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1
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Zhang J, Xie Y, Chen J, Song L. Monocarboxyoctyl phthalate is associated with platelet count: evidence from a large cross-sectional study. Front Public Health 2025; 13:1559808. [PMID: 40352847 PMCID: PMC12061924 DOI: 10.3389/fpubh.2025.1559808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 03/31/2025] [Indexed: 05/14/2025] Open
Abstract
Introduction Phthalates are environmental pollutants that are harmful to human health. However, the impact of phthalate on platelet count remains unclear. This study aimed to examine the correlation between five phthalate metabolites in urine and platelet count, as well as the impact of phthalate metabolite exposure on platelet count in adults. Methods This cross-sectional study included 11,409 non-pregnant participants aged >20 years using data available from the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2018. Weighted logistic regression, restricted cubic spline (RCS) modeling, and weighted quantile sum (WQS) were employed to investigate the effects of mono-(carboxyisononyl) phthalate (MCNP), mono-(carboxyoctyl) phthalate (MCOP), mono-(3-carboxypropyl) phthalate (MCPP), mono-isobutyl phthalate (MiBP) and mono-isononyl phthalate (MNP) on platelet count. Results Logistic regression analysis suggested that MCOP [odds ratio (OR) (95% confidence interval CI) = 0.009 (0.002-0.036)] was significantly associated with the platelet count. Subgroup analysis showed negative correlations between MCOP and platelet count across all age and sex groups, and MCNP [OR (95% CI) = 0.083(0.013-0.552)] displayed a negative association with platelet count in females. MCOP had a nonlinear relationship with the platelet count in the RCS model. WQS also revealed that MCOP was related to platelet count. Conclusion Higher urinary MCOP level was associated with lower platelet count. Further investigation is necessary to substantiate these findings, considering the shortcomings of the NHANES study.
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Affiliation(s)
- Jian Zhang
- Department of Hematology, People's Hospital of Rizhao, Rizhao, China
| | - Yuhan Xie
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jinqiu Chen
- Department of Hematology, People's Hospital of Rizhao, Rizhao, China
| | - Lei Song
- Department of Hematology, People's Hospital of Rizhao, Rizhao, China
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2
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An O, Deppermann C. Platelet lifespan and mechanisms for clearance. Curr Opin Hematol 2024; 31:6-15. [PMID: 37905750 DOI: 10.1097/moh.0000000000000792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
PURPOSE OF REVIEW Activated or aged platelets are removed from circulation under (patho)physiologic conditions, the exact mechanism of platelet clearance under such conditions remains unclear and are currently being investigated. This review focuses on recent findings and controversies regarding platelet clearance and the disruption of platelet life cycle. RECENT FINDINGS The platelet life span is determined by glycosylation of platelet surface receptors with sialic acid. Recently, it was shown that platelet activation and granule release leads to desialylation of glycans and accelerated clearance of platelets under pathological conditions. This phenomenon was demonstrated to be a main reason for thrombocytopenia being a complication in several infections and immune disorders. SUMMARY Although we have recently gained some insight into how aged platelets are cleared from circulation, we are still not seeing the full picture. Further investigations of the platelet clearance pathways under pathophysiologic conditions are needed as well as studies to unravel the connection between platelet clearance and platelet production.
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Affiliation(s)
- Olga An
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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3
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Casari M, Siegl D, Deppermann C, Schuppan D. Macrophages and platelets in liver fibrosis and hepatocellular carcinoma. Front Immunol 2023; 14:1277808. [PMID: 38116017 PMCID: PMC10728659 DOI: 10.3389/fimmu.2023.1277808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 11/13/2023] [Indexed: 12/21/2023] Open
Abstract
During fibrosis, (myo)fibroblasts deposit large amounts of extracellular matrix proteins, thereby replacing healthy functional tissue. In liver fibrosis, this leads to the loss of hepatocyte function, portal hypertension, variceal bleeding, and increased susceptibility to infection. At an early stage, liver fibrosis is a dynamic and reversible process, however, from the cirrhotic stage, there is significant progression to hepatocellular carcinoma. Both liver-resident macrophages (Kupffer cells) and monocyte-derived macrophages are important drivers of fibrosis progression, but can also induce its regression once triggers of chronic inflammation are eliminated. In liver cancer, they are attracted to the tumor site to become tumor-associated macrophages (TAMs) polarized towards a M2- anti-inflammatory/tumor-promoting phenotype. Besides their role in thrombosis and hemostasis, platelets can also stimulate fibrosis and tumor development by secreting profibrogenic factors and regulating the innate immune response, e.g., by interacting with monocytes and macrophages. Here, we review recent literature on the role of macrophages and platelets and their interplay in liver fibrosis and hepatocellular carcinoma.
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Affiliation(s)
- Martina Casari
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Dominik Siegl
- Institute for Translational Immunology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Carsten Deppermann
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Research Center for Immune Therapy Forschungszentrum für Immuntherapie (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Detlef Schuppan
- Institute for Translational Immunology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Research Center for Immune Therapy Forschungszentrum für Immuntherapie (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
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4
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Wen Y. The Role of Immune Cells in Liver Regeneration. LIVERS 2023; 3:383-396. [DOI: 10.3390/livers3030029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
The liver is the only organ that can regenerate and regain its original tissue-to-body weight ratio within a short period of time after tissue loss. Insufficient liver regeneration in patients after partial hepatectomy or liver transplantation with partial liver grafts often leads to post-hepatectomy liver failure or small-for-size syndrome, respectively. Enhancing liver regeneration after liver injury might improve outcomes and increase patient survival. Liver regeneration comprises hepatocyte proliferation, and hepatic progenitor cell expansion and differentiation into hepatocytes. The immune system is intensively involved in liver regeneration. The current review provides a comprehensive overview of the diverse roles played by immune cells in liver regeneration. Macrophages, neutrophils, eosinophils, basophils, mast cells, platelets, dendritic cells, type 1 innate lymphoid cells, B cells, and T cells are implicated in promoting liver regeneration, while natural killer cells and overactivated natural killer T cells are supposed to inhibit hepatocyte proliferation. We also highlight the predominant underlying mechanisms mediated by immune cells, which may contribute to the development of novel strategies for promoting liver regeneration in patients with liver diseases.
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Affiliation(s)
- Yankai Wen
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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5
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Morris SM, Chauhan A. The role of platelet mediated thromboinflammation in acute liver injury. Front Immunol 2022; 13:1037645. [PMID: 36389830 PMCID: PMC9647048 DOI: 10.3389/fimmu.2022.1037645] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/14/2022] [Indexed: 12/03/2022] Open
Abstract
Acute liver injuries have wide and varied etiologies and they occur both in patients with and without pre-existent chronic liver disease. Whilst the pathophysiological mechanisms remain distinct, both acute and acute-on-chronic liver injury is typified by deranged serum transaminase levels and if severe or persistent can result in liver failure manifest by a combination of jaundice, coagulopathy and encephalopathy. It is well established that platelets exhibit diverse functions as immune cells and are active participants in inflammation through processes including immunothrombosis or thromboinflammation. Growing evidence suggests platelets play a dualistic role in liver inflammation, shaping the immune response through direct interactions and release of soluble mediators modulating function of liver sinusoidal endothelial cells, stromal cells as well as migrating and tissue-resident leucocytes. Elucidating the pathways involved in initiation, propagation and resolution of the immune response are of interest to identify therapeutic targets. In this review the provocative role of platelets is outlined, highlighting beneficial and detrimental effects in a spatial, temporal and disease-specific manner.
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Affiliation(s)
- Sean M. Morris
- The Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom
| | - Abhishek Chauhan
- The Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- *Correspondence: Abhishek Chauhan,
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6
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Till Death Do Us Part-The Multifaceted Role of Platelets in Liver Diseases. Int J Mol Sci 2021; 22:ijms22063113. [PMID: 33803718 PMCID: PMC8003150 DOI: 10.3390/ijms22063113] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/09/2021] [Accepted: 03/16/2021] [Indexed: 02/07/2023] Open
Abstract
Platelets are tightly connected with the liver, as both their production and their clearance are mediated by the liver. Platelets, in return, participate in a variety of liver diseases, ranging from non-alcoholic fatty liver diseases, (viral) hepatitis, liver fibrosis and hepatocellular carcinoma to liver regeneration. Due to their versatile functions, which include (1) regulation of hemostasis, (2) fine-tuning of immune responses and (3) release of growth factors and cellular mediators, platelets quickly adapt to environmental changes and modulate disease development, leading to different layers of complexity. Depending on the (patho)physiological context, platelets exert both beneficial and detrimental functions. Understanding the precise mechanisms through which platelet function is regulated at different stages of liver diseases and how platelets interact with various resident and non-resident liver cells helps to draw a clear picture of platelet-related therapeutic interventions. Therefore, this review summarizes the current knowledge on platelets in acute and chronic liver diseases and aims to shed light on how the smallest cells in the circulatory system account for changes in the (patho)physiology of the second largest organ in the human body.
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Abstract
The liver is unique in its remarkable regenerative capacity, which enables the use of liver resection as a treatment for specific liver diseases, including removal of neoplastic liver disease. After resection, the remaining liver tissue (i.e, liver remnant) regenerates to maintain normal hepatic function. In experimental settings as well as patients, removal of up to two-thirds of the liver mass stimulates a rapid and highly coordinated process resulting in the regeneration of the remaining liver. Mechanisms controlling the initiation and termination of regeneration continue to be discovered, and many of the fundamental signaling pathways controlling the proliferation of liver parenchymal cells (i.e., hepatocytes) have been uncovered. Interestingly, while hemostatic complications (i.e., bleeding and thrombosis) are primarily thought of as a complication of surgery itself, strong evidence suggests that components of the hemostatic system are, in fact, powerful drivers of liver regeneration. This review focuses on the clinical and translational evidence supporting a link between the hemostatic system and liver regeneration, and the mechanisms whereby the hemostatic system directs liver regeneration discovered using experimental settings.
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Affiliation(s)
- Patrick Starlinger
- Department of Surgery, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.,Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - James P Luyendyk
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan
| | - Dafna J Groeneveld
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan
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Amygdalos I, Czigany Z, Bednarsch J, Boecker J, Santana DAM, Meister FA, von der Massen J, Liu WJ, Strnad P, Neumann UP, Lurje G. Low Postoperative Platelet Counts Are Associated with Major Morbidity and Inferior Survival in Adult Recipients of Orthotopic Liver Transplantation. J Gastrointest Surg 2020; 24:1996-2007. [PMID: 31388889 DOI: 10.1007/s11605-019-04337-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 07/19/2019] [Indexed: 01/31/2023]
Abstract
BACKGROUND Platelets (PLT) play an essential functional role in cellular injury and liver regeneration following partial hepatectomy and orthotopic liver transplantation (OLT). Here, we investigated the association of postoperative PLT counts with short- and long-term outcomes in adult OLT recipients. METHODS Three hundred consecutive patients from our prospective OLT database were analyzed retrospectively (May 2010-November 2017). Ninety-day post-OLT complications were graded using the Clavien-Dindo (CD) classification and quantified by the comprehensive complication index (CCI). To determine the prognostic accuracy of PLT counts, the area under the receiver operating characteristic curve (AUROC) was calculated for major complications (CD ≥ 3b). Parametric and non-parametric tests were applied for subgroup analyses. Uni- and multivariable logistic regression analyses were performed to identify risk factors for major complications. Graft and patient survival were analyzed using the Kaplan-Meier method as well as uni- and multivariable Cox regression analyses. RESULTS Postoperative day 6 PLT counts < 70 × 109/L (POD6-70) were identified as the best cutoff for predicting major complications (AUROC = 0.7; p < 0.001; Youden index 0.317). The stratification of patients into low- (n = 113) and high-PLT (n = 187) groups highlighted significant differences in major complications (CCI 68 ± 29 vs. 43 ± 28, p < 0.001); length of hospital and intensive care unit (ICU) stay (53 ± 43 vs. 31 ± 25, p < 0.001; 21 ± 29 vs. 7 ± 11, p < 0.001, respectively) and estimated procedural costs. POD6-70 was associated with inferior 5-year graft survival. Multivariable logistic regression analysis identified POD6-70 as an independent predictor of major complications (odds ratio 2.298, confidence intervals 1.179-4.478, p = 0.015). CONCLUSION In OLT patients, a PLT count on POD6 of less than 70 × 109/L bears a prognostic significance warranting further investigations.
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Affiliation(s)
- Iakovos Amygdalos
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Joerg Boecker
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | | | - Franziska Alexandra Meister
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Jelena von der Massen
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Wen-Jia Liu
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
- Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, Netherlands
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.
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9
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Xu Y, Hu X, Li J, Dong R, Bai X. An Improved Scoring System Based on Platelet-Albumin-Bilirubin in Predicting Posthepatectomy Liver Failure Outcomes. Dig Dis 2020; 39:258-265. [PMID: 32846419 DOI: 10.1159/000511138] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 08/25/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND Posthepatectomy liver failure (PHLF) is one of the major complications of liver resection that causes perioperative mortality. Accurate preoperative assessment of PHLF is of great significance to reduce the complication rate after hepatectomy and improve the survival rate. METHODS A retrospective study of patients who received hepatectomy from January 2016 to October 2019 at Tang Du Hospital was performed. The area under the receiver operating characteristic (ROC) curve was used to compare the predictive effects of various scoring models on PHLF. RESULTS The area under the ROC curve of platelet-albumin-bilirubin (PALBI) score, new platelet-albumin-bilirubin (I-PALBI) score, ALBI score, and MELD score was, respectively, 0.647, 0.772, 0.677, and 0.686 (p < 0.01). The I-PALBI score was significantly better than the other scores. CONCLUSIONS I-PALBI score can be used as a predictive score of PHLF, and its prediction accuracy is better than other scoring systems.
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Affiliation(s)
- Yan Xu
- Department of General Surgery, The Second Affiliated Hospital, The Fourth Military Medical University, Xi'an, China
| | - Xiaoling Hu
- Department of Neurosurgery, The Southern Theater Air Force Hospital, Guangzhou, China
| | - Jiangbin Li
- Department of General Surgery, The Second Affiliated Hospital, The Fourth Military Medical University, Xi'an, China
| | - Rui Dong
- Department of General Surgery, The Second Affiliated Hospital, The Fourth Military Medical University, Xi'an, China,
| | - Xiaoxi Bai
- Department of General Surgery, The Second Affiliated Hospital, The Fourth Military Medical University, Xi'an, China
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10
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Regulation of liver regeneration by prostaglandin E 2 and thromboxane A 2 following partial hepatectomy in rats. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:1437-1446. [PMID: 32162076 DOI: 10.1007/s00210-020-01848-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 03/02/2020] [Indexed: 12/17/2022]
Abstract
The implication of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) in the striking process of liver regeneration has been previously reported. However, their exact roles and downstream signals have not been utterly revealed. Therefore, the present study was conducted to explore whether inhibition of cyclooxygenase-2 (COX-2)-derived PGE2 by celecoxib and blocking of TXA2 action by seratrodast could alter the progression of liver regeneration after 70% partial hepatectomy (PHx) in rats. Celecoxib (20 mg/kg/day) and seratrodast (2 mg/kg/day) were given orally 1 h before PHx and then daily till the end of experiment (1, 3, or 7 days after the operation). Interestingly, celecoxib-treated rats showed a further increase in interleukin-6, p65 nuclear factor κB, and phosphorylated signal transducer and activator of transcription 3 as compared with PHx control rats. Furthermore, the liver contents of growth factors as well as β-catenin and cyclin D1protein expressions were also enhanced by celecoxib. Accordingly, celecoxib significantly improved hepatic proliferation as indicated by the increase in Ki67 expression and liver index. Contrariwise, seratrodast hindered the normal regeneration process and completely abolished the proliferative effect of celecoxib. In conclusion, TXA2 has a major role in liver regeneration that could greatly mediate the triggering effect of celecoxib on hepatocytes proliferation following PHx.
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11
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Matsuda A, Kuriyama N, Mizuno S, Usui M, Sakurai H, Isaji S. Dual Effects of Large Spleen Volume After Splenectomy for the Patients With Chronic Liver Disease. Int Surg 2019; 104:412-422. [DOI: 10.9738/intsurg-d-18-00029.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Background
After splenectomy in patients with chronic liver disease, a large spleen was reported to be not only a risk factor of portal/splenic vein thrombosis (PSVT), but also a prediction for favorable improvement of liver function. This study aimed to evaluate the risk of PSVT and the improvement of liver function after splenectomy, with special attention to spleen volume (SV).
Methods
This studied included 50 patients who underwent splenectomy with diagnosed chronic liver disease between January 2005 and December 2017. After evaluation of risk factors for PSVT the cut-off value of SV for predicting PSVT was determined. According to the cut-off value of SV, 50 patients were divided into 2 groups: small-volume group (SVG) and large-volume group (LVG). Postoperative liver functions were compared between the 2 groups.
Results
Twenty-eight patients developed PSVT. Larger SV was the most significant independent risk factor for PSVT. The cut-off value of SV was 520 mL. Preoperatively, LVG had significantly higher total bilirubin, and MELD (model for end-stage liver disease) score, and had significantly higher rates of pancytopenia than SVG. Postoperatively, compared to SVG, platelet count, choline esterase, and total cholesterol in LVG were significantly increased.
Conclusion
After splenectomy in the patients with chronic liver disease, large SV is an independent risk factor for PSVT, with a clear benefit in improving liver function, if PSVT is properly diagnosed and managed.
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Affiliation(s)
- Akitoshi Matsuda
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
- Present affiliation: Department of Surgery, Mie Chuo Medical Center Hospital, Mie, Japan
| | - Naohisa Kuriyama
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Shugo Mizuno
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Masanobu Usui
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Hiroyuki Sakurai
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Shuji Isaji
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan
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12
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Aryal B, Yamakuchi M, Shimizu T, Kadono J, Furoi A, Gejima K, Komokata T, Hashiguchi T, Imoto Y. Therapeutic implication of platelets in liver regeneration -hopes and hues. Expert Rev Gastroenterol Hepatol 2018; 12:1219-1228. [PMID: 30791793 DOI: 10.1080/17474124.2018.1533813] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Mounting evidence highlights platelet involvement in liver regeneration via interaction with liver cells, growth factors release, and signaling contributions. Existing research suggests a compelling biological rationale for utilizing platelet biology, with the goal of improving liver function and accelerating its regenerative potential. Despite its expanding application in several clinical areas, the contribution of the platelet and its therapeutic implementation in liver regeneration so far has not yet fulfilled the initial high expectations. Areas covered: This review scrutinizes the progress, current updates, and discusses how recent understanding - particularly in the clinical implications of platelet-based therapy - may enable strategies to introduce and harness the therapeutic potential of the platelet during liver regeneration. Expert commentary: Several clinical and translational studies have facilitated a platform for the development of platelet-based therapy to enhance liver regeneration. While some of these therapies are effective to augment liver regeneration, the others have had some detrimental outcomes. The existing evidence represents a challenge for future projects that are focused on directly incorporating platelet-based therapies to induce liver regeneration.
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Affiliation(s)
- Bibek Aryal
- a Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences , Kagoshima University , Kagoshima , Japan
| | - Munekazu Yamakuchi
- b Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences , Kagoshima University , Kagoshima , Japan
| | - Toshiaki Shimizu
- b Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences , Kagoshima University , Kagoshima , Japan
| | - Jun Kadono
- c Department of Surgery , Kirishima Medical Center , Kirishima , Japan
| | - Akira Furoi
- c Department of Surgery , Kirishima Medical Center , Kirishima , Japan
| | - Kentaro Gejima
- a Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences , Kagoshima University , Kagoshima , Japan
| | - Teruo Komokata
- d Department of Surgery , Kagoshima Medical Center . Kagoshima , Japan
| | - Teruto Hashiguchi
- b Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences , Kagoshima University , Kagoshima , Japan
| | - Yutaka Imoto
- a Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences , Kagoshima University , Kagoshima , Japan
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13
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Nwidu LL, Oboma YI, Elmorsy E, Carter WG. Hepatoprotective effect of hydromethanolic leaf extract of Musanga cecropioides (Urticaceae) on carbon tetrachloride-induced liver injury and oxidative stress. J Taibah Univ Med Sci 2018; 13:344-354. [PMID: 31435346 PMCID: PMC6694957 DOI: 10.1016/j.jtumed.2018.04.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 04/05/2018] [Accepted: 04/12/2018] [Indexed: 01/31/2023] Open
Abstract
Objective Natural antioxidant products are gaining popularity as treatments for various pathological liver injuries. Musanga cecropioides (Urticaceae) leaf extract is used in ethnomedicine for the management of jaundice and other hepatic ailments in Ibibio, Nigeria. This study evaluated the hepatoprotective and antioxidant effects of M. cecropioides hydromethanolic leaf (MCHL) extract against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Methods Liver damage was induced by administering CCl4 dissolved in liquid paraffin (2 mL/kg bw 1:1 intraperitoneally) after pretreatment with MCHL extract for 7 days. Thereafter, acute hepatotoxicity was evaluated in 36 Wistar rats divided into six groups (A–F) of six animals each. Group A served as the negative control; B received CCl4 1 mL/kg only; C–E received 70.7, 141.4, and 282.8 mg/kg MCHL extract, respectively; and F received silymarin 100 mg/kg daily for 7 days by oral gavage. After 48 h, the rats were sacrificed, and samples obtained from them were assayed for histological and biochemical biomarkers of hepatotoxicity. Results The MCHL extracts significantly (p < 0.001–0.05) reduced the increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), conjugated bilirubin (CBIL), and total bilirubin (TBIL) levels induced by CCl4 intoxication. There was no significant alteration in haematological indices or weight following administration of the MCHL extracts. Histopathological examinations revealed mitotic bodies in the 141.4 mg/kg MCHL extract-treated rats, an indication of tissue repair processes. Conclusion The MCHL extract has a dose-specific hepatoprotective effect; hence, the utilisation of this extract for the management of hepatitis requires caution.
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Affiliation(s)
- Lucky L Nwidu
- Department of Experimental Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of Port Harcourt, Choba, Nigeria
| | - Yibala I Oboma
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Egypt
| | - Ekramy Elmorsy
- Department of Medical Laboratory Science, Faculty of Basic Medical Sciences, College Health Sciences, Niger Delta University, Wilberforce Island, Bayelsa State, Nigeria
| | - Wayne G Carter
- School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, UK
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14
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Kurokawa T, Ohkohchi N. Role of Platelet, Blood Stem Cell, and Thrombopoietin in Liver Regeneration, Liver Cirrhosis, and Liver Diseases. STEM CELLS AND CANCER IN HEPATOLOGY 2018:159-177. [DOI: 10.1016/b978-0-12-812301-0.00009-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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15
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Kirschbaum M, Jenne CN, Veldhuis ZJ, Sjollema KA, Lenting PJ, Giepmans BNG, Porte RJ, Kubes P, Denis CV, Lisman T. Transient von Willebrand factor-mediated platelet influx stimulates liver regeneration after partial hepatectomy in mice. Liver Int 2017; 37:1731-1737. [PMID: 28178387 DOI: 10.1111/liv.13386] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 02/02/2017] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS In addition to their function in thrombosis and haemostasis, platelets play an important role in the stimulation of liver regeneration. It has been suggested that platelets deliver mitogenic cargo to the regenerating liver, and accumulation of platelets in the regenerating liver has been demonstrated. We studied kinetics of platelet influx in the regenerating liver and investigated the signal that initiates platelet influx. METHODS We visualized platelets in the liver remnant after partial hepatectomy in mice using intravital microscopy and assessed liver regeneration by examination of liver/body weight ratio and the number of proliferating hepatocytes examined by immunohistochemistry. RESULTS We demonstrated rapid but transient platelet influx into the liver remnant after a partial liver resection. Liver regeneration in thrombocytopenic mice was substantially impaired as evidenced by a reduced liver-to-body weight ratio and decreased numbers of proliferating hepatocytes at day 3 compared to mice with normal platelet counts. In contrast, liver regeneration was only mildly impaired when thrombocytopaenia was induced 2 hours after partial liver resection. Platelet influx into the liver remnant was virtually absent in the presence of an antibody to von Willebrand factor (VWF) suggesting that VWF release from liver sinusoidal endothelial cells mediates platelet influx. Additionally, liver regeneration in mice deficient in VWF was markedly impaired. CONCLUSIONS A rapid but transient VWF-dependent platelet influx into the liver remnant drives platelet-mediated liver regeneration.
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Affiliation(s)
- Marc Kirschbaum
- Surgical Research Laboratory Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Craig N Jenne
- Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
| | - Zwanida J Veldhuis
- Surgical Research Laboratory Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Klaas A Sjollema
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Peter J Lenting
- Institut National de la Santé et de la Recherche Médicale, UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276 Le Kremlin-Bicêtre, France
| | - Ben N G Giepmans
- Department of Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J Porte
- Section of Hepatobiliairy Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Paul Kubes
- Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
| | - Cécile V Denis
- Institut National de la Santé et de la Recherche Médicale, UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276 Le Kremlin-Bicêtre, France
| | - Ton Lisman
- Surgical Research Laboratory Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Section of Hepatobiliairy Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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16
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Meyer J, Balaphas A, Fontana P, Sadoul K, Morel P, Gonelle‐Gispert C, Bühler L. Platelets in liver regeneration. ISBT SCIENCE SERIES 2017; 12:455-462. [DOI: 10.1111/voxs.12382] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background and ObjectivesLoss of liver tissue leading to impairment of liver function represents a major cause of mortality. Understanding the mechanism of liver regeneration and developing therapies to sustain liver regeneration are of high therapeutic relevance. In this regard, platelets are considered as potential candidates for stimulating liver regeneration.MethodsWe aim to review the most recent evidence regarding the role of platelets in liver regeneration.ResultsPlatelets stimulate liver regeneration in animal models of liver resection. In humans, platelets are independent predictors of postoperative mortality, liver function and volume recovery. One proposed mechanism by which platelets stimulate liver regeneration relies on their direct effect on hepatocytes. Following partial hepatectomy, platelets accumulate in the residual liver and release their granule content. Platelet‐containing molecules, such as HGF, VEGF, IGF‐1 and serotonin, stimulate hepatocyte proliferation. A putative additional mechanism involves the transfer of platelet mRNA to hepatocytes following platelet internalization. Recent studies have suggested that the effect of platelets relies on their interactions with LSEC. Platelets induce the secretion of IL‐6 from LSEC, a strong initiator of hepatocyte proliferation. Additionally, platelets convey molecules that may impact LSEC function and, by extension, liver regeneration. Platelets potentially interact with Kupffer cells, but the effect of that interaction on liver regeneration remains to be determined.ConclusionPlatelets stimulate liver regeneration. Several mechanisms seem to be involved, acting on the level of hepatocytes, LSEC and potentially Kupffer cells. Identification of the platelet‐molecule(s) involved may lead to targeted therapies for patients with impairment of liver function.
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Affiliation(s)
- J. Meyer
- Division of Digestive and Transplantation Surgery University Hospitals of Geneva Genève Switzerland
- Unit of Surgical Research University of Geneva Genève Switzerland
| | - A. Balaphas
- Division of Digestive and Transplantation Surgery University Hospitals of Geneva Genève Switzerland
- Unit of Surgical Research University of Geneva Genève Switzerland
| | - P. Fontana
- Division of Angiology and Haemostasis University Hospitals of Geneva Genève Switzerland
- Geneva Platelet Group University of Geneva Genève Switzerland
| | - K. Sadoul
- Regulation and pharmacology of the cytoskeleton Institute for Advanced Biosciences Université Grenoble Alpes Grenoble France
| | - P. Morel
- Division of Digestive and Transplantation Surgery University Hospitals of Geneva Genève Switzerland
- Unit of Surgical Research University of Geneva Genève Switzerland
| | | | - L. Bühler
- Division of Digestive and Transplantation Surgery University Hospitals of Geneva Genève Switzerland
- Unit of Surgical Research University of Geneva Genève Switzerland
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17
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Kurokawa T, Ohkohchi N. Platelets in liver disease, cancer and regeneration. World J Gastroenterol 2017; 23:3228-3239. [PMID: 28566882 PMCID: PMC5434428 DOI: 10.3748/wjg.v23.i18.3228] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Revised: 11/17/2016] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
Although viral hepatitis treatments have evolved over the years, the resultant liver cirrhosis still does not completely heal. Platelets contain proteins required for hemostasis, as well as many growth factors required for organ development, tissue regeneration and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD) and cirrhosis, can manifest from decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis, as well as the role of platelets in CLD, is poorly understood. In this paper, experimental evidence of platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. In addition, we describe our current perspective based on the results of these studies. Platelets improve liver fibrosis by inactivating hepatic stellate cells, which decreases collagen production. The regenerative effect of platelets in the liver involves a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these observations, we ascertained the direct effect of platelet transfusion on improving several indicators of liver function in patients with CLD and liver cirrhosis. However, unlike the results of our previous clinical study, the smaller incremental changes in liver function in patients with CLD who received eltrombopag for 6 mo were due to patient selection from a heterogeneous population. We highlight the current knowledge concerning the role of platelets in CLD and cancer and anticipate a novel application of platelet-based clinical therapies to treat liver disease.
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18
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Lv J, Liu F. The Role of Serotonin beyond the Central Nervous System during Embryogenesis. Front Cell Neurosci 2017. [DOI: 10.3389/fnpit.2017.00400] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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19
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Lv J, Liu F. The Role of Serotonin beyond the Central Nervous System during Embryogenesis. Front Cell Neurosci 2017; 11:74. [PMID: 28348520 PMCID: PMC5346549 DOI: 10.3389/fncel.2017.00074] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 02/28/2017] [Indexed: 12/29/2022] Open
Abstract
Serotonin, or 5-hydroxytryptamine (5-HT), is a well-known neurotransmitter that plays vital roles in neural activities and social behaviors. Clinically, deficiency of serotonin is linked with many psychiatric disorders. Interestingly, a large proportion of serotonin is also produced outside the central nervous system (CNS). There is increasing evidence demonstrating important roles of serotonin in the peripheral tissues. Here, we will describe the multiple biological functions of serotonin in hematopoietic system, such as development of hematopoietic stem and progenitor cells (HSPCs), differentiation of hematopoietic cells, maintenance of vascular system, and relationship with hematological diseases. The roles of serotonin in inflammatory responses mediated by hematopoietic cells as well as in liver regeneration are also discussed. Our recent understandings of the impact of serotonin on hematopoietic system, immune responses, and tissue regeneration support utilization of serotonin as a potential therapeutic target for the treatment of hematological diseases and organ repair in clinic.
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Affiliation(s)
- Junhua Lv
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of SciencesBeijing, China; University of Chinese Academy of SciencesBeijing, China
| | - Feng Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of SciencesBeijing, China; University of Chinese Academy of SciencesBeijing, China
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20
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Chauhan A, Adams DH, Watson SP, Lalor PF. Platelets: No longer bystanders in liver disease. Hepatology 2016; 64:1774-1784. [PMID: 26934463 PMCID: PMC5082495 DOI: 10.1002/hep.28526] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 02/17/2016] [Accepted: 02/21/2016] [Indexed: 12/17/2022]
Abstract
UNLABELLED Growing lines of evidence recognize that platelets play a central role in liver homeostasis and pathobiology. Platelets have important roles at every stage during the continuum of liver injury and healing. These cells contribute to the initiation of liver inflammation by promoting leukocyte recruitment through sinusoidal endothelium. They can activate effector cells, thus amplifying liver damage, and by modifying the hepatic cellular and cytokine milieu drive both hepatoprotective and hepatotoxic processes. CONCLUSION In this review we summarize how platelets drive such pleiotropic actions and attempt to reconcile the paradox of platelets being both deleterious and beneficial to liver function; with increasingly novel methods of manipulating platelet function at our disposal, we highlight avenues for future therapeutic intervention in liver disease. (Hepatology 2016;64:1774-1784).
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Affiliation(s)
- Abhishek Chauhan
- Centre for Liver Research, and NIHR Birmingham Liver Biomedical Research Unit, Institute of Biomedical Research, Birmingham, UK.
| | - David H. Adams
- Centre for Liver Research, and NIHR Birmingham Liver Biomedical Research UnitInstitute of Biomedical ResearchBirminghamUK
| | - Steve P. Watson
- Institute for Cardiovascular Sciences, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUK
| | - Patricia F. Lalor
- Centre for Liver Research, and NIHR Birmingham Liver Biomedical Research UnitInstitute of Biomedical ResearchBirminghamUK
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21
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López ML, Uribe-Cruz C, Osvaldt A, Kieling CO, Simon L, Tobar S, Andrades M, Matte U. Encapsulated platelets modulate kupffer cell activation and reduce oxidative stress in a model of acute liver failure. Liver Transpl 2016; 22:1562-1572. [PMID: 27509591 DOI: 10.1002/lt.24524] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 07/23/2016] [Indexed: 12/13/2022]
Abstract
Acute liver failure (ALF) is characterized by massive hepatocyte cell death. Kupffer cells (KC) are the first cells to be activated after liver injury. They secrete cytokines and produce reactive oxygen species, leading to apoptosis of hepatocytes. In a previous study, we showed that encapsulated platelets (PLTs) increase survival in a model of ALF. Here, we investigate how PLTs exert their beneficial effect. Wistar rats submitted to 90% hepatectomy were treated with PLTs encapsulated in sodium alginate or empty capsules. Animals were euthanized at 6, 12, 24, 48, and 72 hours after hepatectomy, and livers were collected to assess oxidative stress, caspase activity, and gene expression related to oxidative stress or liver function. The number of KCs in the remnant liver was evaluated. Interaction of encapsulated PLTs and KCs was investigated using a coculture system. PLTs increase superoxide dismutase and catalase activity and reduce lipid peroxidation. In addition, caspase 3 activity was reduced in animals receiving encapsulated PLTs at 48 and 72 hours. Gene expression of endothelial nitric oxide synthase and nuclear factor kappa B were elevated in the PLT group at each time point analyzed. Gene expression of albumin and factor V also increased in the PLT group. The number of KCs in the PLT group returned to normal levels at 12 hours but remained elevated in the control group until 72 hours. Finally, PLTs modulate interleukin (IL) 6 and IL10 expression in KCs after 24 hours of coculture. In conclusion, these results indicate that PLTs interact with KCs in this model and exert their beneficial effect through reduction of oxidative stress that results in healthier hepatocytes and decreased apoptosis. Liver Transplantation 22 1562-1572 2016 AASLD.
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Affiliation(s)
- Mónica Luján López
- Gene Therapy Center, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil.,Post-Graduation Program on Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Carolina Uribe-Cruz
- Gene Therapy Center, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil.,Post-Graduation Program on Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Alessandro Osvaldt
- Post-Graduation Program in Surgery, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Carlos Oscar Kieling
- Experimental Hepatology Laboratory, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil
| | - Laura Simon
- Post-Graduation Program on Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Santiago Tobar
- Cardiovascular Laboratory, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil
| | - Michael Andrades
- Molecular and Protein Analysis Unit, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil
| | - Ursula Matte
- Gene Therapy Center, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil. .,Post-Graduation Program on Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
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22
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Starlinger P, Assinger A, Brostjan C, Gruenberger T. Liver surgery for metastatic colorectal cancer: the surgical oncologist perspective. COLORECTAL CANCER 2016. [DOI: 10.2217/crc-2016-0004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Neoadjuvant/conversion chemotherapy has emerged as an indispensable tool to achieve resectability of initially unresectable metastatic colorectal cancer and improves oncological outcomes. In parallel, surgical strategy has adopted a more aggressive treatment approach to achieve complete tumor clearance. However, chemotherapy affects liver function and combined with extensive liver resection, morbidity has increased, thereby compromising oncological outcome. There is an imperative need for careful patient selection to optimize patient management. In this review, we discuss available evidence and indications for neoadjuvant treatment in the management of colorectal cancer liver metastases, on preoperative patient selection and identification of high-risk patients, potential treatment strategies to promote postoperative liver regeneration to avoid postoperative morbidity and potentially deleterious side effects of these therapies on tumor growth.
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Affiliation(s)
- Patrick Starlinger
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Alice Assinger
- Center for Physiology & Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Christine Brostjan
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
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23
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Kurokawa T, Zheng YW, Ohkohchi N. Novel functions of platelets in the liver. J Gastroenterol Hepatol 2016; 31:745-751. [PMID: 26632220 DOI: 10.1111/jgh.13244] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 10/18/2015] [Accepted: 11/06/2015] [Indexed: 12/12/2022]
Abstract
Platelets contain not only proteins needed for hemostasis but also many growth factors that are required for organ development, tissue regeneration, and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD) and cirrhosis, is due to various causes, such as decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis and the role of platelets in CLD are poorly understood. Thus, in this paper, the experimental evidence for platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. Platelets improve liver fibrosis by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cAMP is increased by adenosine through its receptors on hepatic stellate cells, thereby resulting in inactivation of these cells. Adenosine is produced by degradation of adenine nucleotides, which are stored in abundance within the dense granules of platelets. The regenerative effect of platelets in the liver consists of three mechanisms: a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these experiments, a clinical trial suggested that the increase in platelets induced by platelet transfusion improved liver function in patients with CLD in a clinical setting.We highlight the current knowledge concerning the role of platelets in CLD and expect to open a novel avenue for application of these clinical therapies to treat liver disease.
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Affiliation(s)
- Tomohiro Kurokawa
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery, and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yun-Wen Zheng
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery, and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Nobuhiro Ohkohchi
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery, and Organ Transplantation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
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24
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The Role of IL-1 Family Members and Kupffer Cells in Liver Regeneration. BIOMED RESEARCH INTERNATIONAL 2016; 2016:6495793. [PMID: 27092311 PMCID: PMC4820608 DOI: 10.1155/2016/6495793] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 02/22/2016] [Indexed: 02/06/2023]
Abstract
Interleukin-1 (IL-1) family and Kupffer cells are linked with liver regeneration, but their precise roles remain unclear. IL-1 family members are pleiotropic factors with a range of biological roles in liver diseases, inducing hepatitis, cirrhosis, and hepatocellular carcinoma, as well as liver regeneration. Kupffer cells are the main source of IL-1 and IL-1 receptor antagonist (IL-1Ra), the key members of IL-1 family. This systemic review highlights a close association of IL-1 family members and Kupffer cells with liver regeneration, although their specific roles are inconclusive. Moreover, IL-1 members are proposed to induce effects on liver regeneration through Kupffer cells.
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25
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Margonis GA, Amini N, Buettner S, Besharati S, Kim Y, Sobhani F, Kamel IR, Pawlik TM. Impact of early postoperative platelet count on volumetric liver gain and perioperative outcomes after major liver resection. Br J Surg 2016; 103:899-907. [DOI: 10.1002/bjs.10120] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 12/13/2015] [Accepted: 01/05/2016] [Indexed: 12/17/2022]
Abstract
Abstract
Background
Although perioperative platelet count has been associated with postoperative morbidity and mortality, its impact on liver regeneration has not been examined directly. This study sought to determine the impact of platelet count on liver regeneration after major liver resection using cross-sectional imaging volumetric assessment.
Methods
Patients who underwent major liver resection between 2004 and 2015 and had available data on immediate postoperative platelet count, as well as preoperative and postoperative CT images, were identified retrospectively. Resected liver volume was subtracted from total liver volume (TLV) to define postoperative remnant liver volume (RLVp). The liver regeneration index was defined as the relative increase in liver volume within 2 months ((RLV2m – RLVp)/RLVp, where RLV2m is the remnant liver volume around 2 months after surgery). The association between platelet count, liver regeneration and outcomes was assessed.
Results
A total of 99 patients met the inclusion criteria. Overall, 25 patients (25 per cent) had a low platelet count (less than 150 × 109/l), whereas 74 had a normal–high platelet count (at least 150 × 109/l). Despite having comparable clinicopathological characteristics and RLVp/TLV at surgery (P = 0·903), the relative increase in liver volume within 2 months was considerably lower in the low-platelet group (3·9 versus 16·5 per cent; P = 0·043). Patients with a low platelet count had an increased risk of postoperative complications (72 versus 38 per cent; P = 0·003), longer hospital stay (8 versus 6 days; P = 0·004) and worse median overall survival (24·5 versus 67·3 months; P = 0·005) than those with a normal or high platelet count.
Conclusion
After major liver resection, a low postoperative platelet count was associated with inhibited liver regeneration, as well as worse short- and long-term outcomes. Immediate postoperative platelet count may be an early indicator to identify patients at increased risk of worse outcomes.
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Affiliation(s)
- G A Margonis
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - N Amini
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - S Buettner
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - S Besharati
- Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Y Kim
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - F Sobhani
- Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - I R Kamel
- Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - T M Pawlik
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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26
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Meyer J, Lejmi E, Fontana P, Morel P, Gonelle-Gispert C, Bühler L. A focus on the role of platelets in liver regeneration: Do platelet-endothelial cell interactions initiate the regenerative process? J Hepatol 2015; 63:1263-1271. [PMID: 26169159 DOI: 10.1016/j.jhep.2015.07.002] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 06/05/2015] [Accepted: 07/02/2015] [Indexed: 12/13/2022]
Abstract
Platelets are involved in the early phases of liver regeneration. Moreover, platelet transfusion and thrombocytosis were recently shown to enhance hepatocyte proliferation. However, the precise mechanisms remain elusive. This review discusses the latest updates regarding the mechanisms by which platelets stimulate liver regeneration, focusing on their interactions with liver sinusoidal endothelial cells and on their fate within the liver. Following liver injury, platelets are recruited to and trapped within the liver, where they adhere to the endothelium. Subsequent platelet activation results in the release of platelet granules, which stimulate hepatocyte proliferation through activation of the Akt and ERK1/2 signalling pathways. Platelets activate liver sinusoidal endothelial cells, leading to the secretion of growth factors, such as interleukin-6. Finally, liver sinusoidal cells and hepatocytes can also internalize platelets, but the effects of this alternate process on liver regeneration remain to be explored. A better understanding of the mechanisms by which platelets stimulate liver regeneration could lead to improvement in post-operative organ function and allow hepatectomies of a greater extent to be performed.
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Affiliation(s)
- Jeremy Meyer
- Division of Visceral and Transplantation Surgery, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland; Unit of Surgical Research, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland.
| | - Esma Lejmi
- Unit of Surgical Research, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland
| | - Pierre Fontana
- Division of Angiology and Haemostasis, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland; Geneva Platelet Group, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland
| | - Philippe Morel
- Division of Visceral and Transplantation Surgery, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland; Unit of Surgical Research, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland
| | - Carmen Gonelle-Gispert
- Unit of Surgical Research, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland
| | - Léo Bühler
- Division of Visceral and Transplantation Surgery, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland; Unit of Surgical Research, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland
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27
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Starlinger P, Assinger A, Gruenberger T, Brostjan C. The role of platelets and portal venous pressure fluctuations in postoperative liver regeneration. Eur Surg 2015. [DOI: 10.1007/s10353-015-0352-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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28
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Horizontal RNA transfer mediates platelet-induced hepatocyte proliferation. Blood 2015; 126:798-806. [PMID: 26056167 DOI: 10.1182/blood-2014-09-600312] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 06/03/2015] [Indexed: 02/07/2023] Open
Abstract
Liver regeneration is stimulated by blood platelets, but the molecular mechanisms involved are largely unexplored. Although platelets are anucleate, they do contain coding or regulatory RNAs that can be functional within the platelet or, after transfer, in other cell types. Here, we show that platelets and platelet-like particles (PLPs) derived from the megakaryoblastic cell line MEG-01 stimulate proliferation of HepG2 cells. Platelets or PLPs were internalized within 1 hour by HepG2 cells and accumulated in the perinuclear region of the hepatocyte. Platelet internalization also occurred following a partial hepatectomy in mice. Annexin A5 blocked platelet internalization and HepG2 proliferation. We labeled total RNA of MEG-01 cells by incorporation of 5-ethynyluridine (EU) and added EU-labeled PLPs to HepG2 cells. PLP-derived RNA was detected in the cytoplasm of the HepG2 cell. We next generated PLPs containing green fluorescent protein (GFP)-tagged actin messenger RNA. PLPs did not synthesize GFP, but in coculture with HepG2 cells, significant GFP protein synthesis was demonstrated. RNA-degrading enzymes partly blocked the stimulating effect of platelets on hepatocyte proliferation. Thus, platelets stimulate hepatocyte proliferation via a mechanism that is dependent on platelet internalization by hepatocytes followed by functional transfer of RNA stored in the anucleate platelet. This mechanism may contribute to platelet-mediated liver regeneration.
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29
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Haegele S, Offensperger F, Pereyra D, Lahner E, Assinger A, Fleischmann E, Gruenberger B, Gruenberger T, Brostjan C, Starlinger P. Deficiency in thrombopoietin induction after liver surgery is associated with postoperative liver dysfunction. PLoS One 2015; 10:e0116985. [PMID: 25611592 PMCID: PMC4303418 DOI: 10.1371/journal.pone.0116985] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 12/17/2014] [Indexed: 12/27/2022] Open
Abstract
Background and Aims Thrombopoietin (TPO) has been implicated in the process of liver regeneration and was found to correlate with hepatic function in patients with liver disease. With this investigation we aimed to determine if perioperative TPO levels were associated with postoperative outcome in patients undergoing liver resection. Methods Perioperative TPO was analyzed prior to liver resection as well as on the first and fifth postoperative day in 46 colorectal cancer patients with liver metastasis (mCRC) as well as 23 hepatocellular carcinoma patients (HCC). Serum markers of liver function within the first postoperative week were used to define liver dysfunction. Results While circulating TPO levels significantly increased one day after liver resection in patients without liver cirrhosis (mCRC) (P < 0.001), patients with underlying liver disease (HCC) failed to significantly induce TPO postoperatively. Accordingly, HCC patients had significantly lower TPO levels on POD1 and 5. Similarly, patients with major resections failed to increase circulating TPO levels. Perioperative dynamics of TPO were found to specifically predict liver dysfunction (AUC: 0.893, P < 0.001) after hepatectomy and remained an independent predictor upon multivariate analysis. Conclusions We here demonstrate that perioperative TPO dynamics are associated with postoperative LD. Postoperative TPO levels were found to be lowest in high-risk patients (HCC patients undergoing major resection) but showed an independent predictive value. Thus, a dampened TPO increase after liver resection reflects a poor capacity for hepatic recovery and may help to identify patients who require close monitoring or intervention for potential complications.
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Affiliation(s)
- Stefanie Haegele
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Florian Offensperger
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - David Pereyra
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Elisabeth Lahner
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Alice Assinger
- Institute of Physiology, Medical University of Vienna, Vienna, Austria
| | - Edith Fleischmann
- Department of Anesthesiology, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Birgit Gruenberger
- Department of Internal Medicine, Brothers of Charity Hospital, Vienna, Austria
| | - Thomas Gruenberger
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
- Department of Surgery I, Rudolf Foundation Clinic, Vienna, Austria
| | - Christine Brostjan
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
- * E-mail: (CB); (PS)
| | - Patrick Starlinger
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
- * E-mail: (CB); (PS)
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Noji T, Tsuchikawa T, Ebihara Y, Nakamura T, Kato K, Matsumoto J, Tanaka E, Shichinohe T, Hirano S. Post-operative depletion of platelet count is associated with anastomotic insufficiency following intrahepatic cholangiojejunostomy: a case-control study from the results of 220 cases of intrahepatic cholangiojejunostomy. BMC Surg 2014; 14:81. [PMID: 25323783 PMCID: PMC4274695 DOI: 10.1186/1471-2482-14-81] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 10/07/2014] [Indexed: 12/15/2022] Open
Abstract
Background Post-operative anastomotic insufficiency following major hepato-biliary surgery has significant impacts on the post-operative course. Recent reports have revealed that platelets play an important role in liver regeneration and wound healing. From these experimental and clinical results on platelet function, we hypothesized that post-operative platelet depletion (to <10 × 104/μL) would be associated with delayed liver regeneration as well as anastomotic insufficiency of intrahepatic cholangiojejunostomy. However, little information is available regarding correlations between platelet count and these complications. The purposes of the present study were, firstly, to evaluate the incidence of anastomotic insufficiency following intrahepatic cholangiojejunostomy and, secondly, to evaluate whether platelet depletion represents a risk factor for anastomotic insufficiency in intrahepatic cholangiojejunostomy. Methods Participants in this study comprised 220 consecutive patients who underwent intrahepatic cholangiojejunostomy following hepato-biliary resection for biliary malignancies between September 1998 and December 2010. Anastomotic insufficiency was confirmed by cholangiographic demonstration of leakage from the anastomosis using contrast medium introduced via a biliary drainage tube or prophylactic drain placed during surgery. Results Anastomotic insufficiency of the intrahepatic cholangiojejunostomy occurred in 13 of 220 patients (6%). Thirteen of the 220 patients, including one with anastomotic insufficiency, died during the study. Uni- and multivariate analyses both revealed that platelet depletion on post-operative day 1 (<10 × 104/μL) correlated with anastomotic insufficiency. Conclusion Post-operative platelet depletion was closely associated with anastomotic insufficiency following intrahepatic cholangiojejunostomy. This correlation has been established, but the underlying mechanisms have not.
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Affiliation(s)
- Takehiro Noji
- Department of Gastroenterological Surgery II, Graduate School of Medicine, Hokkaido University, N15W7, Kita-ku, Sapporo Hokkaido 060-8638, Japan.
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López ML, Kieling CO, Uribe Cruz C, Osvaldt A, Ochs de Muñoz G, Meurer L, Silla L, Matte U. Platelet increases survival in a model of 90% hepatectomy in rats. Liver Int 2014; 34:1049-56. [PMID: 24119092 DOI: 10.1111/liv.12326] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 08/29/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Ninety per cent hepatectomy in rodents is a model for acute liver failure. It has been reported that platelets have a strong effect enhancing liver regeneration, because of the production of several growth factors such as serotonin. The aim of this study was to investigate the role of microencapsulated platelets on 90% hepatectomy in rats. METHODS Platelets (PLT) were microencapsulated in sodium alginate and implanted in the peritoneum of rats after 90% partial hepatectomy (PH). Control group received empty capsules (EC). Animals were euthanized at 6, 12, 24, 48 and 72 h post PH (n=9-12/group/time) to evaluate liver regeneration rate, mitotic index, liver content, serum and tissue levels of Interleukin 6 (IL-6) and serotonin and its receptor 5-hydroxytryptamine type 2B (5Ht2b). Survival rate in 10 days was evaluated in a different set of animals (n=20/group). RESULTS Platelets group showed the highest survival rate despite the lowest liver regeneration rate at any time point. Mitotic and BrdU index showed no difference between groups. However, the number of hepatocytes was higher and the internuclear distance was shorter for PLT group. Liver dry weight was similar in both groups indicating that water was the main responsible factor for the weight difference. Gene expression of IL-6 in the liver was significantly higher in EC group 6 h after PH, whereas 5Ht2b was up-regulated at 72 h in PLT group. CONCLUSIONS Platelets enhance survival of animals with 90% PH, probably by an early protective effect on hepatocytes and the increase in growth factor receptors.
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Affiliation(s)
- Mónica L López
- Gene Therapy Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, do Rio Grande do Sul, Brazil; Post-Graduation Program on Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, do Rio Grande do Sul, Brazil
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Murata S, Maruyama T, Nowatari T, Takahashi K, Ohkohchi N. Signal transduction of platelet-induced liver regeneration and decrease of liver fibrosis. Int J Mol Sci 2014; 15:5412-5425. [PMID: 24686514 PMCID: PMC4013572 DOI: 10.3390/ijms15045412] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Revised: 03/16/2014] [Accepted: 03/20/2014] [Indexed: 12/16/2022] Open
Abstract
Platelets contain three types of granules: alpha granules, dense granules, and lysosomal granules. Each granule contains various growth factors, cytokines, and other physiological substances. Platelets trigger many kinds of biological responses, such as hemostasis, wound healing, and tissue regeneration. This review presents experimental evidence of platelets in accelerating liver regeneration and improving liver fibrosis. The regenerative effect of liver by platelets consists of three mechanisms; i.e., the direct effect on hepatocytes, the cooperative effect with liver sinusoidal endothelial cells, and the collaborative effect with Kupffer cells. Many signal transduction pathways are involved in hepatocyte proliferation. One is activation of Akt and extracellular signal-regulated kinase (ERK)1/2, which are derived from direct stimulation from growth factors in platelets. The other is signal transducer and activator of transcription-3 (STAT3) activation by interleukin (IL)-6 derived from liver sinusoidal endothelial cells and Kupffer cells, which are stimulated by contact with platelets during liver regeneration. Platelets also improve liver fibrosis in rodent models by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cyclic adenosine monophosphate (cyclic AMP) is increased by adenosine through its receptors on hepatic stellate cells, resulting in inactivation of these cells. Adenosine is produced by the degradation of adenine nucleotides such as adenosine diphosphate (ADP) and adenosine tri-phosphate (ATP), which are stored in abundance within the dense granules of platelets.
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Affiliation(s)
- Soichiro Murata
- Department of Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Takehito Maruyama
- Department of Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Takeshi Nowatari
- Department of Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Kazuhiro Takahashi
- Department of Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Nobuhiro Ohkohchi
- Department of Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
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Nowatari T, Murata S, Fukunaga K, Ohkohchi N. Role of platelets in chronic liver disease and acute liver injury. Hepatol Res 2014; 44:165-72. [PMID: 23841688 DOI: 10.1111/hepr.12205] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Revised: 07/03/2013] [Accepted: 07/07/2013] [Indexed: 12/13/2022]
Abstract
Platelets contain not only hemostatic factors but also many growth factors that play important roles in wound healing and tissue repair. Platelets have already been used for the promotion of tissue regeneration in the clinical setting, such as dental implantation and plastic surgery. Thrombocytopenia, which is frequently found in patients with chronic liver disease and cirrhosis, is due to various causes such as decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism. However, the relationship between thrombocytopenia and hepatic pathogenesis and the role of platelets in chronic liver disease are poorly understood. In acute liver injury, it is reported that platelets are recruited to the liver and contribute to liver damage by promoting the induction of chemotactic factors and the accumulation of leukocytes in the liver, whereas platelets or mediators released by platelets can have a protective effect against liver injury. In this review, we highlight the recent accumulated knowledge concerning the role of platelets in chronic liver disease and acute liver injury.
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Affiliation(s)
- Takeshi Nowatari
- Department of Surgery, Division of Gastroenterological and Hepatobiliary Surgery, and Organ Transplantation, University of Tsukuba, Tsukuba, Japan
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Lesurtel M, Raptis DA, Melloul E, Schlegel A, Oberkofler C, El-Badry AM, Weber A, Mueller N, Dutkowski P, Clavien PA. Low platelet counts after liver transplantation predict early posttransplant survival: the 60-5 criterion. Liver Transpl 2014; 20:147-55. [PMID: 24123804 DOI: 10.1002/lt.23759] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Accepted: 09/19/2013] [Indexed: 02/06/2023]
Abstract
Platelets play a critical role in liver injury and regeneration. Thrombocytopenia is associated with increases in postoperative complications after partial hepatectomy, but it is unknown whether platelet counts could also predict outcomes after transplantation, a procedure that is often performed in thrombocytopenic patients. Therefore, the aim of this study was to evaluate whether platelet counts could be indicators of short- and long-term outcomes after liver transplantation (LT). Two hundred fifty-seven consecutive LT recipients (January 2003-December 2011) from our prospective database were analyzed. Preoperative and daily postoperative platelet counts were recorded until postoperative day 7 (POD7). Univariate and multivariate analyses were performed to assess whether low perioperative platelet counts were a risk factor for postoperative complications and graft and patient survival. The median pretransplant platelet count was 88 × 10(9) /L [interquartile range (IQR) = 58-127 × 10(9) /L]. The lowest platelet counts occurred on POD3: the median was 56 × 10(9) /L (IQR = 41-86 × 10(9) /L). Patients with low platelet counts on POD5 had higher rates of severe (grade IIIb/IV) complications [39% versus 29%, odds ratio (OR) = 1.09 (95% CI = 1.1-3.3), P = 0.02] and 90-day mortality [16% versus 8%, OR = 2.25 (95% CI = 1.0-5.0), P = 0.05]. In the multivariate analysis, POD5 platelet counts < 60 × 10(9) /L were identified as an independent risk factor for grade IIIb/IV complications [OR = 1.96 (95% CI = 1.07-3.56), P = 0.03)], graft survival [hazard ratio (HR) = 2.0 (95% CI = 1.1-3.6), P = 0.03)], and patient survival [HR = 2.2 (95% CI = 1.1-4.6), P = 0.03)]. The predictive value of platelet counts for graft and patient survival was lost in patients who survived 90 days. In conclusion, after LT, platelet counts < 60 × 10(9) /L on POD5 (the 60-5 criterion) are an independent factor associated with severe complications and early graft and patient survival. These findings may help us to develop protective strategies or specific interventions for high-risk patients.
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Affiliation(s)
- Mickaël Lesurtel
- Swiss Hepatopancreatobiliary and Transplantation Center, Department of Surgery, University Hospital of Zurich, Zurich, Switzerland
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Takahashi K, Murata S, Ohkohchi N. Novel therapy for liver regeneration by increasing the number of platelets. Surg Today 2013; 43:1081-1087. [PMID: 23180116 DOI: 10.1007/s00595-012-0418-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Accepted: 08/30/2012] [Indexed: 12/14/2022]
Abstract
Platelets are the smallest blood constitutes which contain three types of granules; alpha granules, dense granules, and lysosomal granules. Each granule contains various biophysiological substances such as growth factors, cytokines, etc. Platelets have been conventionally viewed as a trigger of inflammatory responses and injury in the liver. Some studies revealed that platelets have strong effects on promoting liver regeneration. This review presents experimental evidence of platelets in accelerating liver regeneration and describes three different mechanisms involved; (1) the direct effect on hepatocytes, where platelets translocate to the space of Disse and release growth factors through direct contact with hepatocytes, (2) the cooperative effect with liver sinusoidal endothelial cells, where the dense concentration of sphingosine-1-phosphate in platelets induces excretion of interleukin-6 from liver sinusoidal endothelial cells, and (3) the collaborative effect with Kupffer cells, where the functions of Kupffer cells are enhanced by platelets.
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Affiliation(s)
- Kazuhiro Takahashi
- Organ Transplantation Gastroenterological and Hepatobiliary Surgery, Faculty of Medicine, Division of Clinical Medicine, Graduate School of University of Tsukuba, 1-1-1, Tennoudai, Tsukuba, Ibaraki, 305-8575, Japan
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36
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Nozaki R, Murata S, Nowatari T, Maruyama T, Ikeda N, Kawasaki T, Fukunaga K, Ohkohchi N. Effects of thrombopoietin on growth of hepatocellular carcinoma: Is thrombopoietin therapy for liver disease safe or not? Hepatol Res 2013; 43:610-20. [PMID: 23157389 DOI: 10.1111/hepr.12006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Revised: 09/19/2012] [Accepted: 10/15/2012] [Indexed: 12/13/2022]
Abstract
AIM Liver cirrhosis (LC) is the end stage of chronic liver disease. No definitive pharmacological treatment is currently available. We previously reported that thrombopoietin (TPO) promoted liver regeneration and improved liver cirrhosis by increasing platelet count. TPO is therefore considered to be a therapeutic agent for LC; however, it is unclear whether TPO has proliferative effects on hepatocellular carcinoma (HCC), which arises frequently in cirrhotic livers. In this study, we examined the effects of TPO on growth of HCC. METHODS Expression of the TPO receptor, myeloproliferative leukemia virus oncogene (MPL) was examined in various liver tumor cell lines and liver cell types. In an in vitro study, the effects of TPO on signal transduction, cell proliferation, migration and invasion were examined in Huh7 cells, in which MPL is highly expressed. In an in vivo study, we subcutaneously transplanted Huh7 cells into nude mice that were divided into a TPO-treated group and a control group, and the tumor volume of each group was measured. RESULTS MPL was expressed strongly in hepatocytes but not in other cell types. Among liver tumor cell lines, Huh7 showed the highest expression of MPL. In Huh7, the addition of TPO activated Akt phosphorylation but not cell proliferation, migration or invasion. In the mouse experiment, there was no significant difference in tumor volume between the two groups. CONCLUSION TPO had no proliferative effect on HCC in vitro or in vivo, and could therefore be useful in the treatment of liver cirrhosis.
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Affiliation(s)
- Reiji Nozaki
- Department of Surgery, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
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Takahashi K, Kozuma Y, Suzuki H, Tamura T, Maruyama T, Fukunaga K, Murata S, Ohkohchi N. Human platelets promote liver regeneration with Kupffer cells in SCID mice. J Surg Res 2013; 180:62-72. [PMID: 23260232 DOI: 10.1016/j.jss.2012.11.030] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2012] [Revised: 10/02/2012] [Accepted: 11/15/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND Platelets contain several growth factors, including vascular endothelial growth factor (VEGF) and insulin-like growth factor. We examined the role of human platelets in liver regeneration with a focus on Kupffer cells (KCs). MATERIALS AND METHODS Severe combined immunodeficiency mice were subjected to 70% hepatectomy and phosphate-buffered saline administration (PBS); 70% hepatectomy and human platelet transfusion (hPLT); 70% hepatectomy, KC depletion, and PBS administration (KD + PBS); 70% hepatectomy, KC depletion, and human platelet transfusion (KD + hPLT); or a sham operation and human platelet transfusion (sham). The groups were evaluated for liver regeneration, accumulation and activation of human platelets in the liver, and/or co-localization of platelets and KCs. RESULTS The liver-to-body weight ratio was significantly higher 48 h post-transfusion in the hPLT group compared with the PBS, KD + PBS, and KD + hPLT groups. Human VEGF concentrations were higher in liver tissues from the hPLT group, whereas VEGF was not detected in the other groups. Hepatic levels of KC-derived cytokines were elevated in the hPLT group compared with the PBS group. Molecules in signaling cascades downstream of these cytokines were phosphorylated earlier and more robustly in the hPLT group than in the PBS group. Activated human platelets accumulated in livers in the hPLT group, whereas fewer platelets accumulated and many were not activated in the sham and KD + hPLT groups. In the hPLT group, most human platelets were attached to KCs. CONCLUSIONS Human platelet transfusion promoted liver regeneration in severe combined immunodeficiency mice. Together, human platelets and KCs resulted in growth factor release and enhanced liver regeneration.
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Affiliation(s)
- Kazuhiro Takahashi
- Department of Surgery, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
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Characterization of transcriptional profiling of Kupffer cells during liver regeneration in rats. Cell Biol Int 2012; 36:721-32. [PMID: 22452802 DOI: 10.1042/cbi20110104] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
KCs (Kupffer cells), as an important hepatic immunoregulatory cells, play a key role in LR (liver regeneration). Uncovering the transcriptional profiling of KCs after PH (partial hepatectomy) would likely clarify its implication in LR. Here, we isolated KCs by methods of Percoll density gradient centrifugation and immunomagnetic beads. Transcriptional profiles of KCs were monitored up to 168 h post-PH using microarray. By comparing the expression profile of KCs at 2-168 h post-PH with that of the control and applying the statistical and bioinformatics criteria, we found 1407 known and 927 unknown genes related to LR. K-means clustering analysis grouped these 1407 genes into robust 14 time-course clusters representing distinct patterns of regulation. Based on gene-set enrichment analysis, genes encoding products involved in cytokine signalling, inflammatory response and cell chaemotaxis were highly enriched in the cluster characterized by gradual up-regulation and then return; genes in defence response and immune response were enriched in clusters 'the general down-regulation during LR'; genes in fatty acid synthesis and sterol metabolism were preferentially distributed in the cluster 'gradual increase'; whereas genes in the categories 'lipid catabolism' and 'glycolysis' were enriched in cluster 'decrease at two intervals'. According to the above analysis, KCs were seemingly sensitive to operative stimulus; immune defence and detoxification function of KCs obviously dropped post-operatively; fatty acid synthesis were enhanced, whereas lipid catabolism and glycolysis were reduced after PH. This study provides a detailed in vivo gene expression profile of KCs, providing a framework to better understand the molecular mechanisms underlying the regeneration process at cellular level.
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Serotonin: A double-edged sword for the liver? Surgeon 2012; 10:107-13. [DOI: 10.1016/j.surge.2011.11.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Revised: 11/06/2011] [Accepted: 11/07/2011] [Indexed: 12/21/2022]
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Regulation of signal transduction and role of platelets in liver regeneration. Int J Hepatol 2012; 2012:542479. [PMID: 22811921 PMCID: PMC3395153 DOI: 10.1155/2012/542479] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Accepted: 06/08/2012] [Indexed: 12/18/2022] Open
Abstract
Among all organs, the liver has a unique regeneration capability after sustaining injury or the loss of tissue that occurs mainly due to mitosis in the hepatocytes that are quiescent under normal conditions. Liver regeneration is induced through a cascade of various cytokines and growth factors, such as, tumor necrosis factor alpha, interleukin-6, hepatocyte growth factor, and insulin-like growth factor, which activate nuclear factor κB, signal transducer and activator of transcription 3, and phosphatidyl inositol 3-kinase signaling pathways. We previously reported that platelets can play important roles in liver regeneration through a direct effect on hepatocytes and collaborative effects with the nonparenchymal cells of the liver, including Kupffer cells and liver sinusoidal endothelial cells, which participate in liver regeneration through the production of various growth factors and cytokines. In this paper, the roles of platelets and nonparenchymal cells in liver regeneration, including the associated cytokines, growth factors, and signaling pathways, are described.
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Yang T, Zhang J, Lu JH, Yang GS, Wu MC, Yu WF. Risk factors influencing postoperative outcomes of major hepatic resection of hepatocellular carcinoma for patients with underlying liver diseases. World J Surg 2011; 35:2073-2082. [PMID: 21656309 DOI: 10.1007/s00268-011-1161-0] [Citation(s) in RCA: 147] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Major hepatic resection of more than three segments in patients with hepatocellular carcinoma (HCC) is a high-risk operation, especially in patients with co-existing underlying liver diseases. The present study evaluated risk factors for postoperative morbidity and mortality after major hepatic resection in HCC patients with underlying liver diseases. METHODS Perioperative data of 305 HCC patients with underlying liver diseases who underwent major hepatic resection were evaluated by univariate and multivariate analyses to identify risk factors for postoperative morbidity and mortality. RESULTS The overall morbidity rate was 37.0% (n = 113), caused by pleural effusion (n = 56), ascites (n = 43), subphrenic effusion/infection (n = 23), hepatic dysfunction (n = 22), bile leakage (n = 10), respiratory infection (n = 7), incision infection (n = 7), intra-abdominal hemorrhage (n = 5), and others. The hospital mortality rate was 2.6% (n = 8), primarily caused by liver failure (4/8). Multivariate logistic regression analysis showed that preoperative platelet count <100 × 10(9)/l (P = 0.006), and increased intraoperative blood loss (≥ 800 ml) (P = 0.008) were independent risk factors of postoperative morbidity, and that preoperative prothrombin time >14 s (P = 0.015) and preoperative platelet count <100 × 10(9)/l (P = 0.007) were independent risk factors for significant hospital mortality. CONCLUSIONS Careful preoperative selection of patients in terms of the Child-Pugh classification and decrease of intraoperative blood loss are important measures to reduce postoperative morbidity after major hepatic resection in HCC patients with underlying liver diseases. Moreover, we should be aware that preoperative platelet count is independently associated with postoperative morbidity and mortality for those patients following major hepatic resection.
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Affiliation(s)
- Tian Yang
- Department of 2nd Hepatobiliary Surgery and Intensive Care Unit, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, No. 225 Changhai Road, Shanghai, China
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Influence of platelet lysate on the recovery and metabolic performance of cryopreserved human hepatocytes upon thawing. Transplantation 2011; 91:1340-6. [PMID: 21516066 DOI: 10.1097/tp.0b013e31821aba37] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Storage of human hepatocytes is essential for their use in research and liver cell transplantation. However, cryopreservation and thawing (C/T) procedures have detrimental effects on the viability and functionality compared with fresh cells. The aim of this study was to upgrade the standard C/T methodology to obtain better quality hepatocytes for cell transplantation to improve the overall clinical outcome. METHODS Human hepatocytes isolated from donor livers were cryopreserved in University of Wisconsin solution with 10% dimethyl sulfoxide (standard medium), which was supplemented with 10% or 20% of platelet lysate. Thawing media supplemented with up to 30 mM glucose was also investigated. The effects on cell viability, adhesion proteins (e-cadherin, β-catenin, and β1-integrin) expression, attachment efficiency, apoptotic indicators, Akt signaling, ATP levels, and cytochrome P450 activities have been evaluated. RESULTS The results indicate that the hepatocytes cryopreserved in a medium supplemented with platelet lysate show better recovery than those preserved in the standard medium: higher expression of adhesion molecules, higher attachment efficiency and cell survival; decreased number of apoptotic nuclei and caspase-3 activation; maintenance of ATP levels; and drug biotransformation capability close to those in fresh hepatocytes. Supplementation of thawing media with glucose led to a significant decrease in caspase-3 activation and to increased adhesion molecules preservation and Akt signal transduction after C/T. Minor nonsignificant changes in cell viability and attachment efficiency were observed. CONCLUSIONS These promising results could lead to a new cryopreservation procedure to improve human hepatocyte cryopreservation outcome.
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Kawasaki T, Murata S, Takahashi K, Nozaki R, Ohshiro Y, Ikeda N, Pak S, Myronovych A, Hisakura K, Fukunaga K, Oda T, Sasaki R, Ohkohchi N. Activation of human liver sinusoidal endothelial cell by human platelets induces hepatocyte proliferation. J Hepatol 2010; 53:648-654. [PMID: 20615569 DOI: 10.1016/j.jhep.2010.04.021] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2009] [Revised: 03/11/2010] [Accepted: 04/09/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS We previously reported that platelets promote hepatocyte proliferation. In this study, we focused on the role of platelets in liver sinusoidal endothelial cells (LSECs) in addition to their role in hepatocyte in liver regeneration. METHODS Immortalized human LSECs (TMNK-1) were used. The LSECs were co-cultured with human platelets, and the proliferation of LSECs and the excretion of growth factors and interleukin-6 (IL-6) were subsequently measured. The main factor from platelets which induced the excretion of IL-6 from LSECs was determined using inhibitors of each component contained in the platelets. The need for direct contact between platelets and LSECs was investigated using cell culture inserts. The proliferation of human primary hepatocytes was measured after the addition of the supernatant of LSECs cultured with or without platelets. RESULTS The number of LSECs cocultured with platelets significantly increased. Excretion of IL-6 and vascular endothelial growth factor (VEGF) increased in LSECs with platelets. JTE-013, a specific antagonist for sphingosine 1-phosphate (S1P) 2 receptors, inhibited the excretion of IL-6 from LSECs after the addition of platelets. When the platelets and LSECs were separated by the cell culture insert, the excretion of IL-6 from LSECs was decreased. DNA synthesis was significantly increased in human primary hepatocytes cultured with the supernatant of LSECs with platelets. CONCLUSIONS Platelets promote LSEC proliferation and induce IL-6 and VEGF production. Direct contact between the platelets and LSECs and S1P, that are contained in platelets, were involved in the excretion of IL-6 from LSECs. IL-6 from LSECs induced proliferation of parenchymal hepatocytes.
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Affiliation(s)
- Takuya Kawasaki
- Department of Surgery, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan
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Pak S, Kondo T, Nakano Y, Murata S, Fukunaga K, Oda T, Sasaki R, Ohkohchi N. Platelet adhesion in the sinusoid caused hepatic injury by neutrophils after hepatic ischemia reperfusion. Platelets 2010; 21:282-8. [PMID: 20218909 DOI: 10.3109/09537101003637265] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Liver ischemia-reperfusion (I/R) injury is one of the most serious complications of hepatic surgery. In I/R, activated Kupffer cells cause platelet adhesion to sinusoidal endothelium as well as neutrophils and cause liver dysfunction. The aim of this study was to evaluate platelet dynamics in the hepatic microcirculation after I/R by intravital microscopy (IVM) and to clarify the relationship between platelet adhesion and neutrophil activation. Male Sprague-Dawley (SD) rats were divided into two groups: the control (administration of saline) group and the sivelestat group in which neutrophil activation was suppressed by sivelestat before I/R. The number of adherent platelets in sinusoid was observed up to 120 minutes after I/R by IVM. Samples of liver tissue and blood were taken for examination of histological findings, liver enzymes and inflammatory cytokines. The number of adherent platelets was significantly increased after I/R in both groups. Compared with the control group, the number of adherent platelets significantly decreased after hepatic I/R in the sivelestat group. Moreover, sivelestat improved changes of histological findings and elevation of liver enzymes. However, there was no significant difference in inflammatory cytokines of TNF-alpha, IL-1beta or IL-6. Platelet adhesion in the sinusoid is associated with liver dysfunction after I/R as well as neutrophils. Activated neutrophils induce platelet adhesion in the sinusoid of the liver.
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Affiliation(s)
- Sugiru Pak
- Department of Surgery, Doctoral Program in Clinical Science, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan
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Nanashima A, Tobinaga S, Abo T, Sumida Y, Araki M, Hayashi H, Sakamoto I, Kudo T, Takeshita H, Hidaka S, Sawai T, Hatano K, Nagayasu T. Relationship of hepatic functional parameters with changes of functional liver volume using technetium-99m galactosyl serum albumin scintigraphy in patients undergoing preoperative portal vein embolization: a follow-up report. J Surg Res 2010; 164:e235-42. [PMID: 20869076 DOI: 10.1016/j.jss.2010.06.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2010] [Revised: 05/05/2010] [Accepted: 06/01/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND To identify predictors of changes in functional hepatic volumes after portal vein embolization (PVE) before hepatectomy, we examined the relationship between hepatic functional parameters and changes in functional volume of the embolized and non-embolized liver based on a previous volumetric analysis. MATERIAL AND METHODS Subjects were 24 patients who underwent PVE, which was performed through the trans-ileocolic vein (n = 4) or by percutaneous transhepatic puncture (n = 20). The RI liver volume parameter was measured by liver scintigraphy with technetium-(99m) galactosyl human serum albumin ((99m)Tc-GSA). Computed tomography (CT) volume parameter was also measured. RESULTS Significant atrophy of the embolized liver and hypertrophy of the non-embolized liver (change of 72 ± 108 cm(3) and 111 ± 91 cm(3), respectively) (change of 7.8%) was observed after PVE. The change in these RI volume parameters (change of 173 ± 175 cm(3) and 145 ± 137 cm(3) , respectively) (16.5%) was significantly greater than CT volume parameters (P < 0.01). CT vol and RI vol in the embolized and non-embolized liver were well correlated (r = 0.75 and 0.69, respectively). However, the correlation between CT and RI volume parameters in the embolized and non-embolized liver after PVE was very weak (r = 0.17 and 0.03, respectively). Only alkaline phosphatase level correlated negatively with atrophic CT volume parameter of the embolized liver (r = -0.455, P < 0.05). When compared with CT volume parameter, more parameters were significantly correlated with changes of RI volume parameter in the embolized liver: pre-PVE pressure; ICGR15; and serum levels of hyaluronate, total bilirubin, albumin, and alkaline phosphatase. Only platelet count was significantly correlated with hypertrophy of the non-embolized liver. CONCLUSION RI volume parameter might more accurately reflect functional changes in the embolized liver and non-embolized liver than CT volume parameter. Correlated parameters might allow us to predict the functional effect of PVE.
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Affiliation(s)
- Atsushi Nanashima
- Division of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
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Platelets prevent acute liver damage after extended hepatectomy in pigs. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2010; 17:855-64. [PMID: 20734209 DOI: 10.1007/s00534-010-0276-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2009] [Accepted: 02/25/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND/PURPOSE Platelets develop tissue repair and promote liver regeneration. We investigated whether platelets prevented acute liver damage after extended hepatectomy in pigs. METHODS Thrombocytosis was induced by the following two methods; afterwards 80% hepatectomy was performed in pigs. In the first method, the pigs received administration of thrombopoietin [TPO (+) group], and they were compared with a control group [TPO (-) group]. In the second method, the pigs received a splenectomy [Sp (+) group], and theywere compared with another control group [Sp (-) group]. Platelet counts, biochemical examination of blood, and histopathological findings of the residual liver were examined. RESULTS Serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and total bilirubin (T-Bil) levels were significantly decreased in the thrombocytotic groups compared with the control groups in the early period after hepatectomy. In the histopathological findings, hemorrhagic necrosis with a bile plug was observed in the control groups, but this phenomenon was not observed in the thrombocytotic groups. On transmission electron microscopy, the sinusoidal endothelial lining was destroyed and detached into the sinusoidal space with enlargement of Disse's spaces in the thrombocytotic groups, but these findings were not observed in the control groups. CONCLUSION An increased number of platelets prevents acute liver damage after extended hepatectomy.
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Single administration of thrombopoietin prevents progression of liver fibrosis and promotes liver regeneration after partial hepatectomy in cirrhotic rats. Ann Surg 2008; 248:821-8. [PMID: 18948810 DOI: 10.1097/sla.0b013e31818584c7] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To evaluate the effect of thrombopoietin on liver regeneration after hepatectomy and antifibrosis under conditions of liver cirrhosis in rats. SUMMARY BACKGROUND DATA We revealed that platelets induced by thrombopoietin administration promote liver regeneration after hepatectomy in the normal liver. METHODS Seventy percent hepatectomy was carried out in rats, which were subsequently divided into 4 groups: (1) normal group without any treatment, (2) liver cirrhosis (LC) group, (3) combined thrombopoietin and liver cirrhosis (LC+TPO) group, and (4) combined thrombopoietin, antiplatelet serum and liver cirrhosis (LC+TPO+APS) group. Growth kinetics in the liver regeneration and growth factors were analyzed. Liver fibrotic area and activation of hepatic stellate cells were also investigated. RESULTS In LC group, liver regeneration was significantly delayed compared with normal group 24 hours after hepatectomy. On the other hand, liver regeneration of LC+TPO group increased significantly compared with LC group, to a level that was the same as that recorded in normal group. In LC group, liver fibrotic area before hepatectomy was significantly higher compared with the normal group. Liver fibrosis of LC+TPO group was significantly reduced compared with LC group. The antifibrotic and liver regeneration promoting effects of LC+TPO group were inhibited by antiplatelet serum in LC+TPO+APS group. CONCLUSION The administration of thrombopoietin reduces liver fibrosis and stimulates regeneration after hepatectomy through increment and accumulation of platelets in the cirrhotic liver. This could be a potentially useful treatment for liver cirrhosis.
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