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de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
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Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
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Casillas-Ramírez A, Micó-Carnero M, Sánchez-González A, Maroto-Serrat C, Trostchansky A, Peralta C. NO-IL-6/10-IL-1β axis: a new pathway in steatotic and non-steatotic liver grafts from brain-dead donor rats. Front Immunol 2023; 14:1178909. [PMID: 37593740 PMCID: PMC10427871 DOI: 10.3389/fimmu.2023.1178909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 07/11/2023] [Indexed: 08/19/2023] Open
Abstract
INTRODUCTION Brain death (BD) and steatosis are both risk factors for organ dysfunction or failure in liver transplantation (LT). MATERIAL AND METHODS Here, we examine the role of interleukin 6 (IL- 6) and IL-10 in LT of both non-steatotic and steatotic liver recovered from donors after brain death (DBDs), as well as the molecular signaling pathways underlying the effects of such cytokines. RESULTS BD reduced IL-6 levels only in nonsteatotic grafts, and diminished IL-10 levels only in steatotic ones. In both graft types, BD increased IL-1β, which was associated with hepatic inflammation and damage. IL-6 administration reduced IL-1β only in non-steatotic grafts and protected them against damage and inflammation. Concordantly, IL-1β inhibition via treatment with an IL-1 receptor antagonist caused the same benefits in non-steatotic grafts. Treatment with IL-10 decreased IL-1β only in steatotic grafts and reduced injury and inflammation specifically in this graft type. Blockading the IL-1β effects also reduced damage and inflammation in steatotic grafts. Also, blockade of IL-1β action diminished hepatic cAMP in both types of livers, and this was associated with a reduction in liver injury and inflammation, then pointing to IL-1β regulating cAMP generation under LT and BD conditions. Additionally, the involvement of nitric oxide (NO) in the effects of interleukins was evaluated. Pharmacological inhibition of NO in LT from DBDs prompted even more evident reductions of IL-6 or IL-10 in non-steatotic and steatotic grafts, respectively. This exacerbated the already high levels of IL-1β seen in LT from DBDs, causing worse damage and inflammation in both graft types. The administration of NO donors to non-steatotic grafts potentiated the beneficial effects of endogenous NO, since it increased IL-6 levels, and reduced IL-1β, inflammation, and damage. However, treatment with NO donors in steatotic grafts did not modify IL-10 or IL-1β levels, but induced more injurious effects tan the induction of BD alone, characterized by increased nitrotyrosine, lipid peroxidation, inflammation, and hepatic damage. CONCLUSION Our study thus highlights the specificity of new signaling pathways in LT from DBDs: NO-IL-6-IL-1β in non-steatotic livers and NO-IL-10-IL-1β in steatotic ones. This opens up new therapeutic targets that could be useful in clinical LT.
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Affiliation(s)
- Araní Casillas-Ramírez
- Department of Teaching and Research Sub-Direction, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria, Mexico
- Facultad de Medicina e Ingeniería en Sistemas Computacionales de Matamoros, Universidad Autónoma de Tamaulipas, Matamoros, Mexico
| | - Marc Micó-Carnero
- Department of Liver, Digestive System and Metabolism, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Alfredo Sánchez-González
- Department of Teaching and Research Sub-Direction, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria, Mexico
| | - Cristina Maroto-Serrat
- Department of Liver, Digestive System and Metabolism, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Andrés Trostchansky
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Carmen Peralta
- Department of Liver, Digestive System and Metabolism, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
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Bi J, Zhang J, Ke M, Wang T, Wang M, Liu W, Du Z, Ren Y, Zhang S, Wu Z, Lv Y, Wu R. HSF2BP protects against acute liver injury by regulating HSF2/HSP70/MAPK signaling in mice. Cell Death Dis 2022; 13:830. [PMID: 36167792 PMCID: PMC9515097 DOI: 10.1038/s41419-022-05282-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 09/15/2022] [Accepted: 09/16/2022] [Indexed: 01/23/2023]
Abstract
Heat shock proteins (HSPs) depletion and protein misfolding are important causes of hepatocyte death and liver regeneration disorder in liver injury. HSF2BP, as its name implies, is a binding protein of HSF2, but the specific role of HSF2BP in heat shock response (HSR) remains unknown. The aim of this study is to identify the role of HSF2BP in HSR and acute liver injury. In this study, we found that HSF2BP expression increased significantly within 24 h after APAP administration, and the trend was highly consistent with that of HSP70. hsf2bp-KO and hsf2bp-TG mouse models demonstrated HSF2BP reduced hepatocyte death, ameliorated inflammation, and improved liver function in APAP- or D-GalN/LPS- induced liver injury. Meanwhile, a significant increase of the survival rate was observed in hsf2bp-TG mice after APAP administration. Further studies showed that HSF2BP upregulated the expression of HSF2 and HSP70 and inhibited the activation of Jnk1/2 and P38 MAPK. Additionally, HSP70 siRNA pretreatment abolished the effect of HSF2BP on the MAPK pathway in APAP-treated hepatocytes. The results reveal that HSF2BP is a protective factor in acute liver injury, and the HSF2BP/HSP70/MAPK regulatory axis is crucial for the pathogenesis of liver injury. HSF2BP is a potential therapeutic target for liver injury.
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Affiliation(s)
- Jianbin Bi
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Jia Zhang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Mengyun Ke
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Tao Wang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Mengzhou Wang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Wuming Liu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Zhaoqing Du
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
- Department of Hepatobiliary Surgery, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi Province, China
| | - Yifan Ren
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Shuqun Zhang
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Zheng Wu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
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Lee HM, Choi JW, Choi MS. Role of Nitric Oxide and Protein S-Nitrosylation in Ischemia-Reperfusion Injury. Antioxidants (Basel) 2021; 11:57. [PMID: 35052559 PMCID: PMC8772765 DOI: 10.3390/antiox11010057] [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: 11/03/2021] [Revised: 12/06/2021] [Accepted: 12/24/2021] [Indexed: 12/19/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) is a process in which damage is induced in hypoxic tissue when oxygen supply is resumed after ischemia. During IRI, restoration of reduced nitric oxide (NO) levels may alleviate reperfusion injury in ischemic organs. The protective mechanism of NO is due to anti-inflammatory effects, antioxidant effects, and the regulation of cell signaling pathways. On the other hand, it is generally known that S-nitrosylation (SNO) mediates the detrimental or protective effect of NO depending on the action of the nitrosylated target protein, and this is also applied in the IRI process. In this review, the effect of each change of NO and SNO during the IRI process was investigated.
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Affiliation(s)
- Hyang-Mi Lee
- College of Pharmacy, Dongduk Women’s University, Seoul 02748, Korea;
| | - Ji Woong Choi
- College of Pharmacy, Gachon University, Incheon 21936, Korea
| | - Min Sik Choi
- Laboratory of Pharmacology, College of Pharmacy, Dongduk Women’s University, Seoul 02748, Korea
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Gunata M, Parlakpinar H. A review of myocardial ischaemia/reperfusion injury: Pathophysiology, experimental models, biomarkers, genetics and pharmacological treatment. Cell Biochem Funct 2020; 39:190-217. [PMID: 32892450 DOI: 10.1002/cbf.3587] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 08/03/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022]
Abstract
Cardiovascular diseases are known to be the most fatal diseases worldwide. Ischaemia/reperfusion (I/R) injury is at the centre of the pathology of the most common cardiovascular diseases. According to the World Health Organization estimates, ischaemic heart disease is the leading global cause of death, causing more than 9 million deaths in 2016. After cardiovascular events, thrombolysis, percutaneous transluminal coronary angioplasty or coronary bypass surgery are applied as treatment. However, after restoring coronary blood flow, myocardial I/R injury may occur. It is known that this damage occurs due to many pathophysiological mechanisms, especially increasing reactive oxygen types. Besides causing cardiomyocyte death through multiple mechanisms, it may be an important reason for affecting other cell types such as platelets, fibroblasts, endothelial and smooth muscle cells and immune cells. Also, polymorphonuclear leukocytes are associated with myocardial I/R damage during reperfusion. This damage may be insufficient in patients with co-morbidity, as it is demonstrated that it can be prevented by various endogenous antioxidant systems. In this context, the resulting data suggest that optimal cardioprotection may require a combination of additional or synergistic multi-target treatments. In this review, we discussed the pathophysiology, experimental models, biomarkers, treatment and its relationship with genetics in myocardial I/R injury. SIGNIFICANCE OF THE STUDY: This review summarized current information on myocardial ischaemia/reperfusion injury (pathophysiology, experimental models, biomarkers, genetics and pharmacological therapy) for researchers and reveals guiding data for researchers, especially in the field of cardiovascular system and pharmacology.
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Affiliation(s)
- Mehmet Gunata
- Department of Medical Pharmacology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Hakan Parlakpinar
- Department of Medical Pharmacology, Faculty of Medicine, Inonu University, Malatya, Turkey
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Orhan E, Gündüz Ö, Kaya O, Öznur M, Şahin E. Transferring the protective effect of remote ischemic preconditioning on skin flap among rats by blood serum. J Plast Surg Hand Surg 2019; 53:198-203. [DOI: 10.1080/2000656x.2019.1582422] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Erkan Orhan
- Department of Plastic Surgery, School of Medicine, Gaziantep University, Gaziantep, Turkey
| | - Özgür Gündüz
- Department of Medical Pharmacology, School of Medicine, Trakya University, Edirne, Turkey
| | - Oktay Kaya
- Department of Physiology, School of Medicine, Trakya University, Edirne, Turkey
| | - Meltem Öznur
- Department of Pathology, School of Medicine, Namik Kemal University, Tekirdağ, Turkey
| | - Ertan Şahin
- Department of Nuclear Medicine, School of Medicine, Gaziantep University, Gaziantep, Turkey
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Hypoxia-induced microRNA-191 contributes to hepatic ischemia/reperfusion injury through the ZONAB/Cyclin D1 axis. Cell Death Differ 2018; 26:291-305. [PMID: 29769640 DOI: 10.1038/s41418-018-0120-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 04/12/2018] [Accepted: 04/12/2018] [Indexed: 01/30/2023] Open
Abstract
Hepatic ischemia/reperfusion injury (IRI) is a common cause of morbidity and mortality in liver transplantation settings and involves severe cell death and inflammatory responses. MicroRNA-191 has recently been reported to be abnormally expressed in hepatocellular carcinoma and other liver diseases in the regulation of important cellular processes. However, little is known about its function and molecular mechanism in IRI. Here, we demonstrate that miR-191 is significantly upregulated in a cultured cell line during hypoxia/reperfusion (H/R) and in liver tissue during IRI in mice. The activation of miR-191 under hypoxic conditions is mediated by hypoxia-inducible factor-1α (HIF1α) binding to its promoter region. Global miR-191 KO mice were constructed by CRISPR/Cas9 system, and we found that miR-191 deficiency markedly reduces liver tissue damage, cell inflammatory responses and cell death in a mouse hepatic IRI model. Under the H/R condition, miR-191 overexpression promotes G0/G1 cell cycle arrest and cell apoptosis, but inhibition of miR-191 facilitates cell cycle progression and decreases cell death. Mechanistically, upon induction by hypoxia or ischemia, miR-191 suppresses expression of ZO-1-associated Y-box factor (ZONAB) and its downstream factor Cyclin D1, consequently resulting in cell death and tissue injury. Moreover, the effects of miR-191 on cell cycle arrest and cell apoptosis are abrogated by ZONAB overexpression, and vice versa. Taken together, our results indicate an important role of the HIF1α/miR-191/ZONAB signaling pathway in hepatic IRI and suggest miR-191 as a novel therapeutic target for the treatment of liver IRI.
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Abstract
BACKGROUND The protective role (decrease ischemia-reperfusion injury) of ischemic preconditioning (IP) before continuous vascular occlusion in liver resection is controversial. This meta-analysis aimed to compare the advantages and any potential disadvantages of IP maneuver. METHODS A systematic search in the Embase, Medline, PubMed databases, and the Cochrane Library was performed using both medical subject headings (MeSH) and truncated word searches to identify all randomized controlled trials (RCTs) published on this topic. The primary outcomes were postoperative morbidity, mortality, postoperative aspartate aminotransferase (AST) level, alanine aminotransferase (ALT) level, and total bilirubin (TB) level. Pooled odds ratios (ORs) and weighted mean differences (WMDs) with 95% confidence intervals (95% CIs) were calculated using either the random effects model or fixed effects model. RESULTS Thirteen RCTs involving 918 patients were analyzed to achieve a summated outcome. The patients have been divided into IP group (n = 455) and no IP group (n = 463) before continuous vascular occlusion. No significant difference was found in postoperative mortality between both groups (P = .30). Subgroup analysis revealed that the postoperative morbidity in the cirrhosis subgroup was significantly less for the IP group compared with the control group (P = .01). In the cirrhosis subgroup, the result was stable (P = .04), without heterogeneity (P = .59; I = 0%). Meta-analysis of AST level on postoperative day (POD) 1 indicated lower postoperative AST level in the IP group (P = .04). The analysis of ALT level showed lower ALT level in the IP group versus control group (P = .02). However, there was no difference in postoperative AST and ALT level after excluding 1 study with statistical heterogeneity (all P > .05). With respect to postoperative TB level, there was no significant difference between 2 groups. CONCLUSION IP cannot decrease the hospital mortality for patients undergoing hepatectomy. IP may be beneficial for patients with cirrhosis due to less morbidity in patients with liver cirrhosis. However, we cannot conclude that IP can decrease ischemia-reperfusion injury because it did not significantly decrease postoperative AST, ALT, and TB levels.
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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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Liu M, Chen P. Proliferation‑inhibiting pathways in liver regeneration (Review). Mol Med Rep 2017; 16:23-35. [PMID: 28534998 DOI: 10.3892/mmr.2017.6613] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 03/13/2017] [Indexed: 12/14/2022] Open
Abstract
Liver regeneration, an orchestrated process, is the primary compensatory mechanism following liver injury caused by various factors. The process of liver regeneration consists of three stages: Initiation, proliferation and termination. Proliferation‑promoting factors, which stimulate the recovery of mitosis in quiescent hepatocytes, are essential in the initiation and proliferation steps of liver regeneration. Proliferation‑promoting factors act as the 'motor' of liver regeneration, whereas proliferation inhibitors arrest cell proliferation when the remnant liver reaches a suitable size. Certain proliferation inhibitors are also expressed and activated in the first two steps of liver regeneration. Anti‑proliferation factors, acting as a 'brake', control the speed of proliferation and determine the terminal point of liver regeneration. Furthermore, anti‑proliferation factors function as a 'steering‑wheel', ensuring that the regeneration process proceeds in the right direction by preventing proliferation in the wrong direction, as occurs in oncogenesis. Therefore, proliferation inhibitors to ensure safe and stable liver regeneration are as important as proliferation‑promoting factors. Cytokines, including transforming growth factor‑β and interleukin‑1, and tumor suppressor genes, including p53 and p21, are important members of the proliferation inhibitor family in liver regeneration. Certain anti‑proliferation factors are involved in the process of gene expression and protein modification. The suppression of liver regeneration led by metabolism, hormone activity and pathological performance have been reviewed previously. However, less is known regarding the proliferation inhibitors of liver regeneration and further investigations are required. Detailed information regarding the majority of known anti‑proliferation signaling pathways also remains fragmented. The present review aimed to understand the signalling pathways that inhbit proliferation in the process of liver regeneration.
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Affiliation(s)
- Menggang Liu
- Department of Hepatobiliary Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042, P.R. China
| | - Ping Chen
- Department of Hepatobiliary Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042, P.R. China
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Gao DD, Fu J, Qin B, Huang WX, Yang C, Jia B. Recombinant adenovirus containing hyper-interleukin-6 and hepatocyte growth factor ameliorates acute-on-chronic liver failure in rats. World J Gastroenterol 2016; 22:4136-4148. [PMID: 27122664 PMCID: PMC4837431 DOI: 10.3748/wjg.v22.i16.4136] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 02/01/2016] [Accepted: 03/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the protective efficacy of recombinant adenovirus containing hyper-interleukin-6 (Hyper-IL-6, HIL-6) and hepatocyte growth factor (HGF) (Ad-HGF-HIL-6) compared to that of recombinant adenovirus containing either HIL-6 or HGF (Ad-HIL-6 or Ad-HGF) in rats with acute-on-chronic liver failure (ACLF).
METHODS: The recombinant adenoviruses containing HIL-6 and/or HGF were constructed. We established an ACLF model, and rats were randomly assigned to control, model, Ad-GFP, Ad-HIL-6, Ad-HGF or Ad-HGF-HIL-6 group. We collected serum and liver tissue samples to test pathological changes, biochemical indexes and molecular biological indexes.
RESULTS: Attenuated alanine aminotransferase, prothrombin time, high-mobility group box 1 (HMGB1), endotoxin, tumour necrosis factor (TNF)-α and interferon-γ were observed in the Ad-HGF-, Ad-HIL-6- and Ad-HGF-HIL-6-treated rats with ACLF. Likewise, reduced hepatic damage and apoptotic activity, as well as reduced HMGB1 and Bax proteins, but raised expression of Ki67 and Bcl-2 proteins and Bcl-2/Bax ratio were also observed in the Ad-HGF-, Ad-HIL-6- and Ad-HGF-HIL-6-treated rats with ACLF. More significant changes were observed in the Ad-HGF-HIL-6 treatment group without obvious side effects. Furthermore, caspase-3 at the protein level decreased in the Ad-HIL-6 and Ad-HGF-HIL-6 treatment groups, more predominantly in the latter group.
CONCLUSION: This study identifies that the protective efficacy of Ad-HGF-HIL-6 is more potent than that of Ad-HGF or Ad-HIL-6 in ACLF rats, with no significant side effects.
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Hamilton K, Wolfswinkel EM, Weathers WM, Xue AS, Hatef DA, Izaddoost S, Hollier LH. The Delay Phenomenon: A Compilation of Knowledge across Specialties. Craniomaxillofac Trauma Reconstr 2014; 7:112-8. [PMID: 25071876 DOI: 10.1055/s-0034-1371355] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 04/22/2013] [Indexed: 12/19/2022] Open
Abstract
Objective The purpose of this article is to review and integrate the available literature in different fields to gain a better understanding of the basic physiology and optimize vascular delay as a reconstructive surgery technique. Methods A broad search of the literature was performed using the Medline database. Two queries were performed using "vascular delay," a search expected to yield perspectives from the field of plastic and reconstructive surgery, and "ischemic preconditioning," (IPC) which was expected to yield research on the same topic in other fields. Results The combined searches yielded a total of 1824 abstracts. The "vascular delay" query yielded 76 articles from 1984 to 2011. The "ischemic preconditioning" query yielded 6534 articles, ranging from 1980 to 2012. The abstracts were screened for those from other specialties in addition to reconstructive surgery, analyzed potential or current uses of vascular delay in practice, or provided developments in understanding the pathophysiology of vascular delay. 70 articles were identified that met inclusion criteria and were applicable to vascular delay or ischemic preconditioning. Conclusion An understanding of IPC's implementation and mechanisms in other fields has beneficial implications for the field of reconstructive surgery in the context of the delay phenomenon. Despite an incomplete model of IPC's pathways, the anti-oxidative, anti-apoptotic and anti-inflammatory benefits of IPC are well recognized. The activation of angiogenic genes through IPC could allow for complex flap design, even in poorly vascularized regions. IPC's promotion of angiogenesis and reduction of endothelial dysfunction remain most applicable to reconstructive surgery in reducing graft-related complications and flap failure.
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Affiliation(s)
| | | | | | - Amy S Xue
- Plastic Surgery, Baylor College of Medicine, Houston, Texas
| | - Daniel A Hatef
- Plastic Surgery, Baylor College of Medicine, Houston, Texas
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13
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Elias-Miró M, Jiménez-Castro MB, Rodés J, Peralta C. Current knowledge on oxidative stress in hepatic ischemia/reperfusion. Free Radic Res 2013; 47:555-568. [PMID: 23738581 DOI: 10.3109/10715762.2013.811721] [Citation(s) in RCA: 135] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ischemia/reperfusion (I/R) injury associated with hepatic resections and liver transplantation remains a serious complication in clinical practice, despite several attempts to solve the problem. The redox balance, which is pivotal for normal function and integrity of tissues, is dysregulated during I/R, leading to an accumulation of reactive oxygen species (ROS). Formation of ROS and oxidant stress are the disease mechanisms most commonly invoked in hepatic I/R injury. The present review examines published results regarding possible sources of ROS and their effects in the context of I/R injury. We also review the effect of oxidative stress on marginal livers, which are more vulnerable to I/R-induced oxidative stress. Strategies to improve the viability of marginal livers could reduce the risk of dysfunction after surgery and increase the number of organs suitable for transplantation. The review also considers the therapeutic strategies developed in recent years to reduce the oxidative stress induced by hepatic I/R, and we seek to explain why some of them have not been applied clinically. New antioxidant strategies that have yielded promising results for hepatic I/R injury are discussed.
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Affiliation(s)
- M Elias-Miró
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona (IDIBAPS), Spain
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14
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Andreas M, Schmid AI, Doberer D, Schewzow K, Weisshaar S, Heinze G, Bilban M, Moser E, Wolzt M. Heme arginate improves reperfusion patterns after ischemia: a randomized, placebo-controlled trial in healthy male subjects. J Cardiovasc Magn Reson 2012; 14:55. [PMID: 22857721 PMCID: PMC3438022 DOI: 10.1186/1532-429x-14-55] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2011] [Accepted: 07/09/2012] [Indexed: 12/30/2022] Open
Abstract
UNLABELLED BACKGROUND Heme arginate can induce heme oxygenase-1 to protect tissue against ischemia-reperfusion injury. Blood oxygen level dependent (BOLD) functional magnetic resonance imaging measures changes in tissue oxygenation with a high spatial and temporal resolution. BOLD imaging was applied to test the effect of heme arginate on experimental ischemia reperfusion injury in the calf muscles. METHODS A two period, controlled, observer blinded, crossover trial was performed in 12 healthy male subjects. Heme arginate (1 mg/kg body weight) or placebo were infused 24 h prior to a 20 min leg ischemia induced by a thigh cuff. 3 Tesla BOLD-imaging of the calf was performed and signal time courses from soleus, gastrocnemius and tibialis anterior muscle were available from 11 participants for technical reasons. RESULTS Peak reactive hyperemia signal of the musculature was significantly increased and occurred earlier after heme arginate compared to placebo (106.2 ± 0.6% at 175 ± 16s vs. 104.5 ± 0.6% at 221 ± 19s; p = 0.025 for peak reperfusion and p = 0.012 for time to peak). CONCLUSIONS A single high dose of heme arginate improves reperfusion patterns during ischemia reperfusion injury in humans. BOLD sensitive, functional MRI is applicable for the assessment of experimental ischemia reperfusion injury in skeletal muscle.
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Affiliation(s)
- Martin Andreas
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
- Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
| | - Albrecht Ingo Schmid
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
- MR Center of Excellence, Center for Biomedical Engineering and Physics, Medical University of Vienna, Vienna, Austria
| | - Daniel Doberer
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Kiril Schewzow
- MR Center of Excellence, Center for Biomedical Engineering and Physics, Medical University of Vienna, Vienna, Austria
| | - Stefan Weisshaar
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Georg Heinze
- Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Martin Bilban
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Ewald Moser
- MR Center of Excellence, Center for Biomedical Engineering and Physics, Medical University of Vienna, Vienna, Austria
| | - Michael Wolzt
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
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15
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Padrissa-Altés S, Zaouali MA, Boncompagni E, Bonaccorsi-Riani E, Carbonell T, Bardag-Gorce F, Oliva J, French SW, Bartrons R, Roselló-Catafau J. The use of a reversible proteasome inhibitor in a model of Reduced-Size Orthotopic Liver transplantation in rats. Exp Mol Pathol 2012; 93:99-110. [PMID: 22475623 DOI: 10.1016/j.yexmp.2012.03.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2012] [Accepted: 03/19/2012] [Indexed: 12/18/2022]
Abstract
Ischemia/reperfusion injury (IRI), inherent in liver transplantation (LT), is the main cause of initial deficiencies and primary non-function of liver allografts. Living-related LT was developed to alleviate the mortality resulting from the scarcity of suitable deceased grafts. The main problem in using living-related LT for adults is graft size disparity. In this study we propose for the first time that the use of a proteasome inhibitor (Bortezomib) treatment could improve liver regeneration and reduce IRI after Reduced-Size Orthotopic Liver transplantation (ROLT). Rat liver grafts were reduced by removing the left lateral lobe and the two caudate lobes and preserved in UW or IGL-1 preservation solution for 1h liver and then subjected to ROLT with or without Bortezomib treatment. Our results show that Bortezomib reduces IRI after LT and is correlated with a reduction in mitochondrial damage, oxidative stress and endoplasmic reticulum stress. Furthermore, Bortezomib also increased liver regeneration after reduced-size LT and increased the expression of well-known ischemia/reperfusion protective proteins such as nitric oxide synthase, heme oxigenase 1 (HO-1) and Heat Shock Protein 70. Our results open new possibilities for the study of alternative therapeutic strategies aimed at reducing IRI and increasing liver regeneration after LT. It is hoped that the results of our study will contribute towards improving the understanding of the molecular processes involved in IRI and liver regeneration, and therefore help to improve the outcome of this type of LT in the future.
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Affiliation(s)
- Susagna Padrissa-Altés
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d´Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas, Barcelona, Spain
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16
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Gomez D, Burn JL, Graham A, Homer-Vanniasinkam S, Prasad KR. Ischaemic Preconditioning and Intermittent Clamping Does not Influence Mediators of Liver Regeneration in a Human Liver Sinusoidal Endothelial Cell Model of Ischaemia-Reperfusion Injury. Gastroenterology Res 2012; 5:85-96. [PMID: 27785187 PMCID: PMC5051121 DOI: 10.4021/gr449w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/13/2012] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND The role of surgical technique on liver regeneration following surgery remains inconclusive. The aim of the study was to assess the effect of ischaemic preconditioning (IPC) and intermittent clamping (IC) on mediators of regeneration produced by human liver sinusoidal endothelial cells (SECs), using an in vitro hypoxia-reoxygenation model to mimic ischaemia-reperfusion injury (IRI). METHODS Following extraction from samples obtained from liver resection (n = 5), confluent culture flasks of SECs were subjected to IRI (1 hour hypoxia + 1 hour reoxygenation), IPC prior to IRI (10 minutes hypoxia + 10 minutes reoxygenation + 1 hour hypoxia + 1 hour reoxygenation), IC (15 minutes hypoxia + 5 minutes reoxygenation x 3 + 1 hour reoxygenation) and compared to controls. The production of various mediators was determined over 48 hours. RESULTS Interleukin (IL)-6, IL-8, granulocyte-colony stimulating factor (G-CSF) and hepatocyte growth factor (HGF) were produced by SECs. Both IPC and IC did not significantly influence the profile of IL-6, IL-8, G-CSF and HGF by SECs compared to IRI over the study period. CONCLUSION IPC and IC did not influence the production of pro-regenerative mediators in a SECs model of IRI. The role of surgical technique on liver regeneration remains to be determined.
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Affiliation(s)
- Dhanwant Gomez
- Department of Hepatobiliary Surgery and Transplantation, St. James's University Hospital, Leeds, UK
| | - J Lance Burn
- Section of Oncology, University of Sheffield, UK
| | - Ann Graham
- Department of Biomedical Sciences, University of Bradford, Bradford, UK
| | | | - K Rajendra Prasad
- Department of Hepatobiliary Surgery and Transplantation, St. James's University Hospital, Leeds, UK
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17
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Abstract
The liver is the body's most important detoxification organ and has an extreme ability to regenerate. The regeneration process can be divided into three stages: initiation, proliferation and termination. Most of previous studies focus on the initial stage and proliferative stage, while the mechanism for the proper termination of liver regeneration is still poorly understood. The termination stage involves a variety of cytokines and growth factors, which mainly function to inhibit mitogen-mediated liver cell growth-promoting effect and promote the apoptosis of excessively proliferating liver cells. In this paper we will discuss the major factors involved in the termination of liver regeneration.
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18
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Abu-Amara M, Yang SY, Seifalian A, Davidson B, Fuller B. The nitric oxide pathway--evidence and mechanisms for protection against liver ischaemia reperfusion injury. Liver Int 2012; 32:531-43. [PMID: 22316165 DOI: 10.1111/j.1478-3231.2012.02755.x] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Accepted: 12/29/2011] [Indexed: 02/13/2023]
Abstract
Ischaemia reperfusion (IR) injury is a clinical entity with a major contribution to the morbidity and mortality of liver surgery and transplantation. A central pathway of protection against IR injury utilizes nitric oxide (NO). Nitric oxide synthase (NOS) enzymes manufacture NO from L-arginine. NO generated by the endothelial NOS (eNOS) isoform protects against liver IR injury, whereas inducible NOS (iNOS)-derived NO may have either a protective or a deleterious effect during the early phase of IR injury, depending on the length of ischaemia, length of reperfusion and experimental model. In late phase hepatic IR injury, iNOS-derived NO plays a protective role. In addition to NOS consumption of L-arginine during NO synthesis, this amino acid may also be metabolized by arginase, an enzyme whose release is increased during prolonged ischaemia, and therefore diverts L-arginine away from NOS metabolism leading to a drop in the rate of NO synthesis. NO most commonly acts through the soluble guanylyl cyclase-cyclic GMP- protein kinase G pathway to ameliorate hepatic IR injury. Both endogenously generated and exogenously administered NO donors protect against liver IR injury. The beneficial effects of NO on liver IR are not, however, universal, and certain conditions, such as steatosis, may influence the protective effects of NO. In this review, the evidence for, and mechanisms of these protective actions of NO are discussed, and areas in need of further research are highlighted.
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Affiliation(s)
- Mahmoud Abu-Amara
- Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital, London, UK
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19
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Hahn O, Blázovics A, Váli L, Kupcsulik PK. The effect of ischemic preconditioning on redox status during liver resections--randomized controlled trial. J Surg Oncol 2011; 104:647-53. [PMID: 21744346 DOI: 10.1002/jso.21907] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2010] [Accepted: 02/14/2011] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND OBJECTIVES Portal clamping during liver resection decreases intraoperative blood loss, but causes ischemic-reperfusion (I-R) injury. Intermittent portal clamping (IPC) and ischemic preconditioning (IP) decreased I-R injury in animal models. Most of the human studies about IP excluded cirrhotic patients, whose liver is more vulnerable to I-R injury. The effect of IP and IPC during extended liver resection was investigated in this randomized controlled trial, with special respect to cirrhotic patients. METHODS One hundred sixty patients (100 normal liver, 60 cirrhotic) undergoing major liver resection were randomized to receive IPC (15 min ischemia, 5 min reperfusion), or IP (10 min ischemia, 10 min reperfusion). Serum oxygen-derived free radicals (ODFR) and antioxidant concentrations (preoperative, after reperfusion and 7th postoperative day), such as "conventional" liver tests (preoperative, 1st, 3rd, and 7th postoperative day) were measured. RESULTS IP resulted in significantly lower peak ODFR, AST, ALT, and bilirubin levels after liver resection than IPC (P < 0.05). The level of serum antioxidants after reperfusion was significantly higher in IP than in IPC groups (P < 0.05). In cirrhotic patients without IP none of these values normalized until the 7th postoperative day. CONCLUSIONS Ischemic preconditioning--especially in patients with liver cirrhosis--is a suitable method to decrease the I-R injury of the liver.
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Affiliation(s)
- Oszkár Hahn
- 1st Department of Surgery, Semmelweis University, Budapest, Hungary.
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20
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Li F, Lu S, Zhu R, Zhou Z, Ma L, Cai L, Liu Z. Heme oxygenase-1 is induced by thyroid hormone and involved in thyroid hormone preconditioning-induced protection against renal warm ischemia in rat. Mol Cell Endocrinol 2011; 339:54-62. [PMID: 21458530 DOI: 10.1016/j.mce.2011.03.019] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2010] [Revised: 02/13/2011] [Accepted: 03/24/2011] [Indexed: 01/05/2023]
Abstract
Thyroid hormone pretreatment was indicated to increase tissue tolerance to ischemia-reperfusion injury (IRI) in various organs, but the underlying molecular mechanisms remains largely unknown. Induction of heme oxygenase-1 (HO-1) protects organs against IRI. The present study investigated the effect of thyroid hormone on HO-1 expression and the possible relation between HO-1 and the thyroid hormone induced renal protection. T(3) administration in rat kidneys induced HO-1 expression in a time-dependent and dose-dependent way, and its expression was accompanied with significant depletion of reduced glutathione and increase in malondialdehyde content, showing a moderate oxidative stress that turns to normal level 48 h after drug injection. Thyroid hormone pretreatment (10 μg/100g body weight) 48 h before IR procedure significantly decreased serum creatinine and urea nitrogen and preserved renal histology, with significant reduction of parameters about oxidative stress and over-expression of HO-1 compared with that of IR group. In conclusion, T(3) administration involving oxidative stress in kidney exerts significant enhancement of HO-1 expression which may, at least in part, account for the renal preconditioning induced by T(3).
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Affiliation(s)
- Fei Li
- Central Laboratory, Changzhou NO.2 hospital affiliated to Nanjing Medical University, Changzhou 213000, PR China
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21
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Abstract
Liver regeneration is known to be a process involving highly organized and ordered tissue growth triggered by the loss of liver tissue, and remains a fascinating topic. A large number of genes are involved in this process, and there exists a sequence of stages that results in liver regeneration, while at the same time inhibitors control the size of the regenerated liver. The initiation step is characterized by priming of quiescent hepatocytes by factors such as TNF-α, IL-6 and nitric oxide. The proliferation step is the step during which hepatocytes enter into the cell cycle's G1 phase and are stimulated by complete mitogens including HGF, TGF-α and EGF. Hepatic stimulator substance, glucagon, insulin, TNF-α, IL-1 and IL-6 have also been implicated in regulating the regeneration process. Inhibitors and stop signals of hepatic regeneration are not well known and only limited information is available. Furthermore, the effects of other factors such as VEGF, PDGF, hypothyroidism, proliferating cell nuclear antigen, heat shock proteins, ischemic-reperfusion injury, steatosis and granulocyte colony-stimulating factor on liver regeneration are also systematically reviewed in this article. A tissue engineering approach using isolated hepatocytes for in vitro tissue generation and heterotopic transplantation of liver cells has been established. The use of stem cells might also be very attractive to overcome the limitation of donor liver tissue. Liver-specific differentiation of embryonic, fetal or adult stem cells is currently under investigation.
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Affiliation(s)
- Changku Jia
- Department of Hepatobiliary Surgery, Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China.
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22
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Abstract
Ischemia/reperfusion (I/R) injury still represents an important cause of morbidity following hepatic surgery and limits the use of marginal livers in hepatic transplantation. Transient blood flow interruption followed by reperfusion protects tissues against damage induced by subsequent I/R. This process known as ischemic preconditioning (IP) depends upon intrinsic cytoprotective systems whose activation can inhibit the progression of irreversible tissue damage. Compared to other organs, liver IP has additional features as it reduces inflammation and promotes hepatic regeneration. Our present understanding of the molecular mechanisms involved in liver IP is still largely incomplete. Experimental studies have shown that the protective effects of liver IP are triggered by the release of adenosine and nitric oxide and the subsequent activation of signal networks involving protein kinases such as phosphatidylinositol 3-kinase, protein kinase C δ/ε and p38 MAP kinase, and transcription factors such as signal transducer and activator of transcription 3, nuclear factor-κB and hypoxia-inducible factor 1. This article offers an overview of the molecular events underlying the preconditioning effects in the liver and points to the possibility of developing pharmacological approaches aimed at activating the intrinsic protective systems in patients undergoing liver surgery.
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Abstract
Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in heme catabolism that converts heme to Fe++, carbon monoxide and biliverdin. HO-1 acts anti-inflammatory and modulates apoptosis in many pathological conditions. In transplantation, HO-1 is overexpressed in organs during brain death, when undergoing ischemic damage and rejection. However, intentionally induced, it ameliorates pathological processes like ischemia reperfusion injury, allograft, xenograft or islet rejection, facilitates donor specific tolerance and alleviates chronic allograft changes. We herein consistently summarize the huge amount of data on HO-1 and transplantation that have been generated in multiple laboratories during the last 15years and suggest possible clinical implications and applications for the near future.
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Affiliation(s)
- Robert Öllinger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, Innsbruck, Austria.
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24
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Padrissa-Altés S, Zaouali MA, Franco-Gou R, Bartrons R, Boillot O, Rimola A, Arroyo V, Rodés J, Peralta C, Roselló-Catafau J. Matrix metalloproteinase 2 in reduced-size liver transplantation: beyond the matrix. Am J Transplant 2010; 10:1167-1177. [PMID: 20353474 DOI: 10.1111/j.1600-6143.2010.03092.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We studied the contribution of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) to the beneficial effects of preconditioning (PC) in reduced-size orthotopic liver transplantation (ROLT). We also examined the role of c-Jun N-terminal kinase (JNK) and whether it regulates MMP2 in these conditions. Animals were subjected to ROLT with or without PC and pharmacological modulation, and liver tissue samples were then analyzed. We found that MMP2, but notMMP9, is involved in the beneficial effects of PC in ROLT. MMP2 reduced hepatic injury and enhanced liver regeneration. Moreover, inhibition of MMP2 in PC reduced animal survival after transplantation. JNK inhibition in the PC group decreased hepatic injury and enhanced liver regeneration. Furthermore, JNK upregulated MMP2 in PC. In addition, we showed that Tissue inhibitors of matrix metalloproteinases 2 (TIMP2) was also upregulated in PC and that JNK modulation also altered its levels in ROLT and PC. Our results open up new possibilities for therapeutic treatments to reduce I/R injury and increase liver regeneration after ROLT, which are the main limitations in living-donor transplantation.
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Affiliation(s)
- S Padrissa-Altés
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas, Barcelona, Spain
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25
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Czubkowski P, Socha P, Pawlowska J. Current status of oxidative stress in pediatric liver transplantation. Pediatr Transplant 2010; 14:169-77. [PMID: 20113425 DOI: 10.1111/j.1399-3046.2009.01256.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Generation of free radicals in children after liver transplantation is multifactorial from ischemia-reperfusion injury, immunosuppression and post-transplant complications. Thus, this group is at higher risk of oxidative imbalance with molecular and clinical consequences. We discuss pathogenesis and ways of action against oxidative stress in liver transplant recipients.
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Affiliation(s)
- Piotr Czubkowski
- Department of Gastroenterology, Hepatology and Immunology, The Children's Memorial Health Institute, Warsaw, Poland.
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26
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Latanich CA, Toledo-Pereyra LH. Searching for NF-kappaB-based treatments of ischemia reperfusion injury. J INVEST SURG 2010; 22:301-15. [PMID: 19842907 DOI: 10.1080/08941930903040155] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
When a tissue becomes ischemic, a host of changes occur at the cellular level that lead to a shift in transcriptional activity of many inflammatory and cytoprotective compounds, a process which is extensively controlled through a family of transcription factors known as nuclear factor kappa-B (NF-kappaB). This shift in activity paradoxically results in both a cytoprotective effect at the cellular level and upon reperfusion, a generally destructive inflammatory response, a phenomenon referred to as ischemia reperfusion (IR) injury. To date, a number of methods of modifying the activity of NF-kappaB through either physiologic or pharmacologic manipulation have been developed and studied in animal models of IR injury and in some cases in human clinical trials. Nearly every method of NF-kappaB antagonism has demonstrated a discrete protective effect allowing investigators to reduce myocardial infarct sizes by 60% and cerebral infarct sizes by 57% relative to untreated control animals. The problem of IR injury is all too common and represents a discrete threat not only to the tissues directly involved in the ischemic event, but also to distal sites as well as is seen in the evolution of acute respiratory distress and severe inflammatory response syndromes. In the course of this review, the nature of NF-kappaB and its involvement in IR injury is examined along with the efficacy of the various NF-kappaB-based investigational treatment developed to date.
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27
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Kuriyama N, Isaji S, Hamada T, Kishiwada M, Ohsawa I, Usui M, Sakurai H, Tabata M, Hayashi T, Suzuki K. The cytoprotective effects of addition of activated protein C into preservation solution on small-for-size grafts in rats. Liver Transpl 2010; 16:1-11. [PMID: 20035525 DOI: 10.1002/lt.21923] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Small-for-size liver grafts are a serious obstacle for partial orthotopic liver transplantation. Activated protein C (APC), a potent anticoagulant serine protease, is known to have cell-protective properties due to its anti-inflammatory and antiapoptotic activities. This study was designed to examine the cytoprotective effects of a preservation solution containing APC on small-for-size liver grafts, with special attention paid to ischemia-reperfusion injury and shear stress in rats. APC exerted cytoprotective effects, as evidenced by (1) increased 7-day graft survival; (2) decreased initial portal pressure and improved hepatic microcirculation; (3) decreased levels of aminotransferase and improved histological features of hepatic ischemia-reperfusion injury; (4) suppressed infiltration of neutrophils and monocytes/macrophages; (5) reduced hepatic expression of tumor necrosis factor alpha and interleukin 6; (6) decreased serum levels of hyaluronic acid, which indicated attenuation of sinusoidal endothelial cell injury; (7) increased hepatic levels of nitric oxide via up-regulated hepatic endothelial nitric oxide synthesis expression together with down-regulated hepatic inducible nitric oxide synthase expression; (8) decreased hepatic levels of endothelin 1; and (9) reduced hepatocellular apoptosis by down-regulated caspase-8 and caspase-3 activities. These results suggest that a preservation solution containing APC is a potential novel and safe product for small-for-size liver transplantation, alleviating graft injury via anti-inflammatory and antiapoptotic effects and vasorelaxing conditions.
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Affiliation(s)
- Naohisa Kuriyama
- Department of Hepatobiliary Pancreatic Surgery, Mie University Graduate School of Medicine, Mie, Japan.
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28
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Zeynalov E, Shah ZA, Li RC, Doré S. Heme oxygenase 1 is associated with ischemic preconditioning-induced protection against brain ischemia. Neurobiol Dis 2009; 35:264-9. [PMID: 19465127 DOI: 10.1016/j.nbd.2009.05.010] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2009] [Revised: 05/12/2009] [Accepted: 05/15/2009] [Indexed: 02/01/2023] Open
Abstract
Ischemic preconditioning (IPC) protects brain against ischemic injury by activating specific mechanisms. Our goal was to determine if the inducible heme oxygenase 1 (HO1) is required for such protection. IPC before transient or permanent ischemia reduced cortical infarct volumes by 57.4% and 33.9%, respectively at 48 h in wildtype adult mice. Interestingly, IPC failed to protect the HO1 gene deleted mice against permanent ischemic brain injury. IPC also resulted in a significant increase in HO1 protein levels in the brain and correlated with reduced neurological deficits after permanent and transient brain ischemia. Our study demonstrates that neuroprotective effects of IPC are at least partially mediated via HO1. Elucidating the physiological/cellular role by which HO1 is protective against brain ischemia may aid the development of selective drugs to treat stroke and its associated neurological disorders.
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Affiliation(s)
- Emil Zeynalov
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 365, Baltimore, MD 21205, USA
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29
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Variable activation of phosphoinositide 3-kinase influences the response of liver grafts to ischemic preconditioning. J Hepatol 2009; 50:937-47. [PMID: 19303157 DOI: 10.1016/j.jhep.2008.11.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2008] [Revised: 11/07/2008] [Accepted: 11/25/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS The efficacy of ischemic preconditioning (IPC) in preventing reperfusion injury in human liver transplants is still questioned. Phosphoinositide-3-kinase (PI3K) is essential for IPC development in rodent livers. This work investigates whether PI3K-dependent signals might account for the inconsistent responses to IPC of transplanted human livers. METHODS Forty livers from deceased donors were randomized to receive or not IPC before recovery. PI3K activation was evaluated in biopsies obtained immediately before IPC and 2 h after reperfusion by measuring the phosphorylation of the PI3K downstream kinase PKB/Akt and the levels of the PI3K antagonist phosphatase tensin-homologue deleted from chromosome 10 (PTEN). RESULTS IPC increased PKB/Akt phosphorylation (p = 0.01) and decreased PTEN levels (p = 0.03) in grafts, but did not significantly ameliorate post-transplant reperfusion injury. By calculating T(2h)/T(0) PKB/Akt phosphorylation ratios, 10/19 (53%) of the preconditioned grafts had ratios above the control threshold (IPC-responsive), while the remaining nine grafts showed ratios comparable to controls (IPC-non-responsive). T(2h)/T(0) PTEN ratios were also decreased (p < or = 0.03) only in IPC-responsive grafts. The patients receiving IPC-responsive organs had ameliorated (p < or = 0.05) post-transplant aminotransferase and bilirubin levels, while prothrombin activity was unchanged. CONCLUSIONS Impaired PI3K signaling might account for the variability in the responses to IPC of human grafts from deceased donors.
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Ramalho FS, Alfany-Fernandez I, Casillas-Ramirez A, Massip-Salcedo M, Serafín A, Rimola A, Arroyo V, Rodés J, Roselló-Catafau J, Peralta C. Are angiotensin II receptor antagonists useful strategies in steatotic and nonsteatotic livers in conditions of partial hepatectomy under ischemia-reperfusion? J Pharmacol Exp Ther 2009; 329:130-140. [PMID: 19116369 DOI: 10.1124/jpet.108.147835] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
We examined whether angiotensin (Ang) II receptor antagonists could be considered a therapeutic strategy in steatotic and nonsteatotic livers in conditions of partial hepatectomy under ischemia-reperfusion (I/R), which is commonly applied in clinical practice to reduce blood loss. We report that Ang II type I receptor (AT1R) antagonist, but not Ang II type II receptor (AT2R) antagonist, increased regeneration in nonsteatotic livers. In the presence of steatosis, both AT1R and AT2R antagonists increased liver regeneration. This effect was stronger when the two were combined. Neither of the Ang II receptor antagonists protected nonsteatotic livers against damage. Only the AT1R antagonist, through nitric oxide inhibition, reduced damage in steatotic livers. The combination of the AT1R and AT2R antagonists in steatotic livers conferred a similar degree of protection to AT1R antagonist alone. Herein, we show that p38 mitogen-activated protein kinase (p38) was a key mechanism in the regeneration induced by the Ang II receptor antagonists in both liver types because when this signaling pathway was inhibited, the beneficial effects of the Ang II receptor antagonists on liver regeneration disappeared, regardless of hepatocyte growth factor or transforming growth factor beta-hepatic levels. In conclusion, in conditions of partial hepatectomy under I/R, the AT1R antagonist for nonsteatotic livers and the AT1R and AT2R antagonists for steatotic livers improved regeneration in the remnant liver through p38 activation. In addition, the combination of the AT1R and AT2R antagonists in steatotic livers led to stronger liver regeneration than either antagonists used separately and also provided the same protection against damage as that afforded by AT1R antagonist alone.
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Affiliation(s)
- Fernando S Ramalho
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas, Barcelona, Spain
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Padrissa-Altés S, Franco-Gou R, Boillot O, Serafín A, Rimola A, Arroyo V, Rodés J, Peralta C, Roselló-Catafau J. Effect of angiotensin II and bradykinin inhibition in rat reduced-size liver transplantation. Liver Transpl 2009; 15:313-320. [PMID: 19242996 DOI: 10.1002/lt.21693] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
This study examined whether angiotensin II (Ang II) blockers [Ang II type I receptor antagonist, Ang II type II receptor antagonist, and angiotensin converting enzyme (ACE) inhibitor] could reduce hepatic injury and improve regeneration in reduced-size orthotopic liver transplantation (ROLT) and whether the beneficial effects of ischemic preconditioning (PC) in ROLT could be explained by changes in Ang II. We show that small liver grafts generated Ang II after ROLT and that this was associated with increased angiotensinogen and ACE messenger RNA expression. Furthermore, inhibition of Ang II did not contribute to PC-induced protection in ROLT. All Ang II blockers reduced hepatic injury, but none of them promoted liver regeneration. Bradykinin (BK) receptor antagonist improved liver regeneration but did not reduce hepatic injury in ROLT. Finally, the combination of Ang II blockers and BK receptor antagonists in ROLT reduced hepatic injury and improved liver regeneration. In conclusion, treatments with either Ang II blockers or BK receptor antagonists cannot, on their own, improve the outcome of ROLT. Although Ang II blockers can reduce hepatic ischemia-reperfusion injury and BK receptor antagonists can promote liver regeneration, neither confers both benefits at the same time. Consequently, it may be of clinical interest to apply both treatments simultaneously.
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Affiliation(s)
- Susagna Padrissa-Altés
- Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Cientícas, Barcelona, Spain
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Phillips L, Toledo AH, Lopez-Neblina F, Anaya-Prado R, Toledo-Pereyra LH. Nitric oxide mechanism of protection in ischemia and reperfusion injury. J INVEST SURG 2009; 22:46-55. [PMID: 19191157 DOI: 10.1080/08941930802709470] [Citation(s) in RCA: 132] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In 1992 nitric oxide (NO) was declared molecule of the year by Science magazine, and ever since research on this molecule continues to increase. Following this award, NO was shown to be a mediator/protector of ischemia and reperfusion injury in many organs, such as the heart, liver, lungs, and kidneys. Controversy has existed concerning the actual protective effects of NO. However, literature from the past 15 years seems to reinforce the consensus that NO is indeed protective. Some of the protective actions of NO in ischemia and reperfusion are due to its potential as an antioxidant and anti-inflammatory agent, along with its beneficial effects on cell signaling and inhibition of nuclear proteins, such as NF-kappa B and AP-1. New therapeutic potentials for this drug are also continuously emerging. Exogenous NO and endogenous NO may both play protective roles during ischemia and reperfusion injury. Sodium nitroprusside and nitroglycerin have been used clinically with much success; though only recently have they been tested and proven effective in attenuating some of the injuries associated with ischemia and reperfusion. NO inhalation has, in the past, mostly been used for its pulmonary effects, but has also recently been shown to be protective in other organs. The potential of NO in the treatment of ischemic disease is only just being realized. Elucidation of the mechanism by which NO exerts its protective effects needs further investigation. Therefore, this paper will focus on the mechanistic actions of NO in ischemia and reperfusion injury, along with the compound's potential therapeutic benefits.
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Affiliation(s)
- Lauren Phillips
- Department of Research, Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, Michigan, USA
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Ischemic preconditioning produces systemic protective and adoptively transferable effects. Kidney Int 2008; 74:622-30. [DOI: 10.1038/ki.2008.208] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Ogasawara T, Morine Y, Ikemoto T, Imura S, Shimada M. Beneficial effects of Kampo medicine Inchin-ko-to on liver function and regeneration after hepatectomy in rats. Hepatol Res 2008; 38:818-24. [PMID: 18479415 DOI: 10.1111/j.1872-034x.2008.00344.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
AIM Inchin-ko-to (ICKT), Kampo medicine, is known to inhibit hepatocyte apoptosis as well as promote the secretion and excretion of bile. The aim of this study is to clarify the effects of ICKT on liver function and hepatic regeneration after massive hepatectomy in rats. METHODS Male Wistar rats received 2 g/kg ICKT from 3 days preoperatively and underwent 90% hepatectomy. Liver sections were stained using immunohistochemistry (hemeoxygenase-1 [HO-1], alpha-smooth muscle actin [SMA], and proliferating cell nuclear antigen [PCNA]). RESULTS The survival period was significantly prolonged, and the remnant liver/body weight ratio was significantly increased postoperatively in the ICKT group. The values of transaminase, total bile acid, and total bilirubin were significantly improved in the ICKT group. In the ICKT group, PCNA and HO-1 were strongly expressed early postoperatively, but the expression of alpha-SMA was weak. CONCLUSION The preoperative administration of ICKT has been suggested to provide beneficial effects in promoting hepatic regeneration and preventing postoperative hepatic failure. The reduced activation of stellate cells may be involved in their mechanisms.
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Affiliation(s)
- Takashi Ogasawara
- Department of Digestive and Pediatric Surgery, The University of Tokushima Graduate School, Tokushima City, Japan
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Ischemic preconditioning prevents free radical production and mitochondrial depolarization in small-for-size rat liver grafts. Transplantation 2008; 85:1322-31. [PMID: 18475191 DOI: 10.1097/tp.0b013e31816de302] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Ischemic preconditioning (IP) renders tissues more tolerant to subsequent longer episodes of ischemia. This study tested whether IP attenuates injury of small-for-size liver grafts by preventing free radical production and mitochondrial dysfunction. METHODS IP was induced by clamping the portal vein and hepatic artery for 9 min. Livers were harvested 5 min after releasing the clamp. Mitochondrial polarization and cell death were assessed by intravital confocal/multiphoton microscopy of rhodamine 123 (Rh123) and propidium iodide. Free radicals were trapped with alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone and measured using electron spin resonance. RESULTS After quarter-size liver transplantation, alanine aminotransferase, serum bilirubin, necrosis, and apoptosis all increased. IP blocked these increases by more than 58%. 5-Bromo-2'-deoxyuridine labeling and increases of graft weight were only approximately 3% and 0.2% in quarter-size grafts without IP, respectively, but increased to 32% and 60% in ischemic-preconditioned grafts, indicating better liver regeneration. Eighteen hours after implantation, viable cells with depolarized mitochondria in quarter-size grafts were 15 per high power field, and dead cells were less than 1 per high power field, indicating that depolarization preceded necrosis. A free radical adduct signal was detected in bile from quarter-size grafts. IP decreased this free radical formation and prevented mitochondrial depolarization. IP did not increase heat shock proteins 10, 27, 32, 60, 70, 72, 75 and Cu/Zn-superoxide dismutase (SOD) but increased heat shock protein-90, a chaperone that facilitates protein import into mitochondria, and mitochondrial Mn-SOD. CONCLUSION Taken together, IP decreases injury and improves regeneration of small-for-size liver grafts, possibly by increasing mitochondrial Mn-SOD, thus protecting against free radical production and mitochondrial dysfunction.
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Blaise SA, Alberto JM, Audonnet-Blaise S, Guéant JL, Daval JL. Influence of preconditioning-like hypoxia on the liver of developing methyl-deficient rats. Am J Physiol Endocrinol Metab 2007; 293:E1492-502. [PMID: 17726145 DOI: 10.1152/ajpendo.00255.2007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Deficiency in nutritional determinants of homocysteine (HCY) metabolism, such as vitamin B(12) and folate, during pregnancy is known to influence HCY levels in the progeny, which in turn may exert adverse effects during development, including liver defects. Since short hypoxia has been shown to induce tolerance to subsequent stress in various cells including hepatocytes, and as vitamins B deficiency and hypoxic episodes may simultaneously occur in neonates, we aimed to investigate the influence of brief postnatal hypoxia (100% N(2) for 5 min) on the liver of rat pups born from dams fed a deficient regimen, i.e., depleted in vitamins B(12), B(2), folate, and choline. Four experimental groups were studied: control, hypoxia, deficiency, and hypoxia + deficiency. Although hypoxia transiently stimulated HCY catabolic pathways, it was associated with a progressive increase of hyperhomocysteinemia in deficient pups, with a fall of cystathionine beta-synthase activity at 21 days. At this stage, inducible NO synthase activity was dramatically increased and glutathione reductase decreased, specifically in the group combining hypoxia and deficiency. Also, hypoxia enhanced the deficiency-induced drop of the S-adenosylmethionine/S-adenosylhomocysteine ratio. In parallel, early exposure to the methyl-deficient regimen induced oxidative stress and led to hepatic steatosis, which was found to be more severe in pups additionally exposed to hypoxia. In conclusion, brief neonatal hypoxia may accentuate the long-term adverse effects of impaired HCY metabolism in the liver resulting from an inadequate nutritional regimen during pregnancy, and our data emphasize the importance of early factors on adult disease.
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Affiliation(s)
- Sébastien A Blaise
- INSERM U724, Faculté de Médecine, 9 Ave. de la Forêt de Haye, BP 184, F-54500 Vandoeuvre-lès-Nancy, France
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Hahn O, Szijártó A, Lotz G, Schaff Z, Vígváry Z, Váli L, Kupcsulik PK. The effect of ischemic preconditioning prior to intraoperative radiotherapy on ischemic and on reperfused rat liver. J Surg Res 2007; 142:32-44. [PMID: 17628599 DOI: 10.1016/j.jss.2006.10.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2006] [Revised: 10/12/2006] [Accepted: 10/16/2006] [Indexed: 11/17/2022]
Abstract
BACKGROUND The purpose of this study was to increase the tolerance of the liver to radiation injury with the proven effect of ischemic precondition (IP) in decreasing oxygen-derived free radicals, and to compare the effect of intraoperative radiotherapy (IORT) during ischemia and during reperfusion on rat liver. MATERIALS AND METHODS Two hundred fifty to 280 g male Wistar rats underwent 45 min of normothermic, segmental liver ischemia with or without IP/5 min ischemia and 10 min reperfusion, in two cycles. During ischemia or reperfusion, IORT doses of 0, 25, or 50 Gy were applied to the ischemic liver lobe. Hepatic microcirculation was monitored by laser Doppler flowmeter. Short- and long-term histological, alkaline phosphatase, bilirubin and tumor necrosis factor-alpha levels, liver tissue, and serum antioxidant alterations were measured. RESULTS Histological, laboratory, as well as flowmetry alterations caused by 25 Gy were reversible after 6 mo. Three mo following IORT, histological examination revealed parenchymal fibrosis, bridging, liver cell atrophy, and bile duct proliferation in the group that was irradiated with 50 Gy during reperfusion, without IP. In this group, the changes were present 6 mo following IORT, and also the levels of tumor necrosis factor-alpha and oxygen-derived free radicals after reperfusion were increased. All these changes were significantly milder in groups with IP, especially those that were irradiated during ischemia. CONCLUSIONS IORT to the liver, up to 25 Gy, can be applied without short- or long-term treatment morbidity. Doses of up to 50 Gy are tolerated with IP, which has never been described before. Irradiation during ischemia is less toxic for the liver tissue.
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Affiliation(s)
- Oszkár Hahn
- First Department of Surgery, Semmelweis University, Budapest, Hungary.
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Han X, Wang F, Yao W, Xing H, Weng D, Song X, Chen G, Xi L, Zhu T, Zhou J, Xu G, Wang S, Meng L, Iadecola C, Wang G, Ma D. Heat shock proteins and p53 play a critical role in K+ channel-mediated tumor cell proliferation and apoptosis. Apoptosis 2007; 12:1837-46. [PMID: 17624594 DOI: 10.1007/s10495-007-0101-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Plasma membrane potassium (K+) channels are required for tumor cell proliferation and apoptosis. However, the signal transduction mechanisms underlying K+ channel-dependent tumor cell proliferation or apoptosis remains elusive. Using HeLa and A2780 cells as study models, we tested the hypothesis that apoptotic proteins are linked with K+ channel-dependent tumor cell cycle and apoptosis. The patch-clamping study using the whole-cell mode revealed two components of voltage-gated outward K+ currents: one is sensitive to either tetraethylammonium (TEA) or tetrandrine (Tet), a maxi-conductance Ca2+-activated K+ (BK) channel blocker, and the other is sensitive to 4-aminopyridine (4-AP), a delayed rectifier K+ channel blocker. MTT and flow cytometry assays showed that TEA, Tet, or iberiotoxin (Ibtx), a selective BK channel blocker, inhibited HeLa and A2780 cell proliferation in a dose-dependent manner with G1 phase arrest. Pretreatment with TEA or Tet also induced apoptosis in HeLa and A2780 cells. However, glibenclamide (Gli), an ATP-sensitive K+ channel blocker, did not influence K+ currents, proliferation or apoptosis. Western blot analyses showed that while pretreatment of TEA and Tet produced an increase in expressions of p53, p21, and Bax, pretreatment of these two agents led to a decrease in expressions of heat shock protein (hsp)90alpha, hsp90beta, and hsp70. Our results indicate that the blockade of BK channels results in tumor cell apoptosis and cycle arrest at G1 phase, and the transduction pathway underlying the anti-proliferative effects is linked to the increased expression of apoptotic protein p53 and the decreased expression of its chaperone proteins hsp.
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Affiliation(s)
- Xiaobing Han
- Cancer Biology Reseach Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
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Zhang W, Wang M, Xie HY, Zhou L, Meng XQ, Shi J, Zheng S. Role of Reactive Oxygen Species in Mediating Hepatic Ischemia-Reperfusion Injury and Its Therapeutic Applications in Liver Transplantation. Transplant Proc 2007; 39:1332-7. [PMID: 17580134 DOI: 10.1016/j.transproceed.2006.11.021] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2006] [Accepted: 11/16/2006] [Indexed: 01/09/2023]
Abstract
Increasing evidence has shown that reactive oxygen species (ROS) are important mediators in liver ischemia/reperfusion injury(IRI). ROS include hydrogen peroxide (H(2)O(2)), superoxide anion (O(-2)), and hydroxyl radical (HO(-)), which may be generated by activated Kupffer cells in the liver, contributing to reperfusion injury. Hepatic IRI is a multistep process that damages liver graft function. To establish a series of therapeutic strategies to improve the outcome of liver transplantation, a good understanding of the mechanisms of IRI is essential. However, the detail mechanisms of how ROS lead to hepatocyte damage in IRI remains unclear. The aim of this review was to describe recent developments in the field of oxidative stress research. The first part of this review focused on the key roles and possible mechanisms of ROS in hepatic IRI. The second part of this review summarizes some findings including novel and classic antioxidant methods to ameliorate the hepatocyte damage during IRI.
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Affiliation(s)
- W Zhang
- Key Lab of Zhejiang Province Combined Multi-Organ Transplantation, Ministry of Public Health, and Dept. of Hepato-Biliary-Pancreatic Surgery, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang 310003, P.R. China
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Qian JM, Zhang H, Wu XF, Li GQ, Chen XP, Wu J. Improvement of recipient survival after small size graft liver transplantation in rats with preischemic manipulation or administering antisense against nuclear factor-kappaB. Transpl Int 2007; 20:784-9. [PMID: 17535306 DOI: 10.1111/j.1432-2277.2007.00502.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The survival rate of small size graft liver transplantation (SSGLT) in rats is inversely related to graft volume. The present study aims to evaluate the protective effects of preischemic manipulation (PIM) and oligodeoxynucleotide (ODN) antisense against NF-kappaB on graft failure and animal survival. The protective effects of PIM and NF-kappaB ODN antisense were investigated in a rat SSGLT model. The graft function and survival of recipient animals over 3 weeks were monitored, and in situ staining for apoptotic cells in the graft tissue was examined. Both PIM and NF-kappaB antisense treatment significantly improved the survival of small graft-transplanted rats compared with the SSGLT group, lowered serum levels of alanine and aspartate aminotransferases, as well as tumor necrosis factor-alpha (TNF-alpha) levels, and minimized apoptotic cell counts in the liver sections. Moreover, the enhanced activation of NF-kappaB in the SSGLT group was diminished in both PIM and NF-kappaB antisense-treated groups. The findings suggest that enhanced NF-kappaB activation and TNF-alpha production may be involved in the ischemia/reperfusion-associated small size graft injury, and that PIM and antisense against NK-kappaB are effective in the attenuation of the small size graft injury, and improve the recipient animal survival.
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Affiliation(s)
- Jiang-Ming Qian
- Liver Transplant Section, Center for Organ Transplantation, Huashan Hospital, Fudan University, Shanghai, China
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Gomez D, Homer-Vanniasinkam S, Graham AM, Prasad KR. Role of ischaemic preconditioning in liver regeneration following major liver resection and transplantation. World J Gastroenterol 2007; 13:657-70. [PMID: 17278187 PMCID: PMC4065997 DOI: 10.3748/wjg.v13.i5.657] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Liver ischaemic preconditioning (IPC) is known to protect the liver from the detrimental effects of ischaemic-reperfusion injury (IRI), which contributes significantly to the morbidity and mortality following major liver surgery. Recent studies have focused on the role of IPC in liver regeneration, the precise mechanism of which are not completely understood. This review discusses the current understanding of the mechanism of liver regeneration and the role of IPC in this setting. Relevant articles were reviewed from the published literature using the Medline database. The search was performed using the keywords “liver”, “ischaemic reperfusion”, “ischaemic preconditioning”, “regeneration”, “hepatectomy” and “transplantation”. The underlying mechanism of liver regeneration is a complex process involving the interaction of cytokines, growth factors and the metabolic demand of the liver. IPC, through various mediators, promotes liver regeneration by up-regulating growth-promoting factors and suppresses growth-inhibiting factors as well as damaging stresses. The increased understanding of the cellular mechanisms involved in IPC will enable the development of alternative treatment modalities aimed at promoting liver regeneration following major liver resection and transplantation.
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Affiliation(s)
- D Gomez
- Department of Hepatobiliary Surgery and Transplantation, St. James's University Hospital, Leeds LS9 7TF, UK
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Abstract
BACKGROUND Ischemia-reperfusion (I/R) injury associated with hepatic resections and liver transplantation remains a serious complication in clinical practice, in spite of several attempts to solve the problem. AIMS To evaluate the response of the hepatocyte to ischemia METHODS Published data are thus revised. RESULTS The response of the hepatocyte to ischemia is based on the sensitivity of hepatocytes to different types of ischemia, the kind of cell death of the hepatocyte when it is subjected to ischemia, and on the response of the hepatocyte to the different times and extents of ischemia. Clinical factors including starvation, graft, age, and hepatic steatosis, all of which contribute to enhancing liver susceptibility to ischemia/reperfusion injury. CONCLUSION Ischemic preconditioning, based on the induction of a brief ischemia to the liver prior to a prolonged ischemia, has been applied in tumor hepatic resections for reducing hepatic I/R injury and recent clinical studies suggest that this surgical strategy could be appropriate for liver transplantation.
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Affiliation(s)
- M Massip-Salcedo
- Experimental Hepatic Ischemia-Reperfusion Unit, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas, Instituto de Investigaciones Biomédicas August Pi i Sunyer, Barcelona, Spain
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Navarro-Sabaté A, Peralta C, Calvo MN, Manzano A, Massip-Salcedo M, Roselló-Catafau J, Bartrons R. Mediators of rat ischemic hepatic preconditioning after cold preservation identified by microarray analysis. Liver Transpl 2006; 12:1615-1625. [PMID: 17058268 DOI: 10.1002/lt.20863] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Hepatic ischemia-reperfusion injury associated with liver transplantation is an as yet unresolved problem in clinical practice. Preconditioning protects the liver against the deleterious effects of ischemia, although the mechanism underlying this preconditioning is still unclear. To profile gene expression patterns involved in hepatic ischemic preconditioning, we analyzed the changes in gene expression in rat livers by DNA microarray analysis. Approximately 116 genes were found to have altered gene expression after 8 hours of cold ischemia. Moreover, the expression of 218 genes was modified by classic preconditioning followed by the same ischemia process. Given the importance of the effects of ischemic preconditioning (IP) in minimizing the liver damage induced by sustained ischemia before reperfusion, this study analyzed the putative genes involved in the beneficial role of IP in liver grafts undergoing cold ischemia before its implantation in the recipient (IP+I). Great differences were found in the gene expression pattern of ischemic preconditioning + long cold ischemia (IP+I) group when compared with the long cold ischemia alone condition (I), which could explain the protective regulatory mechanisms that take place after preconditioning. Twenty-six genes that were downregulated in cold ischemia were found upregulated after preconditioning preceding a long cold ischemia period. These would be genes activated or maintained by preconditioning. Heat shock protein genes and 3-hydroxy-3-methylglutaryl-coenzyme A reductase are among the most markedly induced transcripts.
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Affiliation(s)
- Aurea Navarro-Sabaté
- Unitat de Bioquímica, Departament de Ciències Fisiològiques II, Campus de Bellvitge, IDIBELL-Universitat de Barcelona, Feixa Llarga s/n E-08907 L'Hospitalet, Spain
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Transplantation and the pathologist. Curr Opin Organ Transplant 2006. [DOI: 10.1097/01.mot.0000227844.14205.b9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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