effects of I/R through reducing the oxidative stress and hepatocyte degeneration. Both molecules decreased the elevated inflammatory cytokines and increased the antiapoptotic marker, Bcl2. Both agents increased NO and eNOS expression and decreased iNOS expression. In conclusion, increased NO/eNOS and suppression of iNOS expression have protective effects on I/R injury. While inhibition of eNOS and reduction of NO have deleterious effects on I/R injury. For the first time, we demonstrated that cardamonin improved functional and structural abnormalities of the liver following I/R by improving oxidative stress and inflammation and increasing the availability of NO produced by eNOS. Treatment with cardamonin could be a promising strategy in patients with hepatic I/R injury in different clinical situations.
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Affiliation(s)
- Yara Atef
- Department of Pharmacology & Toxicology & Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt
| | - Hassan M El-Fayoumi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt; Faculty of Pharmacy, Sinai University Qantara, Egypt
| | - Yousra Abdel-Mottaleb
- Department of Pharmacology & Toxicology & Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt
| | - Mona F Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
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miR-494 up-regulates the PI3K/Akt pathway via targetting PTEN and attenuates hepatic ischemia/reperfusion injury in a rat model. Biosci Rep 2017; 37:BSR20170798. [PMID: 28842516 PMCID: PMC5603753 DOI: 10.1042/bsr20170798] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 08/20/2017] [Accepted: 08/22/2017] [Indexed: 01/11/2023] Open
Abstract
A rat HIRI model was constructed and treated with an intraperitoneal injection of agomir-miR-494 or agomir-NC (negative control) for 7 days after the surgery. The pathophysiological changes in sham-operated rats, HIRI, HIRI + agomir-miR-494, and HIRI + agomir-NC were compared. The effect of miR-494 was also assessed in an H2O2-induced apoptosis model. Hepatic AML12 cells were transfected with mimics NC or miR-494 mimics, followed by 6-h H2O2 treatment. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry, respectively. Further, the miR-494 target gene was identified by luciferase reporter assay, and verified both in vitro and in vivo experiments. The activity of AKT pathway was further analyzed in vivo by Western blot. HIRI + agomir-miR-494 rats exhibited significantly higher miR-494 expression, lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and glutamate dehydrogenase (GLDH) level, lower hepatic MDA, TOA, and OSI, alleviated hepatic necrosis, reduced hepatocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI + agomir-NC rats (P<0.05 or 0.01). After H2O2 treatment, AML-12 cells transfected with miR-494 mimics had significantly higher proliferation and lower apoptosis rate compared with mimics NC group (P<0.01). PTEN was identified as an miR-494 target gene. PTEN expression was significantly down-regulated in AML12 cells transfected with miR-494 mimics, and was up-regulated by treatment of miR-494 inhibitor (P<0.01). Moreover, HIRI + agomir-miR-494 rats exhibited significantly lower PTEN expression, and higher p-AKT, p-mTOR, and p-p70S6K levels compared with HIRI + agomir-NC rats. Therefore, miR-494 protected rats against hepatic ischemia/reperfusion (I/R) injury through down-regulating its downstream target gene PTEN, leading to the activation of PI3K/AKT signaling pathway.
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Adipose Tissue Drives Response to Ischemia-Reperfusion Injury in a Murine Pressure Sore Model. Plast Reconstr Surg 2017; 139:1128e-1138e. [PMID: 28445367 DOI: 10.1097/prs.0000000000003271] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Ischemia-reperfusion injury contributes significantly to the pathogenesis of chronic wounds such as pressure sores and diabetic foot ulcers. The authors' laboratory has previously developed a cyclical murine ischemia-reperfusion injury model. The authors here use this model to determine factors underlying tissue response to ischemia-reperfusion injury. METHODS C57BL/6 mice were subjected to cycles of ischemia-reperfusion that varied in number (one to four cycles) and duration of ischemia (1 to 2 hours). For each ischemia-reperfusion condition, the following variables were analyzed: (1) digital photographs for area of necrosis; (2) hematoxylin and eosin staining and immunohistochemistry for inflammatory infiltrate; and (3) expression of inflammatory markers by quantitative polymerase chain reaction. In addition, human adipocytes and fibroblasts were cultured in vitro under conditions of hypoxia and reoxygenation, and expression of inflammatory markers was analyzed by quantitative polymerase chain reaction. RESULTS Increases in both ischemia-reperfusion cycle number and ischemia duration correlated with increased areas of epithelial necrosis both grossly and histologically, and with an increase in cellularity and neutrophil density. This increased inflammatory infiltrate and a significant increase in the expression of proinflammatory markers (Hmox1, interleukin-6, interleukin-1, and monocyte chemoattractant protein-1) was observed in adipose tissue subjected to ischemia-reperfusion injury, but not in dermis. These results were mirrored in human adipose tissue. CONCLUSIONS The authors further characterize a novel, reproducible murine model of ischemia-reperfusion injury. The results of their study indicate that adipose tissue is less tolerant of ischemia-reperfusion than dermal tissue. Rather than being an "innocent bystander," adipose tissue plays an active role in driving the inflammatory response to ischemia-reperfusion injury.
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Tannuri ACA, de Albuquerque Rangel Moreira D, Belon A, Coelho MCM, Gonçalves JO, Serafini S, Tannuri U. Does a meso-caval shunt have positive effects in a pig large-for-size liver transplantation model? Pediatr Transplant 2017; 21. [PMID: 28436075 DOI: 10.1111/petr.12928] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/14/2017] [Indexed: 02/06/2023]
Abstract
In pediatric liver transplantations with LFS grafts, higher incidences of graft dysfunction probably occur due to IRI. It was postulated that increasing the blood supply to the graft by means of a meso-caval shunt could ameliorate the IRI. Eleven pigs underwent liver transplantation and were divided into two groups: LFS and LFS+SHUNT group. A series of flowmetric, metabolic, histologic, and molecular studies were performed. No significant metabolic differences were observed between the groups. One hour after reperfusion, portal flow was significantly lower in the recipients than in the donors, proving that the graft was maintained in low portal blood flow, although the shunt could promote a transient increase in the portal blood flow and a decrease in the arterial flow. Finally, it was verified that the shunt promoted a decrease in inflammation and steatosis scores and a decrease in the expression of the eNOS gene (responsible for the generation of nitric oxide in the vascular endothelium) and an increase in the expression of the proapoptotic gene BAX. The meso-caval shunt was responsible for some positive effects, although other deleterious flowmetric and molecular alterations also occurred.
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Affiliation(s)
- Ana Cristina Aoun Tannuri
- Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), Pediatric Surgery Division, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Daniel de Albuquerque Rangel Moreira
- Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), Pediatric Surgery Division, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Alessandro Belon
- Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), Pediatric Surgery Division, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Maria Cecília Mendonça Coelho
- Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), Pediatric Surgery Division, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Josiane Oliveira Gonçalves
- Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), Pediatric Surgery Division, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Suellen Serafini
- Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), Pediatric Surgery Division, University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Uenis Tannuri
- Pediatric Liver Transplantation Unit and Laboratory of Research in Pediatric Surgery (LIM 30), Pediatric Surgery Division, University of Sao Paulo Medical School, Sao Paulo, Brazil
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Kulik U, Lehner F, Klempnauer J, Borlak J. Primary non-function is frequently associated with fatty liver allografts and high mortality after re-transplantation. Liver Int 2017; 37:1219-1228. [PMID: 28267886 DOI: 10.1111/liv.13404] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 02/27/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The shortage of liver donations demands the use of suboptimal grafts with steatosis being a frequent finding. Although ≤30% macrovesicular steatosis is considered to be safe the risk for primary non-function (PNF) and outcome after re-transplantation (re-OLT) is unknown. METHODS Among 1205 orthotopic liver transplantations performed at our institution the frequency, survival and reason of re-OLT were evaluated. PNF (group A) cases and those with initial transplant function but subsequent need for re-OLT (group B) were analysed. Histopathology and clinical judgement determined the cause of PNF and included an assessment of hepatic steatosis. Additionally, survival of fatty liver allografts (group C) not requiring re-OLT was considered in Kaplan-Meier and multivariate regression analysis. RESULTS A total of 77 high urgency re-OLTs were identified and included 39 PNF cases. Nearly 70% of PNF cases were due to primary fatty liver allografts. The 3-month in-hospital mortality for PNF cases after re-OLT was 46% and the mean survival after re-OLT was 0.5 years as compared to 5.2 and 5.1 years for group B, C, respectively, (P<.008). In multivariate Cox regression analysis only hepatic steatosis was associated with an inferior survival (HR 4.272, P=.002). The MELD score, donor BMI, age, cold ischaemic time, ICU stay, serum sodium and transaminases did not influence overall survival. CONCLUSIONS Our study highlights fatty liver allografts to be a major cause for PNF with excessive mortality after re-transplantation. The findings demand the development of new methods to predict risk for PNF of fatty liver allografts.
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Affiliation(s)
- Ulf Kulik
- Department of General-, Visceral- and Transplantation Surgery, Hannover, Germany
| | - Frank Lehner
- Department of General-, Visceral- and Transplantation Surgery, Hannover, Germany
| | - Jürgen Klempnauer
- Department of General-, Visceral- and Transplantation Surgery, Hannover, Germany
| | - Jürgen Borlak
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
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Quercetin and tin protoporphyrin attenuate hepatic ischemia reperfusion injury: role of HO-1. Naunyn Schmiedebergs Arch Pharmacol 2017; 390:871-881. [DOI: 10.1007/s00210-017-1389-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 05/24/2017] [Indexed: 12/14/2022]
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Attenuation of Ischemia-Reperfusion Injury and Improvement of Survival in Recipients of Steatotic Rat Livers Using CD47 Monoclonal Antibody. Transplantation 2017; 100:1480-9. [PMID: 27331362 DOI: 10.1097/tp.0000000000001186] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Despite the efficacy of orthotopic liver transplantation in the treatment of end-stage liver diseases, its therapeutic utility is severely limited by the availability of donor organs. The ability to rehabilitate marginal organs, such as steatotic allografts, has the potential to address some of the supply limitations of available organs for transplantation. Steatotic livers are more susceptible to ischemia-reperfusion injury (IRI), which is exacerbated by the thrombospondin-1/CD47 pathway through inhibition of nitric oxide signaling. We postulated that CD47 blockade with a monoclonal antibody specific to CD47, clone 400 (CD47mAb400) may reduce the extent of IRI in steatotic liver allografts. METHODS Orthotopic liver transplantation was performed using steatotic liver grafts from Zucker rats transplanted into lean recipients. Control IgG or the CD47mAb400 was administered to the donor livers at procurement. Serum transaminases, histological changes, and animal survival were assessed. Hepatocellular damage, oxidative and nitrosative stress, and inflammation were also quantified. RESULTS Administration of CD47mAb400 to donor livers increased recipient survival and resulted in significant reduction of serum transaminases, bilirubin, triphosphate nick-end labeling staining, caspase-3 activity, oxidative and nitrosative stresses, and proinflammatory cytokine expression of TNF-α, IL-6 and IL-1β. CONCLUSIONS We conclude that administration of CD47mAb400 to donor grafts may reduce IRI through CD47 blockade to result in improved function of steatotic liver allografts and increased survival of recipients and represent a novel strategy to allow the use of livers with higher levels of steatosis.
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Bystrom P, Foley N, Toledo-Pereyra L, Quesnelle K. Ischemic preconditioning modulates ROS to confer protection in liver ischemia and reperfusion. EXCLI JOURNAL 2017; 16:483-496. [PMID: 28694752 PMCID: PMC5491905 DOI: 10.17179/excli2017-166] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 03/20/2017] [Indexed: 12/24/2022]
Abstract
Ischemia reperfusion (IR) injury is a significant cause of morbidity and mortality in liver transplantation. When oxygen is reintroduced to the liver graft it initiates a cascade of molecular reactions leading to the release of reactive oxygen species (ROS) and pro-inflammatory cytokines. These soluble mediators propagate a sterile immune response to cause significant tissue damage. Ischemic preconditioning (IPC) is one method that reduces hepatocellular injury by altering the immune response and inhibiting the production of ROS. Studies quantifying the effects of IPC in humans have demonstrated an improved liver enzyme panel in patients receiving grafts pretreated with IPC as compared to patients receiving the standard of care. In our review, we explore current literature in the field in order to describe the mechanism through which IPC regulates the production of ROS and improves IR injury.
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Affiliation(s)
- Phillip Bystrom
- Western Michigan University, Homer Stryker M.D. School of Medicine Department of Biomedical Sciences
| | - Nicole Foley
- Western Michigan University, Homer Stryker M.D. School of Medicine Department of Biomedical Sciences
| | - Luis Toledo-Pereyra
- Western Michigan University, Homer Stryker M.D. School of Medicine Department of Surgery
| | - Kelly Quesnelle
- Western Michigan University, Homer Stryker M.D. School of Medicine Department of Biomedical Sciences
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Beal EW, Dumond C, Kim JL, Mumtaz K, Hayes D, Washburn K, Whitson BA, Black SM. Method of Direct Segmental Intra-hepatic Delivery Using a Rat Liver Hilar Clamp Model. J Vis Exp 2017. [PMID: 28447976 PMCID: PMC5564457 DOI: 10.3791/54729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Major hepatic surgery with inflow occlusion, and liver transplantation, necessitate a period of warm ischemia, and a period of reperfusion leading to ischemia/reperfusion (I/R) injury with myriad negative consequences. Potential I/R injury in marginal organs destined for liver transplantation contributes to the current donor shortage secondary to a decreased organ utilization rate. A significant need exists to explore hepatic I/R injury in order to mediate its impact on graft function in transplantation. Rat liver hilar clamp models are used to investigate the impact of different molecules on hepatic I/R injury. Depending on the model, these molecules have been delivered using inhalation, epidural infusion, intraperitoneal injection, intravenous administration or injection into the peripheral superior mesenteric vein. A rat liver hilar clamp model has been developed for use in studying the impact of pharmacologic molecules in ameliorating I/R injury. The described model for rat liver hilar clamp includes direct cannulation of the portal supply to the ischemic hepatic segment via a side branch of the portal vein, allowing for direct segmental hepatic delivery. Our approach is to induce ischemia in the left lateral and median lobes for 60 min, during which time the substance under study is infused. In this case, pegylated-superoxide dismutase (PEG-SOD), a free radical scavenger, is infused directly into the ischemic segment. This series of experiments demonstrates that infusion of PEG-SOD is protective against hepatic I/R injury. Advantages of this approach include direct injection of the molecule into the ischemic segment with consequent decrease in volume of distribution and reduction in systemic side effects.
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Affiliation(s)
- Eliza W Beal
- Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Lab, Division of Transplant, Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center
| | - Curtis Dumond
- Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Lab, Division of Transplant, Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center
| | - Jung-Lye Kim
- Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Lab, Division of Transplant, Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center
| | - Khalid Mumtaz
- Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Lab, Division of Transplant, Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center
| | - Don Hayes
- Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Lab, Division of Transplant, Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center
| | - Ken Washburn
- Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Lab, Division of Transplant, Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center
| | - Bryan A Whitson
- Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Lab, Division of Transplant, Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center
| | - Sylvester M Black
- Collaboration for Organ Perfusion, Protection, Engineering and Regeneration (COPPER) Lab, Division of Transplant, Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center;
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Akter S, Kawauchi S, Sato S, Aosasa S, Yamamoto J, Nishidate I. In vivo imaging of hepatic hemodynamics and light scattering property during ischemia-reperfusion in rats based on spectrocolorimetry. BIOMEDICAL OPTICS EXPRESS 2017; 8:974-992. [PMID: 28270997 PMCID: PMC5330569 DOI: 10.1364/boe.8.000974] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 01/11/2017] [Accepted: 01/14/2017] [Indexed: 05/13/2023]
Abstract
A red-green-blue camera-based imaging method is proposed for estimating spatial maps of concentrations of oxyhemoglobin (CHbO), deoxyhemoglobin (CHbR), total hemoglobin (CHbT), tissue oxygen saturation (StO2), and scattering power (b) in liver tissue. Hemodynamic responses to hepatic ischemia-reperfusion of in vivo rat liver tissues induced by portal triad occlusion were evaluated. Upon portal triad occlusion, this method yielded images of decreased CHbO, CHbT, StO2, and b, and increased CHbR followed by a progressive increase in CHbO and StO2 during reperfusion. Time courses of the changes in CHbO, CHbR, CHbT, and StO2 over different regions of interest (ROIs) revealed that ischemia results in an abrupt significant (P<0.05) reduction in CHbO, CHbT, and StO2 with a simultaneous increase in CHbR compared to the baseline level, indicative of the hemodynamic responses during hepatic ischemia-reperfusion. Upon reperfusion, there was a gradual increase in CHbO and StO2, and decrease in CHbR. The change in average scattering power b implies the presence of morphological alterations in the cellular and subcellular structures induced by ischemia or anoxia. This study shows the potential of monitoring spatiotemporal changes in hemodynamic parameters and morphological changes in studies of hepatic pathophysiology.
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Affiliation(s)
- Sharmin Akter
- Graduate School of Bio-Applications & Systems Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan
| | - Satoko Kawauchi
- Division of Biomedical Information Sciences, National Defense Medical College Research Institute, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Shunichi Sato
- Division of Biomedical Information Sciences, National Defense Medical College Research Institute, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Suefumi Aosasa
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Junji Yamamoto
- Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
| | - Izumi Nishidate
- Graduate School of Bio-Applications & Systems Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan
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Suyavaran A, Thirunavukkarasu C. Preconditioning methods in the management of hepatic ischemia reperfusion- induced injury: Update on molecular and future perspectives. Hepatol Res 2017; 47:31-48. [PMID: 26990696 DOI: 10.1111/hepr.12706] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 02/12/2016] [Accepted: 03/11/2016] [Indexed: 12/14/2022]
Abstract
Hepatic IR (ischemia reperfusion) injury is a commonly encountered obstacle in the post-operative management of hepatic surgery. Hepatic IR occurs during 'Pringle maneuver' for reduction of blood loss or during a brief period of cold storage followed by reperfusion of liver grafts. The stress induced during hepatic IR, triggers a spectrum of cellular responses leading to the varying degrees of hepatic complications which in turn affect the post operative care. Different preconditioning methods either activate or subdue different sets of molecular signals, resulting in varied levels of protection against hepatic IR injury. Yet, there is a serious lacuna in the knowledge regarding the choice of preconditioning methods and the resulting molecular changes in order to assess the efficiency and choice of these methods correctly. This review provides an update on the various preconditioning approaches such as surgical/ischemic, antioxidant, pharmaceutical and genetic preconditioning strategies published during last six years (2009-2015). Further, we discuss the attenuation or inhibition of specific inflammatory, apoptotic and necrotic markers in the various experimental models of liver IR subjected to different preconditioning strategies. While enlisting the controversies in the ischemic preconditioning strategy, we bring out the uncertainties in the existing molecular targets and their reliability in the attenuation of hepatic IR injury. Future research studies would include the novel preconditioning strategies employ i) the targeted gene silencing of key molecular targets inducing IR, ii) hyper expression of beneficial molecular signals against IR via gene transfer techniques. The above studies would see the combination of these latest techniques with the established preconditioning strategies for better post-operative hepatic management.
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Affiliation(s)
- Arumugam Suyavaran
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
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48
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Fukazawa K, Lang JD. Role of nitric oxide in liver transplantation: Should it be routinely used? World J Hepatol 2016; 8:1489-1496. [PMID: 28008339 PMCID: PMC5143429 DOI: 10.4254/wjh.v8.i34.1489] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 08/06/2016] [Accepted: 10/18/2016] [Indexed: 02/06/2023] Open
Abstract
Ischemia-reperfusion injury (IRI) continues to be a major contributor to graft dysfunction, thus supporting the need for therapeutic strategies focused on minimizing organ damage especially with growing numbers of extended criteria grafts being utilized which are more vulnerable to cold and warm ischemia. Nitric oxide (NO·) is highly reactive gaseous molecule found in air and regarded as a pollutant. Not surprising, it is extremely bioactive, and has been demonstrated to play major roles in vascular homeostasis, neurotransmission, and host defense inflammatory reactions. Under conditions of ischemia, NO· has consistently been demonstrated to enhance microcirculatory vasorelaxation and mitigate pro-inflammatory responses, making it an excellent strategy for patients undergoing organ transplantation. Clinical studies designed to test this hypothesis have yielded very promising results that includes reduced hepatocellular injury and enhanced graft recovery without any identifiable complications. By what means NO· facilitates extra-pulmonary actions is up for debate and speculation. The general premise is that they are NO· containing intermediates in the circulation, that ultimately mediate either direct or indirect effects. A plethora of data exists explaining how NO·-containing intermediate molecules form in the plasma as S-nitrosothiols (e.g., S-nitrosoalbumin), whereas other compelling data suggest nitrite to be a protective mediator. In this article, we discuss the use of inhaled NO· as a way to protect the donor liver graft against IRI in patients undergoing liver transplantation.
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49
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Sahin Ersoy G, Kurek Eken M, Cevik O, Cilingir OT, Tal R. Mycophenolate mofetil attenuates uterine ischaemia/reperfusion injury in a rat model. Reprod Biomed Online 2016; 34:115-123. [PMID: 27913135 DOI: 10.1016/j.rbmo.2016.11.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 11/03/2016] [Accepted: 11/08/2016] [Indexed: 10/20/2022]
Abstract
This study evaluated the effect of mycophenolate mofetil (MMF) on uterine tissue preservation following ischaemia/reperfusion (I/R) injury. Uterine I/R injury was induced in rats by clamping the lower abdominal aorta and ovarian arteries for 30 min. Group I/R + V (n = 7) received vehicle alone while Group I/R + M (n = 7) received 20 mg/kg/day MMF. Control groups underwent sham surgery and received vehicle (Group C) or 20 mg/kg/day MMF (Group M) (n = 7 for both). Four hours after detorsion, uterine tissue 8-hydroxy-2'-deoxyguanosine (8-OHdG), glutathione, malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD) and serum ischaemia modified albumin (IMA) concentrations were measured. Histopathological analyses were performed. The I/R + M group showed significant reduction in serum IMA and uterine tissue 8-OHdG, MDA and MPO and significant increase in SOD concentrations compared with the I/R + V group, indicating a protective effect against I/R oxidative damage (P = 0.009, P = 0.006, P = 0.002, P = 0.003 and P = 0.009, respectively). Histopathological evaluation revealed MMF treatment resulted in significantly less tissue and cellular damage and apoptosis compared with the I/R + V group. These results indicate MMF is effective in attenuating uterine tissue damage and preventing apoptosis following uterine I/R injury, probably via anti-inflammatory and anti-oxidative action.
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Affiliation(s)
- Gulcin Sahin Ersoy
- Department of Obstetrics and Gynecology, Kartal Dr Lutfi Kirdar Education and Research Hospital, Istanbul, Turkey.
| | - Meryem Kurek Eken
- Department of Obstetrics and Gynecology, Zeynep Kamil Education and Research Hospital, Istanbul, Turkey
| | - Ozge Cevik
- Department of Biochemistry, Faculty of Pharmacy, Cumhuriyet University, Sivas, Turkey
| | - Ozlem T Cilingir
- Department of Histology and Embryology, Marmara University School of Medicine, Istanbul, Turkey
| | - Reshef Tal
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
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50
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Hrydziuszko O, Perera MTPR, Laing R, Kirwan J, Silva MA, Richards DA, Murphy N, Mirza DF, Viant MR. Mass Spectrometry Based Metabolomics Comparison of Liver Grafts from Donors after Circulatory Death (DCD) and Donors after Brain Death (DBD) Used in Human Orthotopic Liver Transplantation. PLoS One 2016; 11:e0165884. [PMID: 27835640 PMCID: PMC5105997 DOI: 10.1371/journal.pone.0165884] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 10/19/2016] [Indexed: 12/14/2022] Open
Abstract
Use of marginal liver grafts, especially those from donors after circulatory death (DCD), has been considered as a solution to organ shortage. Inferior outcomes have been attributed to donor warm ischaemic damage in these DCD organs. Here we sought to profile the metabolic mechanisms underpinning donor warm ischaemia. Non-targeted Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry metabolomics was applied to biopsies of liver grafts from donors after brain death (DBD; n = 27) and DCD (n = 10), both during static cold storage (T1) as well as post-reperfusion (T2). Furthermore 6 biopsies from DBD donors prior to the organ donation (T0) were also profiled. Considering DBD and DCD together, significant metabolic differences were discovered between T1 and T2 (688 peaks) that were primarily related to amino acid metabolism, meanwhile T0 biopsies grouped together with T2, denoting the distinctively different metabolic activity of the perfused state. Major metabolic differences were discovered between DCD and DBD during cold-phase (T1) primarily related to glucose, tryptophan and kynurenine metabolism, and in the post-reperfusion phase (T2) related to amino acid and glutathione metabolism. We propose tryptophan/kynurenine and S-adenosylmethionine as possible biomarkers for the previously established higher graft failure of DCD livers, and conclude that the associated pathways should be targeted in more exhaustive and quantitative investigations.
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Affiliation(s)
- Olga Hrydziuszko
- School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom
| | - M. Thamara P. R. Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2TH, United Kingdom
| | - Richard Laing
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2TH, United Kingdom
| | - Jennifer Kirwan
- School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom
| | - Michael A. Silva
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2TH, United Kingdom
| | - Douglas A. Richards
- The Department of Pharmacology, School of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom
| | - Nick Murphy
- Department of Critical Care and Anaesthesia, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, B15 2TH, United Kingdom
| | - Darius F. Mirza
- School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom
| | - Mark R. Viant
- School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom
- * E-mail:
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