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Lin H, Wieser A, Zhang J, Regel I, Nieß H, Mayerle J, Gerbes AL, Liu S, Steib CJ. Gram-negative bacteria-driven increase of cytosolic phospholipase A2 leads to activation of Kupffer cells. Cell Mol Life Sci 2024; 82:22. [PMID: 39725773 DOI: 10.1007/s00018-024-05451-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 05/07/2024] [Accepted: 05/29/2024] [Indexed: 12/28/2024]
Abstract
Bacterial infections are prevalent and the major cause of morbidity and mortality in cirrhosis. Activation of human Kupffer cells (HKCs) from livers is essential for human innate immunity. Cytosolic phospholipase A2 (cPLA2) plays a crucial role in the control and balance of innate immune and inflammatory reactions. Uncharacterized is the role of cPLA2 in HKC activation by bacterial infection. This work aimed to determine the function and mechanism of cPLA2 in gram-negative bacteria (GNB)-induced HKC activation. In this study, we found that Escherichia coli (E. coli)-induced activation of HKCs led to a rise in cPLA2 mRNA and protein expression, where the ERK and NF-κB pathways were concurrently triggered. Luciferase activity of cPLA2' promoters, PLA2G4A promoters, was enhanced with the stimulation of E. coli or co-transfection with STAT3 or RelB in HKCs. E. coli massively boosted the binding activity of STAT3 and RelB to the specific regions of the PLA2G4A promoter as measured by ChIP-qPCR. The E. coli-ERK-STAT3 and E. coli-non-canonical NF-κB-RelB signaling axes were then identified using pathway inhibitors and transcription factors in the rescue experiments during E. coli-induced HKC activation. In conclusion, we discovered that cPLA2 is necessary for E. coli-induced HKC activation, and the underlying mechanism could be the transcriptional regulation of STAT3 and RelB on the PLA2G4A promoter following the ERK and non-canonical NF-κB signaling activation, implying that the regulation of cPLA2 expression via the E. coli-ERK/non-canonical NF-κB-STAT3/RelB signaling axis could be effective for controlling GNB-induced HKC activation in cirrhotic patients.
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Affiliation(s)
- Hao Lin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- Department of Medicine II, University Hospital, Liver Centre Munich, LMU Munich, Munich, Germany.
| | - Andreas Wieser
- Medical Microbiology and Hospital Epidemiology, Faculty of Medicine, Max von Pettenkofer Institute, LMU Munich, Munich, Germany
- Division of Infectious Diseases and Tropical Medicine, University Hospital, LMU Munich, Munich, Germany
- German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
| | - Jiang Zhang
- Department of Liver Surgery and Liver Transplantation Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ivonne Regel
- Department of Medicine II, University Hospital, Liver Centre Munich, LMU Munich, Munich, Germany
| | - Hanno Nieß
- Department of General, Visceral and Transplant Surgery, University Hospital, LMU Munich, Munich, Germany
| | - Julia Mayerle
- Department of Medicine II, University Hospital, Liver Centre Munich, LMU Munich, Munich, Germany
| | - Alexander L Gerbes
- Department of Medicine II, University Hospital, Liver Centre Munich, LMU Munich, Munich, Germany
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Christian J Steib
- Department of Internal Medicine and Gastroenterology, Internistisches Klinikum München Süd, Am Isarkanal 36, Munich, Germany.
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Dumitru A, Matei E, Cozaru GC, Chisoi A, Alexandrescu L, Popescu RC, Butcaru MP, Dumitru E, Rugină S, Tocia C. Endotoxin Inflammatory Action on Cells by Dysregulated-Immunological-Barrier-Linked ROS-Apoptosis Mechanisms in Gut-Liver Axis. Int J Mol Sci 2024; 25:2472. [PMID: 38473721 DOI: 10.3390/ijms25052472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 03/14/2024] Open
Abstract
Our study highlighted the immune changes by pro-inflammatory biomarkers in the gut-liver-axis-linked ROS-cell death mechanisms in chronic and acute inflammations when gut cells are exposed to endotoxins in patients with hepatic cirrhosis or steatosis. In duodenal tissue samples, gut immune barrier dysfunction was analyzed by pro-inflammatory biomarker expressions, oxidative stress, and cell death by flow cytometry methods. A significant innate and adaptative immune system reaction was observed as result of persistent endotoxin action in gut cells in chronic inflammation tissue samples recovered from hepatic cirrhosis with the A-B child stage. Instead, in patients with C child stage of HC, the endotoxin tolerance was installed in cells, characterized by T lymphocyte silent activation and increased Th1 cytokines expression. Interesting mechanisms of ROS-cell death were observed in chronic and acute inflammation samples when gut cells were exposed to endotoxins and immune changes in the gut-liver axis. Late apoptosis represents the chronic response to injury induction by the gut immune barrier dysfunction, oxidative stress, and liver-dysregulated barrier. Meanwhile, necrosis represents an acute and severe reply to endotoxin action on gut cells when the immune system reacts to pro-inflammatory Th1 and Th2 cytokines releasing, offering protection against PAMPs/DAMPs by monocytes and T lymphocyte activation. Flow cytometric analysis of pro-inflammatory biomarkers linked to oxidative stress-cell death mechanisms shown in our study recommends laboratory techniques in diagnostic fields.
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Affiliation(s)
- Andrei Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Elena Matei
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
| | - Georgeta Camelia Cozaru
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Anca Chisoi
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Clinical Service of Pathology, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medical Sciences Academy, 1 I.C. Bratianu Street, 030167 Bucharest, Romania
| | - Luana Alexandrescu
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Răzvan Cătălin Popescu
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Mihaela Pundiche Butcaru
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
| | - Eugen Dumitru
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, "Ovidius" University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Sorin Rugină
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
- Academy of Romanian Scientist, 3 Ilfov Street, 050044 Bucharest, Romania
| | - Cristina Tocia
- Gastroenterology Department, "Sf. Apostol Andrei" Emergency County Hospital, 145 Tomis Blvd., 900591 Constanta, Romania
- Medicine Faculty, "Ovidius" University of Constanta, 1 Universitatii Street, 900470 Constanta, Romania
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Hu R, Zeng GF, Fang Y, Nie L, Liang HL, Wang ZG, Yang H. Intravoxel incoherent motion diffusion-weighted imaging for evaluating the pancreatic perfusion in cirrhotic patients. Abdom Radiol (NY) 2024; 49:492-500. [PMID: 38052890 DOI: 10.1007/s00261-023-04063-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/11/2023] [Accepted: 09/13/2023] [Indexed: 12/07/2023]
Abstract
PURPOSE To assess the characteristics of pancreatic perfusion in normal pancreas versus cirrhotic patients using intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI). METHODS A total of 67 cirrhotic patients and 33 healthy subjects underwent IVIM on a 3.0 T MRI scanner. Diffusion coefficient (ADCslow), pseudo-diffusion coefficient (ADCfast), and perfusion fraction (f) were calculated based on the bi-exponential model. The pancreatic IVIM-derived parameters were then compared. In the cirrhotic group, the relationship was analyzed between IVIM-derived pancreatic parameters and different classes of hepatic function as determined by the Child-Pugh classification. Also, the pancreatic IVIM-derived parameters were compared among different classes of cirrhosis as determined by the Child-Pugh classification. RESULTS The f value of the pancreas in cirrhotic patients was significantly lower than that in normal subjects (p = 0.01). In the cirrhotic group, the f value of the pancreas decreased with the increase of the Child-Pugh classification (R = - 0.49, p = 0.00). The f value of the pancreas was significantly higher in Child-Pugh class A patients than in class B and C patients (p = 0.02, 0.00, respectively), whereas there was no significant difference between class B and C patients (p = 0.16). CONCLUSION The IVIM-derived perfusion-related parameter (f value) could be helpful for the evaluation of pancreatic perfusion in liver cirrhosis. Our data also suggest that the blood perfusion decrease in the pancreas is present in liver cirrhosis, and the pancreatic perfusion tends to decrease with the increasing severity of hepatic function. TRIAL REGISTRATION Trial registration number is 2021-ky-68 and date of registration for prospectively registered trials is February 23, 2022.
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Affiliation(s)
- Ran Hu
- Department of Radiology, Chongqing Hospital of Traditional Chinese Medicine, No.6, Panxi 7th Road, Jiangbei District, Chongqing, 400021, People's Republic of China
| | - Guo-Fei Zeng
- Department of Radiology, Chongqing Hospital of Traditional Chinese Medicine, No.6, Panxi 7th Road, Jiangbei District, Chongqing, 400021, People's Republic of China
| | - Yu Fang
- Department of Radiology, Chongqing Hospital of Traditional Chinese Medicine, No.6, Panxi 7th Road, Jiangbei District, Chongqing, 400021, People's Republic of China
| | - Lisha Nie
- GE Healthcare, MR Research China, Beijing, People's Republic of China
| | - Hui-Lou Liang
- GE Healthcare, MR Research China, Beijing, People's Republic of China
| | - Zhi-Gang Wang
- Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong Distinct, Chongqing, 400010, People's Republic of China.
| | - Hua Yang
- Department of Radiology, Chongqing Hospital of Traditional Chinese Medicine, No.6, Panxi 7th Road, Jiangbei District, Chongqing, 400021, People's Republic of China.
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Medina Pizaño MY, Loera Arias MDJ, Montes de Oca Luna R, Saucedo Cárdenas O, Ventura Juárez J, Muñoz Ortega MH. Neuroimmunomodulation of adrenoblockers during liver cirrhosis: modulation of hepatic stellate cell activity. Ann Med 2023; 55:543-557. [PMID: 36826975 PMCID: PMC9970206 DOI: 10.1080/07853890.2022.2164047] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
The sympathetic nervous system and the immune system are responsible for producing neurotransmitters and cytokines that interact by binding to receptors; due to this, there is communication between these systems. Liver immune cells and nerve fibres are systematically distributed in the liver, and the partial overlap of both patterns may favour interactions between certain elements. Dendritic cells are attached to fibroblasts, and nerve fibres are connected via the dendritic cell-fibroblast complex. Receptors for most neuroactive substances, such as catecholamines, have been discovered on dendritic cells. The sympathetic nervous system regulates hepatic fibrosis through sympathetic fibres and adrenaline from the adrenal glands through the blood. When there is liver damage, the sympathetic nervous system is activated locally and systemically through proinflammatory cytokines that induce the production of epinephrine and norepinephrine. These neurotransmitters bind to cells through α-adrenergic receptors, triggering a cellular response that secretes inflammatory factors that stimulate and activate hepatic stellate cells. Hepatic stellate cells are key in the fibrotic process. They initiate the overproduction of extracellular matrix components in an active state that progresses from fibrosis to liver cirrhosis. It has also been shown that they can be directly activated by norepinephrine. Alpha and beta adrenoblockers, such as carvedilol, prazosin, and doxazosin, have recently been used to reverse CCl4-induced liver cirrhosis in rodent and murine models.KEY MESSAGESNeurotransmitters from the sympathetic nervous system activate and increase the proliferation of hepatic stellate cells.Hepatic fibrosis and cirrhosis treatment might depend on neurotransmitter and hepatic nervous system regulation.Strategies to reduce hepatic stellate cell activation and fibrosis are based on experimentation with α-adrenoblockers.
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Affiliation(s)
| | | | | | - Odila Saucedo Cárdenas
- Histology Department, Faculty of Medicine, Autonomous University of Nuevo León, Monterrey, México
| | - Javier Ventura Juárez
- Department of Morphology, Autonomous University of Aguascalientes, Aguascalientes, México
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Zhao J, Yang Q, Liu Z, Xu P, Tian L, Yan J, Li K, Lin B, Bian L, Xi Z, Liu X. The impact of subchronic ozone exposure on serum metabolome and the mechanisms of abnormal bile acid and arachidonic acid metabolisms in the liver. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 252:114573. [PMID: 36701875 DOI: 10.1016/j.ecoenv.2023.114573] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 12/28/2022] [Accepted: 01/22/2023] [Indexed: 06/17/2023]
Abstract
Ambient ozone (O3) pollution can induce respiratory and cardiovascular toxicity. However, its impact on the metabolome and the underlying mechanisms remain unclear. This study first investigated the serum metabolite changes in rats exposed to 0.5 ppm O3 for 3 months using untargeted metabolomic approach. Results showed chronic ozone exposure significantly altered the serum levels of 34 metabolites with potential increased risk of digestive, respiratory and cardiovascular disease. Moreover, bile acid synthesis and secretion, and arachidonic acid (AA) metabolism became the most prominent affected metabolic pathways after O3 exposure. Further studies on the mechanisms found that the elevated serum toxic bile acid was not due to the increased biosynthesis in the liver, but the reduced reuptake from the portal vein to hepatocytes owing to repressed Ntcp and Oatp1a1, and the decreased bile acid efflux in hepatocytes as a results of inhibited Bsep, Ostalpha and Ostbeta. Meanwhile, decreased expressions of detoxification enzyme of SULT2A1 and the important regulators of FXR, PXR and HNF4α also contributed to the abnormal bile acids. In addition, O3 promoted the conversion of AA into thromboxane A2 (TXA2) and 20-hydroxyarachidonic acid (20-HETE) in the liver by up-regulation of Fads2, Cyp4a and Tbxas1 which resulting in decreased AA and linoleic acid (LA), and increased thromboxane B2 (TXB2) and 20-HETE in the serum. Furthermore, apparent hepatic chronic inflammation, fibrosis and abnormal function were found in ozone-exposed rats. These results indicated chronic ozone exposure could alter serum metabolites by interfering their metabolism in the liver, and inducing liver injury to aggravate metabolic disorders.
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Affiliation(s)
- Jiao Zhao
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
| | - Qingcheng Yang
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
| | - Zhiyuan Liu
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
| | - Pengfei Xu
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
| | - Lei Tian
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Jun Yan
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Kang Li
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Bencheng Lin
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Liping Bian
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Zhuge Xi
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
| | - Xiaohua Liu
- Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, Tianjin Sport University, Tianjin 301617, China.
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Alba MM, Ebright B, Hua B, Slarve I, Zhou Y, Jia Y, Louie SG, Stiles BL. Eicosanoids and other oxylipins in liver injury, inflammation and liver cancer development. Front Physiol 2023; 14:1098467. [PMID: 36818443 PMCID: PMC9932286 DOI: 10.3389/fphys.2023.1098467] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/16/2023] [Indexed: 02/05/2023] Open
Abstract
Liver cancer is a malignancy developed from underlying liver disease that encompasses liver injury and metabolic disorders. The progression from these underlying liver disease to cancer is accompanied by chronic inflammatory conditions in which liver macrophages play important roles in orchestrating the inflammatory response. During this process, bioactive lipids produced by hepatocytes and macrophages mediate the inflammatory responses by acting as pro-inflammatory factors, as well as, playing roles in the resolution of inflammation conditions. Here, we review the literature discussing the roles of bioactive lipids in acute and chronic hepatic inflammation and progression to cancer.
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Affiliation(s)
- Mario M. Alba
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Brandon Ebright
- Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Brittney Hua
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Ielyzaveta Slarve
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Yiren Zhou
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Yunyi Jia
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Stan G. Louie
- Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Bangyan L. Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
- Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, Unites States
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Rampa DR, Feng H, Allur-Subramaniyan S, Shim K, Pekcec A, Lee D, Doods H, Wu D. Kinin B1 receptor blockade attenuates hepatic fibrosis and portal hypertension in chronic liver diseases in mice. J Transl Med 2022; 20:590. [PMID: 36514072 PMCID: PMC9746183 DOI: 10.1186/s12967-022-03808-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 12/03/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND AIMS Kinin B1 receptors (B1Rs) are implicated in the pathogenesis of fibrosis. This study examined the anti-fibrotic effects of B1R blockade with BI 113823 in two established mouse models of hepatic fibrosis induced by intraperitoneal carbon tetrachloride (CCl4) injection or bile duct ligation (BDL). The mechanisms underlying the protection afforded by B1R inhibition were examined using human peripheral blood cells and LX2 human hepatic stellate cells (HSCs). METHODS Fibrotic liver diseases were induced in mice by intraperitoneal carbon tetrachloride (CCl4) injection for 6 weeks, and by bile duct ligation (BDL) for 3 weeks, respectively. Mice received daily treatment of vehicle or BI 113823 (B1R antagonist) from onset of the experiment until the end of the study. RESULTS B1Rs were strongly induced in fibrotic mouse liver. BI 113823 significantly attenuated liver fibrosis and portal hypertension (PH), and improved survival in both CCl4 and BDL mice. BI 113823 significantly reduced the expression of fibrotic proteins α-SMA, collagens 1, 3, 4, and profibrotic growth factors PDGF, TGFβ, CTGF, VEGF, proliferating cell nuclear antigen; and reduced hepatic Akt phosphorylation in CCl4- and BDL-induced liver fibrosis. BI 113823 also reduced expression of Cytokines IL-1, IL-6; chemokines MCP-1, MCP-3 and infiltration of inflammatory cells; and inhibited human monocyte and neutrophil activation, transmigration, TNF-α & MPO production in vitro. BI 113823 inhibited TGF-β and B1R agonist-stimulated human-HSC activation, contraction, proliferation, migration and fibrosis protein expression, and inhibited activation of PI3K/Akt signalling pathway. CONCLUSIONS B1Rs merits consideration as a novel therapeutic target for chronic liver fibrosis and PH.
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Affiliation(s)
- Dileep Reddy Rampa
- grid.411545.00000 0004 0470 4320Department of Bio-Nanotechnology and Bio-Convergence Engineering, Jeonbuk National University, Jeonju, South Korea
| | - Huiying Feng
- grid.411545.00000 0004 0470 4320Department of Bio-Nanotechnology and Bio-Convergence Engineering, Jeonbuk National University, Jeonju, South Korea
| | - Sivakumar Allur-Subramaniyan
- grid.411545.00000 0004 0470 4320Department of Animal Biotechnology & Agricultural Convergence Technology, Jeonbuk National University, Jeonju, South Korea
| | - Kwanseob Shim
- grid.411545.00000 0004 0470 4320Department of Animal Biotechnology & Agricultural Convergence Technology, Jeonbuk National University, Jeonju, South Korea
| | - Anton Pekcec
- grid.420061.10000 0001 2171 7500Research Beyond Borders, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Dongwon Lee
- grid.411545.00000 0004 0470 4320Department of Bio-Nanotechnology and Bio-Convergence Engineering, Jeonbuk National University, Jeonju, South Korea
| | - Henri Doods
- grid.420061.10000 0001 2171 7500Research Beyond Borders, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Dongmei Wu
- grid.411545.00000 0004 0470 4320Department of Bio-Nanotechnology and Bio-Convergence Engineering, Jeonbuk National University, Jeonju, South Korea ,grid.410396.90000 0004 0430 4458Department of Research, Mount Sinai Medical Center, Miami Beach, FL USA
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Rahman MS, Pang WK, Amjad S, Ryu DY, Adegoke EO, Park YJ, Pang MG. Hepatic consequences of a mixture of endocrine-disrupting chemicals in male mice. JOURNAL OF HAZARDOUS MATERIALS 2022; 436:129236. [PMID: 35739755 DOI: 10.1016/j.jhazmat.2022.129236] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/22/2022] [Accepted: 05/23/2022] [Indexed: 06/15/2023]
Abstract
The global epidemic of metabolic syndrome has been partially linked to ubiquitous exposure to endocrine-disrupting chemicals (EDCs). Although the impacts of exposure to single EDCs have been thoroughly studied, the consequences of simultaneous uncontrolled exposure to multiple EDCs require further investigations. Therefore, in this study, we evaluated how exposure to mixtures containing bisphenol A and seven phthalates impacts liver functions and metabolic homeostasis. Male mice were gavaged with either EDCs at four different dose combinations or corn oil (control) for six weeks. The results showed that exposure to EDCs at the human daily exposure limit had a negligible impact on liver function. However, EDC at ≥ 25 orders of magnitude of human-relevant doses had detrimental impacts on overall liver function, leading to metabolic abnormalities, steatohepatitis, and hepatic fibrosis via the activation of both genomic and non-genomic pathways. The metabolic phenotype was linked to alterations in key genes involved in hepatic lipid and glucose metabolism. In contrast, alterations in cytokine expression, oxidative stress, and apoptosis impacted steatohepatitis and fibrosis. Because EDC exposure does not occur independently, the findings of the combined effects of exposure to multiple EDCs have significant relevance for public health.
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Affiliation(s)
- Md Saidur Rahman
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea
| | - Won-Ki Pang
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea
| | - Shehreen Amjad
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea
| | - Do-Yeal Ryu
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea
| | - Elikanah Olusayo Adegoke
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea
| | - Yoo-Jin Park
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea
| | - Myung-Geol Pang
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do 17546, Republic of Korea.
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Taher MY, El-Hadidi A, El-Shendidi A, Sedky A. Soluble CD163 for Prediction of High-Risk Esophageal Varices and Variceal Hemorrhage in Patients with Liver Cirrhosis. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2022; 29:82-95. [PMID: 35497666 PMCID: PMC8995632 DOI: 10.1159/000516913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 04/22/2021] [Indexed: 02/18/2025]
Abstract
INTRODUCTION Activation of hepatic macrophages in liver disease is pathogenically related to portal hypertension (PH). Soluble CD163 (sCD163) is shed in blood by activated macrophages and may predict PH progression noninvasively. This study was designed to investigate the relation of serum sCD163 to the grade and bleeding risk of esophageal varices (EV) and its role for prediction of variceal hemorrhage (VH). METHODS The study included cirrhotic patients divided into 3 groups: patients who presented with acute upper gastrointestinal bleeding (UGIB) proved to originate from EV on endoscopy, patients without any history of UGIB but who revealed EV on surveillance endoscopy, and patients without endoscopic evidence of varices. Variceal grade and risk signs and bleeding stigmata were noted simultaneously with measurement of serum sCD163 concentration. RESULTS Serum sCD163 concentration showed a significant increase in cirrhotic patients compared to healthy subjects (p < 0.001) with a stepwise increase among the group without varices, nonbleeder group, and bleeder group sequentially. Serum sCD163 levels correlated positively with the variceal grade and risk signs in both the bleeder and nonbleeder groups (p = 0.002, p < 0.001 and p = 0.004, p < 0.001, respectively). Serum sCD163 at a cutoff value of 3.6 mg/L performed significantly for prediction of EV presence (AUC = 0.888). Serum sCD163 at a cutoff value >4 mg/L significantly predicted large-size and high-risk EV (AUC = 0.910 and AUC = 0.939, respectively) and the index bleed risk (AUC = 0.977). Serum sCD163 at a cutoff value >4.05 mg/L modestly discriminated bleeding EV from those that had never bled (AUC = 0.811). CONCLUSIONS Serum sCD163 levels accurately predicted high-grade and high-risk EV and could help plan for primary prophylaxis. However, it modestly identified VH occurrence, and endoscopy would be required to make a definitive diagnosis.
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Affiliation(s)
- Mohamed Yousri Taher
- Department of Internal Medicine (Hepatology Division), Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Abeer El-Hadidi
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Assem El-Shendidi
- Department of Internal Medicine (Hepatology Division), Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Ahmed Sedky
- Department of Internal Medicine (Hepatology Division), Faculty of Medicine, Alexandria University, Alexandria, Egypt
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Czajka P, Przybyłkowski A, Nowak A, Postula M, Wolska M, Mirowska-Guzel D, Czlonkowska A, Eyileten C. Antiplatelet drugs and liver fibrosis. Platelets 2022; 33:219-228. [PMID: 33577391 DOI: 10.1080/09537104.2021.1883574] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver fibrosis results from an imbalance between extracellular matrix formation and degradation. The background of liver fibrosis is chronic inflammation and subsequent microcirculation disturbance including microthrombosis. Platelets actively participate in liver fibrosis not only as a part of the clotting system but also by releasing granules containing important mediators. In fact, platelets may play a dual role in the pathophysiology of liver fibrosis as they are able to stimulate regeneration as well as aggravate the destruction of the liver. Recent studies revealed that antiplatelet therapy correlates with inhibition of liver fibrosis. However, liver impairment is associated with extensive coagulation disorders thus the safety of antiplatelet therapy is an area for detailed exploration. In this review, the role of platelets in liver fibrosis and accompanying hemostatic disorders are discussed. Additionally, results of animal and human studies on antiplatelet drugs in liver disorders and their potential therapeutic utility are presented.
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Affiliation(s)
- Pamela Czajka
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
| | - Adam Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Anna Nowak
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
| | - Marta Wolska
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
| | - Dagmara Mirowska-Guzel
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
| | - Anna Czlonkowska
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
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11
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Motegi S, Tsuchiya A, Iwasawa T, Sato T, Kumagai M, Natsui K, Nojiri S, Ogawa M, Takeuchi S, Sakai Y, Miyagawa S, Sawa Y, Terai S. A novel prostaglandin I 2 agonist, ONO-1301, attenuates liver inflammation and suppresses fibrosis in non-alcoholic steatohepatitis model mice. Inflamm Regen 2022; 42:3. [PMID: 35101153 PMCID: PMC8805395 DOI: 10.1186/s41232-021-00191-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 12/20/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND ONO-1301 is a novel long-lasting prostaglandin (PG) I2 mimetic with inhibitory activity on thromboxane (TX) A2 synthase. This drug can also induce endogenous prostaglandin (PG)I2 and PGE2 levels. Furthermore, ONO-1301 acts as a cytokine inducer and can initiate tissue repair in a variety of diseases, such as pulmonary hypertension, pulmonary fibrosis, cardiac infarction, and obstructive nephropathy. In this study, our aim was to evaluate the effect of ONO-1301 on liver inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH). METHODS The therapeutic effects of ONO-1301 against liver damage, fibrosis, and occurrence of liver tumors were evaluated using melanocortin 4 receptor-deficient (Mc4r-KO) NASH model mice. The effects of ONO-1301 against macrophages, hepatic stellate cells, and endothelial cells were also evaluated in vitro. RESULTS ONO-1301 ameliorated liver damage and fibrosis progression, was effective regardless of NASH status, and suppressed the occurrence of liver tumors in Mc4r-KO NASH model mice. In the in vitro study, ONO-1301 suppressed LPS-induced inflammatory responses in cultured macrophages, suppressed hepatic stellate cell (HSC) activation, upregulated vascular endothelial growth factor (VEGF) expression in HSCs, and upregulated hepatocyte growth factor (HGF) and VEGF expression in endothelial cells. CONCLUSIONS The results of our study highlight the potential of ONO-1301 to reverse the progression and prevent the occurrence of liver tumors in NASH using in vivo and in vitro models. ONO-1301 is a multidirectional drug that can play a key role in various pathways and can be further analyzed for use as a new drug candidate against NASH.
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Affiliation(s)
- Satoko Motegi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
| | - Takahiro Iwasawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Takeki Sato
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Masaru Kumagai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Kazuki Natsui
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Shunsuke Nojiri
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Suguru Takeuchi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Yosiki Sakai
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Yoshiki Sawa
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
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12
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Simbrunner B, Trauner M, Reiberger T. Review article: therapeutic aspects of bile acid signalling in the gut-liver axis. Aliment Pharmacol Ther 2021; 54:1243-1262. [PMID: 34555862 PMCID: PMC9290708 DOI: 10.1111/apt.16602] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 08/29/2021] [Accepted: 08/31/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Bile acids are important endocrine modulators of intestinal and hepatic signalling cascades orchestrating critical pathophysiological processes in various liver diseases. Increasing knowledge on bile acid signalling has stimulated the development of synthetic ligands of nuclear bile acid receptors and other bile acid analogues. AIM This review summarises important aspects of bile acid-mediated crosstalk between the gut and the liver ("gut-liver axis") as well as recent findings from experimental and clinical studies. METHODS We performed a literature review on bile acid signalling, and therapeutic applications in chronic liver disease. RESULTS Intestinal and hepatic bile acid signalling pathways maintain bile acid homeostasis. Perturbations of bile acid-mediated gut-liver crosstalk dysregulate transcriptional networks involved in inflammation, fibrosis and endothelial dysfunction. Bile acids induce enterohepatic feedback signalling by the release of intestinal hormones, and regulate enterohepatic circulation. Importantly, bile acid signalling plays a central role in maintaining intestinal barrier integrity and antibacterial defense, which is particularly relevant in cirrhosis, where bacterial translocation has a profound impact on disease progression. The nuclear bile acid farnesoid X receptor (FXR) is a central intersection in bile acid signalling and has emerged as a relevant therapeutic target. CONCLUSIONS Experimental evidence suggests that bile acid signalling improves the intestinal barrier and protects against bacterial translocation in cirrhosis. FXR agonists have displayed efficacy for the treatment of cholestatic and metabolic liver disease in randomised controlled clinical trials. However, similar effects remain to be shown in advanced liver disease, particularly in patients with decompensated cirrhosis.
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Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria,Christian‐Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Thomas Reiberger
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria,Christian‐Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
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13
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Ørntoft NW, Blé M, Baiges A, Ferrusquia J, Hernández-Gea V, Turon F, Magaz M, Møller S, Møller HJ, Garcia-Pagan JC, Gronbaek H. Divergences in Macrophage Activation Markers Soluble CD163 and Mannose Receptor in Patients With Non-cirrhotic and Cirrhotic Portal Hypertension. Front Physiol 2021; 12:649668. [PMID: 34177608 PMCID: PMC8231705 DOI: 10.3389/fphys.2021.649668] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022] Open
Abstract
Introduction Macrophages are involved in development and progression of chronic liver disease and portal hypertension. The macrophage activation markers soluble (s)CD163 and soluble mannose receptor (sMR), are associated with portal hypertension in patient with liver cirrhosis but never investigated in patients with non-cirrhotic portal hypertension. We hypothesized higher levels in cirrhotic patients with portal hypertension than patients with non-cirrhotic portal hypertension. We investigated sCD163 and sMR levels in patients with portal hypertension due to idiopathic portal hypertension (IPH) and portal vein thrombosis (PVT) in patients with and without cirrhosis. Methods We studied plasma sCD163 and sMR levels in patients with IPH (n = 26), non-cirrhotic PVT (n = 20), patients with cirrhosis without PVT (n = 31) and with PVT (n = 17), and healthy controls (n = 15). Results Median sCD163 concentration was 1.51 (95% CI: 1.24-1.83) mg/L in healthy controls, 1.96 (95% CI: 1.49-2.56) in patients with non-cirrhotic PVT and 2.16 (95% CI: 1.75-2.66) in patients with IPH. There was no difference between non-cirrhotic PVT patients and healthy controls, whereas IPH patients had significantly higher levels than controls (P < 0.05). The median sCD163 was significantly higher in the cirrhotic groups compared to the other groups, with a median sCD163 of 6.31 (95% CI: 5.16-7.73) in cirrhotics without PVT and 5.19 (95% CI: 4.18-6.46) with PVT (P < 0.01, all). Similar differences were observed for sMR. Conclusion Soluble CD163 and sMR levels are elevated in patients with IPH and patients with cirrhosis, but normal in patients with non-cirrhotic PVT. This suggests that hepatic macrophage activation is more driven by the underlying liver disease with cirrhosis than portal hypertension.
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Affiliation(s)
- Nikolaj Worm Ørntoft
- Department of Hepatology and Gastroenterology, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Aarhus University Hospital, Aarhus, Denmark
| | - Michel Blé
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Anna Baiges
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Jose Ferrusquia
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Virginia Hernández-Gea
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Fanny Turon
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Marta Magaz
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Søren Møller
- Center of Functional and Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine 260, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Juan Carlos Garcia-Pagan
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Henning Gronbaek
- Department of Hepatology and Gastroenterology, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Aarhus University Hospital, Aarhus, Denmark
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14
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Kreisel W, Schaffner D, Lazaro A, Trebicka J, Merfort I, Schmitt-Graeff A, Deibert P. Phosphodiesterases in the Liver as Potential Therapeutic Targets of Cirrhotic Portal Hypertension. Int J Mol Sci 2020; 21:6223. [PMID: 32872119 PMCID: PMC7503357 DOI: 10.3390/ijms21176223] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 08/23/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is a frequent condition with high impact on patients' life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.
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Affiliation(s)
- Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Denise Schaffner
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
- Department of Radiology–Medical Physics, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Adhara Lazaro
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany;
| | - Irmgard Merfort
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
| | | | - Peter Deibert
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
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15
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Zhang J, Wieser A, Lin H, Li H, Hu M, Behrens IK, Schiergens TS, Gerbes AL, Steib CJ. Kupffer cell activation by different microbial lysates: Toll-like receptor-2 plays pivotal role on thromboxane A 2 production in mice and humans. Eur J Immunol 2020; 50:1988-1997. [PMID: 32618365 DOI: 10.1002/eji.201948507] [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: 12/14/2019] [Revised: 05/29/2020] [Accepted: 06/30/2020] [Indexed: 11/11/2022]
Abstract
Thromboxane (TX) A2 has been identified as an important intrahepatic vasoconstrictor upon Kupffer cell (KC) activation during infections such as spontaneous bacterial peritonitis (SBP). The study aimed to investigate the role of TLRs in the TXA2 increase in liver nonparenchymal cells and their related mechanisms. Here, we identified TLR-2 as a common pathway for different microbials: microbial lysates including Gram-positive bacteria, Gram-negative bacteria, and fungi all increased TXA2 secretion via activation of TLR-2 in human KCs, accompanied by increased expression and phosphorylation of Myd88-related pathway. Of all TLR agonists, only TLR-1, -2, and -4 agonists increased TXA2 in human KCs. These results were further confirmed by mouse liver nonparenchymal cells. Comparing the effects of TLR-1, -2, and -4 antagonists, only TLR-2 antagonist showed inhibitory effects with all tested microbial lysates. Pretreatment with TLR-2 antagonist in human KCs blocked the secretion of IL-10, CXCL-10, TNF-α, and IL-6 induced by Gram-positive and Gram-negative bacterial stimulation. IL-23 and IL-1β were only induced by Gram-negative bacteria. Thus, TLR-2 might be a potential marker and an attractive target for future treatment of patients with SBP. In addition, IL-23 and IL-1β might distinguish early between Gram-positive and Gram-negative SBP.
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Affiliation(s)
- Jiang Zhang
- Department of Medicine II, University Hospital, Liver Centre Munich, LMU Munich, Munich, Germany
| | - Andreas Wieser
- Faculty of Medicine, Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, LMU Munich, Munich, Germany.,Division of Infectious Diseases and Tropical Medicine, University Hospital, LMU Munich, Munich, Germany.,German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
| | - Hao Lin
- Department of Medicine II, University Hospital, Liver Centre Munich, LMU Munich, Munich, Germany
| | - Hanwei Li
- Department of Medicine II, University Hospital, Liver Centre Munich, LMU Munich, Munich, Germany
| | - Moyan Hu
- Chair for Fish Diseases and Fisheries Biology, Faculty of Veterinary Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Ina-Kristin Behrens
- Faculty of Medicine, Medical Microbiology and Hospital Epidemiology, Max von Pettenkofer Institute, LMU Munich, Munich, Germany
| | - Tobias S Schiergens
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Alexander L Gerbes
- Department of Medicine II, University Hospital, Liver Centre Munich, LMU Munich, Munich, Germany
| | - Christian J Steib
- Department of Medicine II, University Hospital, Liver Centre Munich, LMU Munich, Munich, Germany
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16
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Pretreatment with zinc protects Kupffer cells following administration of microbial products. Biomed Pharmacother 2020; 127:110208. [PMID: 32417689 DOI: 10.1016/j.biopha.2020.110208] [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: 03/08/2020] [Revised: 04/26/2020] [Accepted: 04/28/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Systemic inflammation and severe fibrosis can reduce serum zinc levels, while zinc supplementation is reported to improve the prognosis of patients with chronic liver disease (CLD). OBJECTIVES We aimed to investigate the clinical application of serum zinc in patients with CLD and the anti-infective mechanism of zinc supplementation. METHODS Based on the serum zinc level, 149 CLD patients were divided into 3 groups and their clinical parameters were compared. In in-vitro experiments, microbial isolates derived from patients were used to stimulate human liver non-parenchymal cells, and the zinc sulfate solution was added in certain experiments. The effect of zinc was compared by LDH and thromboxane A2 levels in the cell supernatant. RESULT Compared with other groups, patients with low serum zinc levels had significantly higher C-reactive protein (CRP), total bilirubin, INR, creatinine, and MELD scores, while albumin and GOT levels were reduced. Only CRP and albumin were significantly correlated with serum zinc in both low and normal-zinc groups. Bacterial isolates significantly increased LDH levels in Kupffer cells (KCs) and stellate cells but had no effect on sinusoidal endothelial cells, whereas zinc pretreatment protected KCs but not stellate cells. Thromboxane A2 secreted by KCs can also be induced by bacterial stimulation, accompanied by increased gene expression of Myd88, MAPK and NF-kB, while zinc pretreatment can attenuate that. CONCLUSION Serum zinc levels can be used to estimate infection and liver fibrosis in CLD patients. As a new antibacterial weapon, zinc supplementation acts on KCs through Myd88-MAPK related pathways.
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17
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The Vascular Involvement in Soft Tissue Fibrosis-Lessons Learned from Pathological Scarring. Int J Mol Sci 2020; 21:ijms21072542. [PMID: 32268503 PMCID: PMC7177855 DOI: 10.3390/ijms21072542] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/27/2020] [Accepted: 04/01/2020] [Indexed: 02/06/2023] Open
Abstract
Soft tissue fibrosis in important organs such as the heart, liver, lung, and kidney is a serious pathological process that is characterized by excessive connective tissue deposition. It is the result of chronic but progressive accumulation of fibroblasts and their production of extracellular matrix components such as collagens. Research on pathological scars, namely, hypertrophic scars and keloids, may provide important clues about the mechanisms that drive soft tissue fibrosis, in particular the vascular involvement. This is because these dermal fibrotic lesions bear all of the fibrotic characteristics seen in soft tissue fibrosis. Moreover, their location on the skin surface means they are readily observable and directly treatable and therefore more accessible to research. We will focus here on the roles that blood vessel-associated cells play in cutaneous scar pathology and assess from the literature whether these cells also contribute to other soft tissue fibroses. These cells include endothelial cells, which not only exhibit aberrant functions but also differentiate into mesenchymal cells in pathological scars. They also include pericytes, hepatic stellate cells, fibrocytes, and myofibroblasts. This article will review with broad strokes the roles that these cells play in the pathophysiology of different soft tissue fibroses. We hope that this brief but wide-ranging overview of the vascular involvement in fibrosis pathophysiology will aid research into the mechanisms underlying fibrosis and that this will eventually lead to the development of interventions that can prevent, reduce, or even reverse fibrosis formation and/or progression.
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18
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The effects of hepatic steatosis on thromboxane A2 induced portal hypertension. GASTROENTEROLOGIA Y HEPATOLOGIA 2019; 42:534-541. [PMID: 31326104 DOI: 10.1016/j.gastrohep.2019.03.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 03/19/2019] [Accepted: 03/29/2019] [Indexed: 01/09/2023]
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19
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Pathophysiological role of prostanoids in coagulation of the portal venous system in liver cirrhosis. PLoS One 2019; 14:e0222840. [PMID: 31644538 PMCID: PMC6808498 DOI: 10.1371/journal.pone.0222840] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 09/08/2019] [Indexed: 12/15/2022] Open
Abstract
Background Prostanoids are important regulators of platelet aggregation and thrombotic arterial diseases. Their involvement in the development of portal vein thrombosis, frequent in decompensated liver cirrhosis, is still not investigated. Methods Therefore, we used pro-thrombotic venous milieu generation by bare metal stent transjugular intrahepatic portosystemic shunt insertion, to study the role of prostanoids in decompensated liver cirrhosis. Here, 89 patients receiving transjugular intrahepatic portosystemic shunt insertion were included in the study, and baseline levels of thromboxane B2, prostaglandin D2 and prostaglandin E2 were measured in the portal and the hepatic vein. Results While the hepatic vein contained higher levels of thromboxane B2 than the portal vein, levels of prostaglandin E2 and D2 were higher in the portal vein (all P<0.0001). Baseline concentrations of thromboxane B2 in the portal vein were independently associated with an increase of portal hepatic venous pressure gradient during short term follow-up, as an indirect sign of thrombogenic potential (multivariable P = 0.004). Moreover, severity of liver disease was inversely correlated with portal as well as hepatic vein levels of prostaglandin D2 and E2 (all P<0.0001). Conclusions Elevated portal venous thromboxane B2 concentrations are possibly associated with the extent of thrombogenic potential in patients with decompensated liver cirrhosis. Trial registration ClinicalTrials.gov identifier: NCT03584204.
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Ischemic Postconditioning (IPostC) Protects Fibrotic and Cirrhotic Rat Livers after Warm Ischemia. Can J Gastroenterol Hepatol 2019; 2019:5683479. [PMID: 31281804 PMCID: PMC6590494 DOI: 10.1155/2019/5683479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 05/14/2019] [Accepted: 05/19/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Decreased organ function following liver resection is a major clinical issue. The practical method of ischemic postconditioning (IPostC) has been studied in heart diseases, but no data exist regarding fibrotic livers. AIMS We aimed to determine whether IPostC could protect healthy, fibrotic, and cirrhotic livers from ischemia reperfusion injury (IRI). METHODS Fibrosis was induced in male SD rats using bile duct ligation (BDL, 4 weeks), and cirrhosis was induced using thioacetamide (TAA, 18 weeks). Fibrosis and cirrhosis were histologically confirmed using HE and EvG staining. For healthy, fibrotic, and cirrhotic livers, isolated liver perfusion with 90 min of warm ischemia was performed in three groups (each with n=8): control, IPostC 8x20 sec, and IPostC 4x60 sec. additionally, healthy livers were investigated during a follow-up study. Lactate dehydrogenase (LDH) and thromboxane B2 (TXB2) in the perfusate, as well as bile flow (healthy/TAA) and portal perfusion pressure, were measured. RESULTS LDH and TXB2 were reduced, and bile flow was increased by IPostC, mainly in total and in the late phase of reperfusion. The follow-up study showed that the perfusate derived from a postconditioned group had much less damaging potential than perfusate derived from the nonpostconditioned group. CONCLUSION IPostC following warm ischemia protects healthy, fibrotic, and cirrhotic livers against IRI. Reduced efflux of TXB2 is one possible mechanism for this effect of IPostC and increases sinusoidal microcirculation. These findings may help to improve organ function and recovery of patients after liver resection.
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Gracia-Sancho J, Marrone G, Fernández-Iglesias A. Hepatic microcirculation and mechanisms of portal hypertension. Nat Rev Gastroenterol Hepatol 2019; 16:221-234. [PMID: 30568278 DOI: 10.1038/s41575-018-0097-3] [Citation(s) in RCA: 170] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The liver microcirculatory milieu, mainly composed of liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs) and hepatic macrophages, has an essential role in liver homeostasis, including in preserving hepatocyte function, regulating the vascular tone and controlling inflammation. Liver microcirculatory dysfunction is one of the key mechanisms that promotes the progression of chronic liver disease (also termed cirrhosis) and the development of its major clinical complication, portal hypertension. In the present Review, we describe the current knowledge of liver microcirculatory dysfunction in cirrhotic portal hypertension and appraise the preclinical models used to study the liver circulation. We also provide a comprehensive summary of the promising therapeutic options to target the liver microvasculature in cirrhosis.
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Affiliation(s)
- Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, CIBEREHD, Barcelona, Spain. .,Hepatology, Department of Biomedical Research, Inselspital, Bern University, Bern, Switzerland.
| | - Giusi Marrone
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, CIBEREHD, Barcelona, Spain
| | - Anabel Fernández-Iglesias
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, CIBEREHD, Barcelona, Spain
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Pardo F, Pons JA, Castells L, Colmenero J, Gómez MÁ, Lladó L, Pérez B, Prieto M, Briceño J. VI consensus document by the Spanish Liver Transplantation Society. Cir Esp 2019; 96:326-341. [PMID: 29776591 DOI: 10.1016/j.ciresp.2017.12.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 11/19/2017] [Accepted: 12/13/2017] [Indexed: 12/20/2022]
Abstract
The goal of the Spanish Liver Transplantation Society (La Sociedad Española de Trasplante Hepático) is to promote and create consensus documents about current topics in liver transplantation with a multidisciplinary approach. To this end, on October 20, 2016, the 6th Consensus Document Meeting was held, with the participation of experts from the 24 authorized Spanish liver transplantation programs. This Edition discusses the following subjects, whose summary is offered below: 1) limits of simultaneous liver-kidney transplantation; 2) limits of elective liver re-transplantation; and 3) liver transplantation after resection and hepatocellular carcinoma with factors for a poor prognosis. The consensus conclusions for each of these topics is provided below.
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Affiliation(s)
- Fernando Pardo
- Sociedad Española de Trasplante Hepático, Unidad de Trasplante Hepático, Clínica Universitaria de Navarra, Pamplona, España
| | - José Antonio Pons
- Sociedad Española de Trasplante Hepático, Unidad de Trasplante Hepático, Hospital Virgen de la Arrixaca, Murcia, España
| | - Lluís Castells
- Unidad de Trasplante Hepático, Hospital Vall d'Hebron, Barcelona, España
| | - Jordi Colmenero
- Unidad de Trasplante Hepático, Hospital Clínic, Barcelona, España
| | - Miguel Ángel Gómez
- Unidad de Trasplante Hepático, Hospital Virgen del Rocío, Sevilla, España
| | - Laura Lladó
- Unidad de Trasplante Hepático, Hospital de Bellvitge, Barcelona, España
| | - Baltasar Pérez
- Unidad de Trasplante Hepático, Hospital Universitario de Valladolid, Valladolid, España
| | - Martín Prieto
- Unidad de Trasplante Hepático, Hospital Universitario La Fe, Valencia, España
| | - Javier Briceño
- Comité Científico de la Sociedad Española de Trasplante Hepático, Unidad de Trasplante Hepático, Hospital Universitario Reina Sofía, Córdoba, España.
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Abstract
The syndrome of decreased immunity caused by cirrhosis is a combination of different immunological mechanisms and reactions which result from an advanced stage of the liver disease. The synthesis of proteins of the acute phase becomes impaired, there develop different deficiencies of the complement system, and there ensues a decrease of receptors that are meant to recognize antigens. The negative changes become apparent in the field of cell responses, e.g. there are changes in the amounts of generated monocytes and macrophages, and their phagocytic capabilities and chemotaxic reactions are impacted as well. The humoral response results in distorted synthesis of particular antigen categories. The risk of detrimental immunoresponses with the end result of endotoxemia is not rarely coupled with both local and global infections. The combination of the aforesaid immunodeficiencies worsens the healing chances of cirrhosis sufferers and more often than not it increases the mortality of the affected patients.
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Pardo F, Pons JA, Castells L, Colmenero J, Gómez MÁ, Lladó L, Pérez B, Prieto M, Briceño J. VI consensus document by the Spanish Liver Transplantation Society. GASTROENTEROLOGIA Y HEPATOLOGIA 2018; 41:406-421. [PMID: 29866511 DOI: 10.1016/j.gastrohep.2018.05.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 02/19/2018] [Accepted: 05/14/2018] [Indexed: 12/13/2022]
Abstract
The goal of the Spanish Liver Transplantation Society (La Sociedad Española de Trasplante Hepático) is to promote and create consensus documents about current topics in liver transplantation with a multidisciplinary approach. To this end, on October 20, 2016, the 6th Consensus Document Meeting was held, with the participation of experts from the 24 authorized Spanish liver transplantation programs. This Edition discusses the following subjects, whose summary is offered below: 1) limits of simultaneous liver-kidney transplantation; 2) limits of elective liver re-transplantation; and 3) liver transplantation after resection and hepatocellular carcinoma with factors for a poor prognosis. The consensus conclusions for each of these topics is provided below.
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Affiliation(s)
- Fernando Pardo
- Sociedad Española de Trasplante Hepático, Unidad de Trasplante Hepático, Clínica Universitaria de Navarra, Pamplona, España
| | - José Antonio Pons
- Sociedad Española de Trasplante Hepático, Unidad de Trasplante Hepático, Hospital Virgen de la Arrixaca, Murcia, España
| | - Lluís Castells
- Unidad de Trasplante Hepático, Hospital Vall d'Hebron, Barcelona, España
| | - Jordi Colmenero
- Unidad de Trasplante Hepático, Hospital Clínic, Barcelona, España
| | - Miguel Ángel Gómez
- Unidad de Trasplante Hepático, Hospital Virgen del Rocío, Sevilla, España
| | - Laura Lladó
- Unidad de Trasplante Hepático, Hospital de Bellvitge, Barcelona, España
| | - Baltasar Pérez
- Unidad de Trasplante Hepático, Hospital Universitario de Valladolid, Valladolid, España
| | - Martín Prieto
- Unidad de Trasplante Hepático, Hospital Universitario La Fe, Valencia, España
| | - Javier Briceño
- Comité Científico de la Sociedad Española de Trasplante Hepático, Unidad de Trasplante Hepático, Hospital Universitario Reina Sofía, Córdoba, España.
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Liu J, Yang XF. Role of cyclooxygenase-2 in immune response in liver fibrosis and mechanisms involved. Shijie Huaren Xiaohua Zazhi 2017; 25:702-708. [DOI: 10.11569/wcjd.v25.i8.702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cyclooxygenase-2 (COX-2), an inducible enzyme, is almost not expressed in normal human and rat liver tissues, but is highly expressed in liver tissues of patients with chronic hepatitis and cirrhosis. Inhibition or interference of COX-2 expression can significantly inhibit the formation of hepatic fibrosis in rats, suggesting that COX-2 is involved in the occurrence and development of hepatic fibrosis; however, the underlying mechanism is unclear. Recent studies have shown that the role of COX-2 in the development of hepatic fibrosis may be related to immune response. In this paper, we review the role of COX-2 and its metabolites in the immune response in liver fibrosis, with an aim to provide a theoretical basis for clinical prevention and treatment of hepatic fibrosis.
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Fernández-Iglesias A, Gracia-Sancho J. How to Face Chronic Liver Disease: The Sinusoidal Perspective. Front Med (Lausanne) 2017; 4:7. [PMID: 28239607 PMCID: PMC5300981 DOI: 10.3389/fmed.2017.00007] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 01/19/2017] [Indexed: 12/20/2022] Open
Abstract
Liver microcirculation plays an essential role in the progression and aggravation of chronic liver disease. Hepatic sinusoid environment, mainly composed by hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, intimately cooperate to maintain global liver function and specific phenotype of each cell type. However, continuous liver injury significantly deregulates liver cells protective phenotype, leading to parenchymal and non-parenchymal dysfunction. Recent data have enlightened the molecular processes that mediate hepatic microcirculatory injury, and consequently, opened the possibility to develop new therapeutic strategies to ameliorate liver circulation and viability. The present review summarizes the main cellular components of the hepatic sinusoid, to afterward focus on non-parenchymal cells phenotype deregulation due to chronic injury, in the specific clinical context of liver cirrhosis and derived portal hypertension. Finally, we herein detail new therapies developed at the bench-side with high potential to be translated to the bedside.
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Affiliation(s)
- Anabel Fernández-Iglesias
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute – CIBEREHD, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute – CIBEREHD, Barcelona, Spain
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Elswefy SES, Abdallah FR, Atteia HH, Wahba AS, Hasan RA. Inflammation, oxidative stress and apoptosis cascade implications in bisphenol A-induced liver fibrosis in male rats. Int J Exp Pathol 2016; 97:369-379. [PMID: 27925325 DOI: 10.1111/iep.12207] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 08/15/2016] [Indexed: 12/15/2022] Open
Abstract
Bisphenol A (BPA) is a key monomer in the production of plastics. It has been shown to be hepatotoxic. Inflammation and oxidative stress are closely linked with liver fibrosis, the major contributing factor to hepatic failure. Therefore, the aim of this study was to evaluate the impact of chronic exposure to BPA on the development of hepatic fibrosis in male rats and to determine the cross-talk between the hepatic cytokine network, oxidative stress and apoptosis. For this purpose, 30 male Wistar albino rats were divided into three equal groups as follows: the first group was given no treatment (normal control group); the second group was given corn oil once daily by oral gavage for 8 weeks (vehicle control group); and the third group received BPA (50 mg/kg body weight/day, p.o.) for 8 weeks. BPA administration induced liver fibrosis as reflected in an increase in serum hepatic enzymes activities, hepatic hydroxyproline content and histopathological changes particularly increased collagen fibre deposition around the portal tract. In addition, there was inflammation (as reflected in increase in interleukin-1beta 'IL-1β', decrease in interleukin-10 'IL-10' serum levels and increase in IL-1β/IL-10 ratio), oxidative stress (as reflected in increase in malondialdehyde (MDA) level, reduction in reduced glutathione (GSH) content and inhibition of catalase (CAT) activity) and apoptosis [as reflected in an increase in caspase-3 level and a decrease in numbers of B-cell lymphoma 2 (BCL2)-immunopositive hepatocytes]. Interestingly, BPA had an upregulating effect on an extracellular matrix turnover gene [as reflected in matrix metalloproteinase-9 (MMP-9)] and a downregulating effect on its inhibitor gene [as reflected in tissue inhibitor of matrix metalloproteinase-2 (TIMP-2)] expression. Thus, the mechanism by which BPA induced liver fibrosis seems to be related to stimulation of the inflammatory response, along with oxidative stress, the apoptotic pathway and activation of extracellular matrix turnover.
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Affiliation(s)
- Sahar El-Sayed Elswefy
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Sharkia Governorate, Egypt
| | - Fatma Rizk Abdallah
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Sharkia Governorate, Egypt
| | - Hebatallah Husseini Atteia
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Sharkia Governorate, Egypt
| | - Alaa Samir Wahba
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Sharkia Governorate, Egypt
| | - Rehab Abdallah Hasan
- Department of Histology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
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Abstract
Cellular crosstalk is a process through which a message is transmitted within an individual cell (intracellular crosstalk) or between different cells (intercellular crosstalk). Intercellular crosstalk within the liver microenvironment is critical for the maintenance of normal hepatic functions and for cells survival. Hepatic cells are closely connected to each other, work in synergy, and produce molecules that modulate their differentiation and activity. This review summarises the current knowledge regarding paracrine communication networks in parenchymal and non-parenchymal cells in liver fibrosis due to chronic injury, and regeneration after partial hepatectomy.
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29
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Sandahl TD, McGrail R, Møller HJ, Reverter E, Møller S, Turon F, Hernández-Gea V, Bendtsen F, Vilstrup H, Garcia-Pagan JC, Grønbaek H. The macrophage activation marker sCD163 combined with markers of the Enhanced Liver Fibrosis (ELF) score predicts clinically significant portal hypertension in patients with cirrhosis. Aliment Pharmacol Ther 2016; 43:1222-31. [PMID: 27061098 DOI: 10.1111/apt.13618] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 09/23/2015] [Accepted: 03/18/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Noninvasive identification of significant portal hypertension in patients with cirrhosis is needed in hepatology practice. AIM To investigate whether the combination of sCD163 as a hepatic inflammation marker and the fibrosis markers of the Enhanced Liver Fibrosis score (ELF) can predict portal hypertension in patients with cirrhosis. METHODS We measured sCD163 and the ELF components (hyaluronic acid, tissue inhibitor of metalloproteinase-1 and procollagen-III aminopeptide) in two separate cohorts of cirrhosis patients that underwent hepatic vein catheterisation. To test the predictive accuracy we developed a CD163-fibrosis portal hypertension score in an estimation cohort (n = 80) and validated the score in an independent cohort (n = 80). A HVPG ≥10 mmHg was considered clinically significant. RESULTS Both sCD163 and the ELF components increased in a stepwise manner with the patients' Child-Pugh score (P < 0.001, all), and also with increasing HVPG (P < 0.001). receiver operator characteristics (ROC) analyses showed that each one of the individual components predicted a HVPG >10 mmHg with AUROC's of approximately 0.80. The combined score optimised by logistic regression analyses improved the AUROC to 0.91 in the estimation cohort and 0.90 in the validation cohort. Furthermore, a high value of the combined score was associated with a high short-term mortality. CONCLUSIONS The combination of the macrophage activation marker sCD163 and the fibrosis markers predicted significant portal hypertension in patients with cirrhosis. This score may prove useful for screening purposes and highlights the importance of both the inflammatory and the fibrotic components of cirrhotic portal hypertension.
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Affiliation(s)
- T D Sandahl
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - R McGrail
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - H J Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - E Reverter
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - S Møller
- Department of Clinical Physiology and Nuclear Medicine, 239 Center for Functional and Diagnostic Imaging and Research, Faculty of Health Sciences Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - F Turon
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - V Hernández-Gea
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - F Bendtsen
- Gastroenterology Unit, Medical Section, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - H Vilstrup
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - J C Garcia-Pagan
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - H Grønbaek
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Gonzalez-Paredes FJ, Hernández Mesa G, Morales Arraez D, Marcelino Reyes R, Abrante B, Diaz-Flores F, Salido E, Quintero E, Hernández-Guerra M. Contribution of Cyclooxygenase End Products and Oxidative Stress to Intrahepatic Endothelial Dysfunction in Early Non-Alcoholic Fatty Liver Disease. PLoS One 2016; 11:e0156650. [PMID: 27227672 PMCID: PMC4882009 DOI: 10.1371/journal.pone.0156650] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 05/17/2016] [Indexed: 01/02/2023] Open
Abstract
Introduction Metabolic syndrome induces endothelial dysfunction, a surrogate marker of cardiovascular disease. In parallel, metabolic syndrome is frequently associated with non-alcoholic fatty liver disease (NAFLD), which may progress to cirrhosis. The aim of the present study was to evaluate intrahepatic endothelial dysfunction related to cyclooxygenase end products and oxidative stress as possible mechanisms involved in the pathophysiology of NAFLD. Materials and Methods Sprague-Dawley rats were fed standard diet (control-diet, CD) or high-fat-diet (HFD) for 6 weeks. Metabolic syndrome was assessed by recording arterial pressure, lipids, glycemia and rat body weight. Splanchnic hemodynamics were measured, and endothelial dysfunction was evaluated using concentration-effect curves to acetylcholine. Response was assessed with either vehicle, L-NG-Nitroarginine (L-NNA), indomethacin, tempol, or a thromboxane receptor antagonist, SQ 29548. We quantified inflammation, fibrosis, oxidative stress, nitric oxide (NO) bioavailability and thromboxane B2 levels. Results HFD rats exhibited metabolic syndrome together with the presence of NAFLD. Compared to control-diet livers, HFD livers showed increased hepatic vascular resistance unrelated to inflammation or fibrosis, but with decreased NO activity and increased oxidative stress. Endothelial dysfunction was observed in HFD livers compared with CD rats and improved after cyclooxygenase inhibition or tempol pre-incubation. However, pre-incubation with SQ 29548 did not modify acetylcholine response. Conclusions Our study provides evidence that endothelial dysfunction at an early stage of NAFLD is associated with reduced NO bioavailability together with increased cyclooxygenase end products and oxidative stress, which suggests that both pathways are involved in the pathophysiology and may be worth exploring as therapeutic targets to prevent progression of the disease.
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Affiliation(s)
- Francisco Javier Gonzalez-Paredes
- Institute of Biomedical Technologies and Center of Biomedical Research of the Canary Islands (CIBICAN), University of La Laguna, La Laguna, Tenerife, Spain
| | - Goretti Hernández Mesa
- Gastroenterology Department, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain
| | - Dalia Morales Arraez
- Gastroenterology Department, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain
| | - Raquel Marcelino Reyes
- Gastroenterology Department, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain
| | - Beatriz Abrante
- Institute of Biomedical Technologies and Center of Biomedical Research of the Canary Islands (CIBICAN), University of La Laguna, La Laguna, Tenerife, Spain
| | - Felicitas Diaz-Flores
- Central Laboratory, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain
| | - Eduardo Salido
- Institute of Biomedical Technologies and Center of Biomedical Research of the Canary Islands (CIBICAN), University of La Laguna, La Laguna, Tenerife, Spain
| | - Enrique Quintero
- Institute of Biomedical Technologies and Center of Biomedical Research of the Canary Islands (CIBICAN), University of La Laguna, La Laguna, Tenerife, Spain
- Gastroenterology Department, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain
- Department of Medicine and Psychiatry, University of La Laguna, La Laguna, Tenerife, Spain
| | - Manuel Hernández-Guerra
- Institute of Biomedical Technologies and Center of Biomedical Research of the Canary Islands (CIBICAN), University of La Laguna, La Laguna, Tenerife, Spain
- Gastroenterology Department, University Hospital of the Canary Islands, La Laguna, Tenerife, Spain
- Department of Medicine and Psychiatry, University of La Laguna, La Laguna, Tenerife, Spain
- * E-mail:
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Mohamed WA, Schaalan MF, El-Abhar HS. Camel Milk: Potential Utility as an Adjunctive Therapy to Peg-IFN/RBV in HCV-4 Infected Patients in Egypt. Nutr Cancer 2015; 67:1305-13. [PMID: 26492130 DOI: 10.1080/01635581.2015.1087041] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The present prospective study aims to investigate the potential therapeutic effect and the underlying mechanisms of drinking camel milk for 60 days as an adjunctive therapy to the standard treatment PEG/RBV. Twenty-five hepatitis C virus (HCV)-infected Egyptian patients, with mild to moderate parenchymal affection to mild cirrhosis were enrolled in this study after proper history taking and clinical examination. Their biomarkers were evaluated before and after the addition of camel milk. The improving effect of camel milk was reflected on the marked inhibition of the serum levels of the proinflammatory markers, viz., tumor necrosis factor-α, monocyte chemotactic protein-1, hyaluronic acid, and TGF-β1, besides PCR, AST, ALT, GGT, bilirubin, prothrombin time, INR, and alpha-fetoprotein. In addition, camel milk elevated significantly (P < 0.001) the serum levels of albumin, the antiapoptotic protein BCL-2, the total antioxidant capacity, interleukin-10, and vitamin D. In conclusion, our study revealed a regulatory function of camel milk on multiple parameters of inflammatory mediators, immunomodulators, antiapoptosis, and antioxidants, giving insight into the potential therapeutic benefit underlying the anti-HCV actions of camel milk. The limitations of the current study include the small sample size recruited and the failure to test it on cohorts with severe stages of hepatitis; like Child-Pugh stage C, and hepatocellular carcinoma.
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Affiliation(s)
- Walid A Mohamed
- a Department of Chemistry , Cairo University , Cairo , Egypt
| | - Mona F Schaalan
- b Department of Biochemistry , Faculty of Pharmacy, Misr International University , Cairo , Egypt
| | - Hanan S El-Abhar
- c Department of Pharmacology and Toxicology , Faculty of Pharmacy, Cairo University , Cairo , Egypt
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Zhao TY, Su LP, Ma CY, Zhai XH, Duan ZJ, Zhu Y, Zhao G, Li CY, Wang LX, Yang D. IGF-1 decreases portal vein endotoxin via regulating intestinal tight junctions and plays a role in attenuating portal hypertension of cirrhotic rats. BMC Gastroenterol 2015; 15:77. [PMID: 26152281 PMCID: PMC4495682 DOI: 10.1186/s12876-015-0311-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 06/29/2015] [Indexed: 12/16/2022] Open
Abstract
Background Intestinal barrier dysfunction is not only the consequence of liver cirrhosis, but also an active participant in the development of liver cirrhosis. Previous studies showed that external administration of insulin-like growth factor 1 (IGF-1) improved intestinal barrier function in liver cirrhosis. However, the mechanism of IGF-1 on intestinal barrier in liver cirrhosis is not fully elucidated. The present study aims to investigate the mechanisms of IGF-1 improving intestinal barrier function via regulating tight junctions in intestines. Methods We used carbon tetrachloride induced liver cirrhotic rats to investigate the effect of IGF-1 on intestinal claudin-1 and occludin expressions, serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, severity of liver fibrosis, portal pressures, enterocytic apoptosis and lipopolysaccharides (LPS) levels in portal vein. The changes of IGF-1 in serum during the development of rat liver cirrhosis were also evaluated. Additionally, we assessed the effect of IGF-1 on claudin-1 and occludin expressions, changes of transepithelial electrical resistance (TEER) and apoptosis in Caco-2 cells to confirm in vivo findings. Results Serum IGF-1 levels were decreased in the development of rat liver cirrhosis, and external administration of IGF-1 restored serum IGF-1 levels. External administration of IGF-1 reduced serum ALT and AST levels, severity of liver fibrosis, LPS levels in portal vein, enterocytic apoptosis and portal pressure in cirrhotic rats. External administration of IGF-1 increased the expressions of claudin-1 and occludin in enterocytes, and attenuated tight junction dysfunction in intestines of cirrhotic rats. LPS decreased TEER in Caco-2 cell monolayer. LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells. Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells. Conclusions Tight junction dysfunction develops during the development of liver cirrhosis, and endotoxemia will develop subsequently. Correspondingly, increased endotoxin in portal system worsens tight junction dysfunction via decreasing intestinal occludin and claudin-1 expressions and increasing enterocytic apoptosis. Endotoxemia and intestinal barrier dysfunction form a vicious circle. External administration of IGF-1 breaks this vicious circle. Improvement of tight junctions might be one possible mechanism of the restoration of intestinal barrier function mediated by IGF-1.
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Affiliation(s)
- Tian-Yu Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning province, China.
| | - Li-Ping Su
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning province, China.
| | - Chun-Ye Ma
- Department of Neurology, The Second Affiliated Hospital of Dalian Medical University, 116023, Dalian, Liaoning province, China.
| | - Xiao-Han Zhai
- Department of Clinical Pharmacology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning province, China.
| | - Zhi-Jun Duan
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning province, China.
| | - Ying Zhu
- Department of Infectious Diseases, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning province, China.
| | - Gang Zhao
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning province, China.
| | - Chun-Yan Li
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning province, China.
| | - Li-Xia Wang
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning province, China.
| | - Dong Yang
- Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning province, China.
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Abstract
Portal hypertension is a common complication of chronic liver disease. Its relevance comes from the fact that it determines most complications leading to death or liver transplantation in patients with cirrhosis of the liver: bleeding from esophageal or gastric varices, ascites and renal dysfunction, sepsis and hepatic encephalopathy. Portal hypertension results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (1) distortion of the liver vascular architecture due to the liver disease causing structural abnormalities (nodule formation, remodeling of liver sinusoids, fibrosis, angiogenesis and vascular occlusion), and (2) increased hepatic vascular tone due to sinusoidal endothelial dysfunction, which results in a defective production of endogenous vasodilators, mainly nitric oxide (NO), and increased production of vasoconstrictors (thromboxane A2, cysteinyl leukotrienes, angiotensin II, endothelins and an activated adrenergic system). Hepatic endothelial dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress, and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSECs) that become proliferative, prothrombotic, proinflammatory and vasoconstrictor. The cross-talk between LSECs and hepatic stellate cells (HSCs) induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis, which further increase the hepatic vascular resistance and worsen liver failure by interfering with the blood perfusion of the liver parenchyma. An additional factor further worsening portal hypertension is an increased blood flow through the portal system due to splanchnic vasodilatation. This is an adaptive response to decreased effective hepatocyte perfusion, and is maximal once portal pressure has increased sufficiently to promote the development of intrahepatic shunts and portal-systemic collaterals, including varices, through which portal blood flow bypasses the liver. In human portal hypertension collateralization and hyperdynamic circulation start at a portal pressure gradient >10 mm Hg. Rational therapy for portal hypertension aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments (the best example being the direct-acting antivirals for hepatitis C viral infection), while architectural disruption and fibrosis can be ameliorated by a variety of antifibrotic drugs and antiangiogenic strategies. Several drugs in this category are currently under investigation in phase II-III randomized controlled trials. Sinusoidal endothelial dysfunction is ameliorated by statins as well as by other drugs increasing NO availability. It is of note that simvastatin has already been proven to be clinically effective in two randomized controlled trials. Splanchnic hyperemia can be counteracted by nonselective β-blockers (NSBBs), vasopressin analogs and somatostatin analogs, drugs that until recently were the only available treatments for portal hypertension, but that are not very effective in the initial stages of cirrhosis. There is experimental and clinical evidence indicating that a more effective reduction of portal pressure is obtained by combining agents acting on these different pathways. It is likely that the treatment of portal hypertension will evolve to use etiological treatments together with antifibrotic agents and/or drugs improving sinusoidal endothelial function in the initial stages of cirrhosis (preprimary prophylaxis), while NSBBs will be added in advanced stages of the disease.
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Affiliation(s)
- Jordi Gracia-Sancho
- Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS, Hospital Clinic de Barcelona, CIBEREHD, Barcelona, Spain
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Abstract
BACKGROUND Microbial infections are a relevant problem for patients with liver cirrhosis. Different types of bacteria are responsible for different kinds of infections: Escherichia coli and Klebsiella pneumoniae are frequently observed in spontaneous bacterial peritonitis or urinary tract infections, and Streptococcus pneumoniae and Mycoplasma pneumoniae in pulmonary infections. Mortality is up to 4-fold higher in infected patients with liver cirrhosis than in patients without infections. Key Messages: Infections in patients with liver cirrhosis are due to three major reasons: bacterial translocation, immune deficiency and an increased incidence of systemic infections. Nonparenchymal liver cells like Kupffer cells, sinusoidal endothelial cells and hepatic stellate cells are the first liver cells to come into contact with microbial products when systemic infection or bacterial translocation occurs. Kupffer cell (KC) activation by Toll-like receptor (TLR) agonists and endothelial sinusoidal dysfunction have been shown to be important mechanisms increasing portal pressure following intraperitoneal lipopolysaccharide pretreatment in cirrhotic rat livers. Reduced intrahepatic vasodilation and increased intrahepatic vasoconstriction are the relevant pathophysiological pathways. Thromboxane A2 and leukotriene (LT) C4/D4 have been identified as important vasoconstrictors. Accordingly, treatment with montelukast to inhibit the cysteinyl-LT1 receptor reduced portal pressure in cirrhotic rat livers. Clinical studies have demonstrated that activation of KCs, estimated by the amount of soluble CD163 in the blood, correlates with the risk for variceal bleeding. Additionally, intestinal decontamination with rifaximin in patients with alcohol-associated liver cirrhosis reduced the portal pressure and the risk for variceal bleeding. CONCLUSIONS TLR activation of nonparenchymal liver cells by pathogens results in portal hypertension. This might explain the pathophysiologic correlation between microbial infections and portal hypertension in patients with liver cirrhosis. These findings are the basis for both better risk stratifying and new treatment options, such as specific inhibition of TLR for patients with liver cirrhosis and portal hypertension.
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Affiliation(s)
- Christian J Steib
- Department of Medicine II, University Hospital LMU Munich, Liver Center Munich, Munich, Germany
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Murase K, Assanai P, Takata H, Matsumoto N, Saito S, Nishiura M. Kinetic analysis of superparamagnetic iron oxide nanoparticles in the liver of body-temperature-controlled mice using dynamic susceptibility contrast magnetic resonance imaging and an empirical mathematical model. Magn Reson Imaging 2015; 33:600-10. [DOI: 10.1016/j.mri.2015.02.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 02/04/2015] [Accepted: 02/08/2015] [Indexed: 12/19/2022]
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Gracia-Sancho J, Maeso-Díaz R, Fernández-Iglesias A, Navarro-Zornoza M, Bosch J. New cellular and molecular targets for the treatment of portal hypertension. Hepatol Int 2015; 9:183-91. [PMID: 25788198 DOI: 10.1007/s12072-015-9613-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 02/10/2015] [Indexed: 12/12/2022]
Abstract
Portal hypertension (PH) is a common complication of chronic liver disease, and it determines most complications leading to death or liver transplantation in patients with liver cirrhosis. PH results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (a) distortion of the liver vascular architecture and (b) hepatic microvascular dysfunction. Increment in hepatic resistance is latterly accompanied by splanchnic vasodilation, which further aggravates PH. Hepatic microvascular dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSEC). The cross-talk between LSEC and hepatic stellate cells induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis. Therapy for PH aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments, while architectural disruption and fibrosis can be ameliorated by a variety of anti-fibrogenic drugs and anti-angiogenic strategies. Sinusoidal endothelial dysfunction is ameliorated by statins and other drugs increasing NO availability. Splanchnic hyperemia can be counteracted by non-selective beta-blockers (NSBBs), vasopressin analogs and somatostatin analogs. Future treatment of portal hypertension will evolve to use etiological treatments together with anti-fibrotic agents and/or drugs improving microvascular function in initial stages of cirrhosis (pre-primary prophylaxis), while NSBBs will be added in advanced stages of the disease.
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Affiliation(s)
- Jordi Gracia-Sancho
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Rosselló 149, 4th Floor, 08036, Barcelona, Spain,
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Freise C, Heldwein S, Erben U, Hoyer J, Köhler R, Jöhrens K, Patsenker E, Ruehl M, Seehofer D, Stickel F, Somasundaram R. K⁺-channel inhibition reduces portal perfusion pressure in fibrotic rats and fibrosis associated characteristics of hepatic stellate cells. Liver Int 2015; 35:1244-52. [PMID: 25212242 DOI: 10.1111/liv.12681] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Accepted: 09/03/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS In liver fibrosis, activated hepatic stellate cells (HSC) secrete excess extracellular matrix, thus, represent key targets for antifibrotic treatment strategies. Intermediate-conductance Ca(2) (+) -activated K(+) -channels (KCa3.1) are expressed in non-excitable tissues affecting proliferation, migration and vascular resistance rendering KCa3.1 potential targets in liver fibrosis. So far, no information about KCa3.1 expression and their role in HSC exists. Aim was to quantify the KCa3.1 expression in HSC depending on HSC activation and investigation of antifibrotic properties of the specific KCa3.1 inhibitor TRAM-34 in vitro and in vivo. METHODS KCa3.1 expression and functionality were studied in TGF-β1-activated HSC by quantitative real time PCR, western-blot and patch-clamp analysis respectively. Effects of TRAM-34 on HSC proliferation, cell cycle and fibrosis-related gene expression were assessed by [(3) H]-thymidine incorporation, FACS-analysis and RT-PCR respectively. In vivo, vascular resistance and KCa3.1 gene and protein expression were determined in bile duct ligated rats by in situ liver perfusion, Taqman PCR and immunohistochemistry respectively. RESULTS Fibrotic tissues and TGF-β1-activated HSC exhibited higher KCa3.1-expressions than normal tissue and untreated cells. KCa3.1 inhibition with TRAM-34 reduced HSC proliferation by induction of cell cycle arrest and reduced TGF-β1-induced gene expression of collagen I, alpha-smooth muscle actin and TGF-β1 itself. Furthermore, TRAM-34 blocked TGF-β1-induced activation of TGF-β signalling in HSC. In vivo, TRAM-34 reduced the thromboxane agonist-induced portal perfusion pressure. CONCLUSION Inhibition of KCa3.1 with TRAM-34 downregulates fibrosis-associated gene expression in vitro, and reduces portal perfusion pressure in vivo. Thus, KCa3.1 may represent novel targets for the treatment of liver fibrosis.
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Affiliation(s)
- Christian Freise
- Department of Gastroenterology, Infectiology and Rheumatology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
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Wang H, Thorling CA, Liang X, Bridle KR, Grice JE, Zhu Y, Crawford DHG, Xu ZP, Liu X, Roberts MS. Diagnostic imaging and therapeutic application of nanoparticles targeting the liver. J Mater Chem B 2015; 3:939-958. [PMID: 32261972 DOI: 10.1039/c4tb01611d] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Liver diseases, particularly viral hepatitis, cirrhosis and hepatocellular carcinoma, are common in clinical practice with high morbidity and mortality worldwide. Many substances for diagnostic imaging and therapy of liver diseases may have either severe adverse effects or insufficient effectiveness in vivo because of their nonspecific uptake. Therefore, by targeting the delivery of drugs into the liver or specific liver cells, drug efficiency may be largely improved. This review summarizes the up-to-date research progress focusing on nanoparticles targeting the liver for both diagnostic and therapeutic purposes. Targeting strategies, mechanisms of enhanced effects, and clinical applications of nanoparticles are discussed specifically. We believe that new targeting nanotechnology such as nanoprobes for multi-modality imaging and multifunctional nanoparticles would facilitate significant advancements in this active research area in the near future.
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Affiliation(s)
- Haolu Wang
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.
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Zhou WC, Zhang QB, Qiao L. Pathogenesis of liver cirrhosis. World J Gastroenterol 2014; 20:7312-7324. [PMID: 24966602 PMCID: PMC4064077 DOI: 10.3748/wjg.v20.i23.7312] [Citation(s) in RCA: 398] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 03/16/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.
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Sipeki N, Antal-Szalmas P, Lakatos PL, Papp M. Immune dysfunction in cirrhosis. World J Gastroenterol 2014; 20:2564-2577. [PMID: 24627592 PMCID: PMC3949265 DOI: 10.3748/wjg.v20.i10.2564] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/25/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality.
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Heeba GH, Mahmoud ME. Therapeutic potential of morin against liver fibrosis in rats: modulation of oxidative stress, cytokine production and nuclear factor kappa B. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2014; 37:662-671. [PMID: 24583409 DOI: 10.1016/j.etap.2014.01.026] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 01/25/2014] [Accepted: 01/31/2014] [Indexed: 06/03/2023]
Abstract
Therapeutic potential of morin, a member of flavonoid family, against carbon tetrachloride (CCl4)-induced liver fibrosis in rats was investigated and compared with that of silymarin. Results show that treatment with morin (30 mg/kg/day) revealed attenuation in liver index and serum biomarkers of liver function that were enhanced by chronic CCl4 intoxication. Further, morin inhibited the elevated levels of malondialdehyde and nitric oxide and restored hepatic reduced glutathione to its normal level. The increased production of hepatic hydroxyproline content by CCl4 was markedly decreased by administration of morin. In addition, treatment with morin significantly attenuated the inflammatory responses caused by CCl4 as evident by the decreased hepatic tumor necrosis factor-alpha (TNF-α) level, immunohistochemical expressions of inducible nitric oxide synthase and nuclear factor kappa B. Collectively, this study indicates that morin possesses antifibrotic effect in the CCl4 model of fibrosis via reducing oxidative stress, inflammatory responses and fibrogenic markers.
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Affiliation(s)
- Gehan H Heeba
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt.
| | - Magda E Mahmoud
- Department of Agricultural Chemistry, Faculty of Agriculture, Minia University, El-Minia, Egypt
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op den Winkel M, Gmelin L, Schewe J, Leistner N, Bilzer M, Göke B, Gerbes AL, Steib CJ. Role of cysteinyl-leukotrienes for portal pressure regulation and liver damage in cholestatic rat livers. J Transl Med 2013; 93:1288-94. [PMID: 24061287 DOI: 10.1038/labinvest.2013.115] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2012] [Revised: 08/06/2013] [Accepted: 08/28/2013] [Indexed: 12/31/2022] Open
Abstract
Kupffer cells (KCs) have a major role in liver injury, and cysteinyl-leukotrienes (Cys-LTs) are known to be involved as well. The KC-mediated pathways for the production and secretion of Cys-LT in cholestatic liver injury have not yet been elucidated. Here, we hypothesized that KC activation by Toll-like receptor ligands results in Cys-LT-mediated microcirculatory alterations and liver injury in acute cholestasis. We hypothesized further that this situation is associated with changes in the secretion and production of Cys-LT. One week after bile duct ligation (BDL), livers showed typical histological signs of cholestatic liver injury. Associated microcirculatory disturbances caused increased basal and maximal portal pressure following KC activation. These differences were determined in BDL livers compared with sham-operated livers in vivo (KC activation by LPS 4 mg/kg b.w.) and in isolated perfused organs (KC activation by Zymosan A, 150 μg/ml). Treatment with the 5-lipoxygenase inhibitor MK-886 alone did not alter portal perfusion pressure, lactate dehydrogenase (LDH) efflux, or bile duct proliferation in BDL animals. Following KC activation, portal perfusion pressure increased. The degree of cell injury was attenuated by MK-886 (3 μM) treatment as estimated by LDH efflux. In normal rats, a large amount of Cys-LT efflux was found in the bile. Only a minor amount was found in the effluent perfusate. In BDL livers, the KC-mediated Cys-LT efflux into the sinusoidal system increased, although the absolute Cys-LT level was still grossly lower than the biliary excretion in sham-operated livers. In conclusion, our results indicate that treatment with Cys-LT inhibitors might be a relevant target for attenuating cholestatic liver damage.
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Affiliation(s)
- Mark op den Winkel
- Department of Medicine II, Hospital of the Ludwig-Maximilians University (LMU) of Munich, Campus Grosshadern, Munich, Germany
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Rosado E, Rodríguez-Vilarrupla A, Gracia-Sancho J, Tripathi D, García-Calderó H, Bosch J, García-Pagán JC. Terutroban, a TP-receptor antagonist, reduces portal pressure in cirrhotic rats. Hepatology 2013; 58:1424-35. [PMID: 23703868 DOI: 10.1002/hep.26520] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 04/12/2013] [Accepted: 05/07/2013] [Indexed: 12/11/2022]
Abstract
UNLABELLED Increased production of vasoconstrictive prostanoids, such as thromboxane A2 (TXA2 ), contributes to endothelial dysfunction and increased hepatic vascular tone in cirrhosis. TXA2 induces vasoconstriction by way of activation of the thromboxane-A2 /prostaglandin-endoperoxide (TP) receptor. This study investigated whether terutroban, a specific TP receptor blocker, decreases hepatic vascular tone and portal pressure in rats with cirrhosis due to carbon tetrachloride (CCl4 ) or bile duct ligation (BDL). Hepatic and systemic hemodynamics, endothelial dysfunction, liver fibrosis, hepatic Rho-kinase activity (a marker of hepatic stellate cell contraction), and the endothelial nitric oxide synthase (eNOS) signaling pathway were measured in CCl4 and BDL cirrhotic rats treated with terutroban (30 mg/kg/day) or its vehicle for 2 weeks. Terutroban reduced portal pressure in both models without producing significant changes in portal blood flow, suggesting a reduction in hepatic vascular resistance. Terutroban did not significantly change arterial pressure in CCl4 -cirrhotic rats but decreased it significantly in BDL-cirrhotic rats. In livers from CCl4 and BDL-cirrhotic terutroban-treated rats, endothelial dysfunction was improved and Rho-kinase activity was significantly reduced. In CCl4 -cirrhotic rats, terutroban reduced liver fibrosis and decreased alpha smooth muscle actin (α-SMA), collagen-I, and transforming growth factor beta messenger RNA (mRNA) expression without significant changes in the eNOS pathway. In contrast, no change in liver fibrosis was observed in BDL-cirrhotic rats but an increase in the eNOS pathway. CONCLUSION Our data indicate that TP-receptor blockade with terutroban decreases portal pressure in cirrhosis. This effect is due to decreased hepatic resistance, which in CCl4 -cirrhotic rats was linked to decreased hepatic fibrosis, but not in BDL rats, in which the main mediator appeared to be an enhanced eNOS-dependent vasodilatation, which was not liver-selective, as it was associated with decreased arterial pressure. The potential use of terutroban for portal hypertension requires further investigation.
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Affiliation(s)
- Eugenio Rosado
- Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Barcelona, Spain
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Steib CJ, Gmelin L, Pfeiler S, Schewe J, Brand S, Göke B, Gerbes AL. Functional relevance of the cannabinoid receptor 2 - heme oxygenase pathway: a novel target for the attenuation of portal hypertension. Life Sci 2013; 93:543-51. [PMID: 24007798 DOI: 10.1016/j.lfs.2013.08.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Revised: 08/13/2013] [Accepted: 08/20/2013] [Indexed: 12/17/2022]
Abstract
AIMS In liver cirrhosis, inflammation triggers portal hypertension. Kupffer cells (KC) produce vasoconstrictors upon activation by bacterial constituents. Here, we hypothesize that the anti-inflammatory action of the cannabinoid receptor 2 (CB2) agonists JWH-133 and GP 1a attenuate portal hypertension. MAIN METHODS In vivo measurements of portal pressures and non-recirculating liver perfusions were performed in rats 4weeks after bile duct ligation (BDL). Zymosan (150μg/ml, isolated liver perfusion) or LPS (4mg/kgb.w., in vivo) was infused to activate the KC in the absence or presence of JWH-133 (10mg/kgb.w.), GP 1a (2.5mg/kgb.w.) or ZnPP IX (1μM). Isolated KC were treated with Zymosan (0.5mg/ml) in addition to JWH-133 (5μM). The thromboxane (TX) B2 levels in the perfusate and KC media were determined by ELISA. Heme oxygenase-1 (HO-1) and CB2 were analyzed by Western blot or confocal microscopy. KEY FINDINGS JWH-133 or GP 1a pre-treatment attenuated portal pressures following KC activation in all experimental settings. In parallel, HO-1 expression increased with JWH-133 pre-treatment. However, the inhibition of HO-1 enhanced portal hypertension, indicating the functional role of this novel pathway. In isolated KC, the expression of CB2 and HO-1 increased with Zymosan, LPS and JWH-133 treatment while TXB2 production following KC activation was attenuated by JWH-133 pre-treatment. SIGNIFICANCE JWH-133 or GP 1a treatment attenuates portal hypertension. HO-1 induction by JWH-133 plays a functional role. Therefore, the administration of JWH-133 or GP 1a represents a promising new treatment option for portal hypertension triggered by microbiological products.
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Key Words
- (6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran
- 2-Chloro-5-nitro-N-phenylbenzamide
- BDL
- Bile duct ligation (BDL)
- CB(2)
- GW 9662
- Gp 1a
- HO
- Heme oxygenase (HO)
- JWH-133
- KC
- Kupffer cell
- LDH
- LPS
- N-(Piperidin-1-yl)-1-(2,4-dichlorophenyl)-1,4-dihydro-6-methylindeno[1,2-c]pyrazole-3-carboxamide
- TLR
- TX
- Thromboxane
- Zy
- Zymosan A
- b. w
- bile duct ligation
- body weight
- cannabinoid receptor 2
- heme oxygenase
- lactate dehydrogenase
- lipopolysaccharide
- thromboxane
- toll like receptor
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Affiliation(s)
- Christian J Steib
- Department of Medicine II (Gastroenterology and Hepatology), Liver Center Munich, University of Munich, Grosshadern, Munich, Germany.
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Waidmann O, Brunner F, Herrmann E, Zeuzem S, Piiper A, Kronenberger B. Macrophage activation is a prognostic parameter for variceal bleeding and overall survival in patients with liver cirrhosis. J Hepatol 2013; 58:956-61. [PMID: 23333526 DOI: 10.1016/j.jhep.2013.01.005] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Revised: 12/12/2012] [Accepted: 01/03/2013] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS Soluble CD163 (sCD163) is shed in the blood circulation by activated macrophages, correlates strongly with the hepatic venous pressure gradient (HVPG) and is thereby a good indicator of portal hypertension. It is unknown whether sCD163 correlates with the risk of variceal bleeding and overall survival (OS) in patients with liver cirrhosis. We performed a prospective study to investigate if sCD163 serum levels correlate with the risk of variceal bleeding and OS in cirrhotic patients. METHODS Patients with liver cirrhosis were prospectively enrolled and followed until death or last contact. At the day of inclusion in the study, blood samples were taken and sCD163 serum levels were assessed by ELISA (enzyme-linked immunosorbent assay). The time until the end points death and variceal bleeding was assessed and the risks of death or variceal bleeding were calculated with uni- and multivariate Cox regression analyses. RESULTS High sCD163 levels (>4100 ng/L) were associated with death independently of the MELD (model of end stage liver disease) score, CRP (C-reactive protein), age and gender. Furthermore, high sCD163 levels were associated with gastrointestinal bleeding independently of the variceal stage and red spots. CONCLUSIONS The sCD163 serum level is a new independent non-invasive risk factor for death and variceal bleeding in cirrhotic patients.
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Affiliation(s)
- Oliver Waidmann
- Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Klinikum der Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany.
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Hammad LN, Abdelraouf SM, Hassanein FS, Mohamed WA, Schaalan MF. Circulating IL-6, IL-17 and vitamin D in hepatocellular carcinoma: potential biomarkers for a more favorable prognosis? J Immunotoxicol 2013; 10:380-6. [PMID: 23350952 DOI: 10.3109/1547691x.2012.758198] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infects primarily hepatocytes, leads to development of fibrosis and/or cirrhosis of the liver and is a significant factor for developing hepatocellular carcinoma (HCC). Evidence indicates that liver fibrosis contains uncontrolled inflammation as a part of its etiology. Normal cell-mediated immunity plays a central role in the mechanisms involved in viral clearance/persistence in the liver. In this context, cytokines modulate the immune system and exert direct anti-viral activity. To this end, this study investigated potential associations of serum IL-17 and IL-6 with exacerbation of hepatic damage in chronic HCV patients to determine their utility as prognostic markers for potential development of HCC. Chronic HCV-patients were recruited, divided into groups according to degree of liver damage, i.e. patients with peri-hepatic fibrosis, hepatic cirrhosis, or HCC, and had their blood collected for analysis of liver function and serum IL-6 and IL-17 levels. Interestingly, increases in serum IL-17 levels in the study groups were associated with aggravation of the clinical state from HCV to cirrhosis and then to HCC. Serum IL-6 levels followed a similar pattern. The association of both cytokines with progressive exacerbation of the initial HCV-induced liver damage was further confirmed by correlation analysis that revealed positive correlations between HCV RNA titer and IL-17 (+0.951, p < 0.05) and IL-6 (+0.85, p < 0.05). A receiver operating characteristics (ROC) analysis revealed their beneficial addition as promising biomarkers for a better prognostic profile of HCC. Interestingly, a significant progressive decline in the active vitamin D status was noted in all three clinical states, and these too were associated with progressive liver disease. This study confirms the necessity of adding screening for IL-6 and IL-17 and vitamin D to that of the classic marker AFP for patients with HCV and cirrhosis to hopefully permit clinicians to initiate measures that ultimately might mitigate/delay development of HCC in these infected patients.
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Pratschke S, Meimarakis G, Bruns CJ, Kaspar M, Prix N, Zachoval R, Guba M, Jauch KW, Loehe F, Angele MK. Temporary intraoperative porto-caval shunt: useless or beneficial in piggy back liver transplantation? Transpl Int 2012; 26:90-8. [PMID: 23237579 DOI: 10.1111/tri.12007] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 07/21/2012] [Accepted: 10/07/2012] [Indexed: 12/26/2022]
Abstract
The role of intraoperative porto-caval shunts in orthotopic liver transplantation (OLT) is controversial. Aim of this study was to analyze the effects of an intraoperative, porto-caval catheter-shunt on graft function and survival following cava sparing OLT. Four hundred and forty-eight piggy back liver transplantations with or without a temporary spontaneous porto-caval shunt between 1997 and 2010 were analyzed (shunt n = 274 vs. no shunt n = 174). Lab MELD scores and donor risk indices (DRI) were calculated. Hepatic injury (ALT, AST), -function (bilirubin, prothrombin ratio), postreperfusion liver blood flow and graft survival were registered [mean follow-up: 50.5 (0-163.0) months]. The impact of a shunt on graft survival was determined using multivariate analysis. Usage of a porto-caval shunt was associated with reduced hepatic injury (ALT, AST), whereas graft function was not affected. The shunt group showed a significantly increased portal venous blood flow after reperfusion. Retransplantation rate was decreased (7.7% vs. 20.1%, P = 0.001) and long-term graft survival was significantly increased with a porto-caval shunt (hazard ratio 2.1, P < 0.001). This effect was even more pronounced for marginal organs. Usage of intraoperative porto-caval catheter-shunts is beneficial in cava sparing OLT and is associated with reduced ischemia-reperfusion injury and improved organ survival in particular for recipients of marginal organs.
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García-Pagán JC, Gracia-Sancho J, Bosch J. Functional aspects on the pathophysiology of portal hypertension in cirrhosis. J Hepatol 2012; 57:458-61. [PMID: 22504334 DOI: 10.1016/j.jhep.2012.03.007] [Citation(s) in RCA: 207] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Revised: 03/19/2012] [Accepted: 03/26/2012] [Indexed: 02/07/2023]
Affiliation(s)
- Juan-Carlos García-Pagán
- Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer and CIBERehd, Spain.
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Grønbaek H, Sandahl TD, Mortensen C, Vilstrup H, Møller HJ, Møller S. Soluble CD163, a marker of Kupffer cell activation, is related to portal hypertension in patients with liver cirrhosis. Aliment Pharmacol Ther 2012; 36:173-80. [PMID: 22591184 DOI: 10.1111/j.1365-2036.2012.05134.x] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Revised: 04/05/2012] [Accepted: 04/25/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Activation of Kupffer cells may be involved in the pathogenesis of portal hypertension by release of vasoconstrictive substances and fibrosis due to co-activation of hepatic stellate cells. AIM To study soluble plasma (s) CD163, a specific marker of activated macrophages, as a biomarker for portal hypertension in patients with liver cirrhosis. METHODS We measured sCD163 concentration and the hepatic venous pressure gradient (HVPG) by liver vein catheterisation in 81 cirrhosis patients (Child-Pugh CP-A: n = 26, CP-B: n = 29, CP-C: n = 26) and 22 healthy subjects. We also measured their cardiac output (CO), cardiac index and systemic vascular resistance (SVR). Liver status was examined by Child-Pugh and MELD-score. RESULTS In cirrhosis, sCD163 concentration was nearly three times higher than in controls (4.7 ± 2.5 vs. 1.6 ± 0.5 mg/L, P < 0.001). sCD163 was also higher, as measured in steps by CP-score (P < 0.001). The HVPG rose steeply to an asymptote of 22 mmHg with sCD163 up to about 5 mg/L and not to higher values with higher sCD163. In a multivariate analysis, sCD163 was the only independent predictor of the HVPG but did not predict any of the systemic circulatory findings. sCD163 > 3.95 mg/L (upper normal limit) predicted HVPG ≥ 10 mmHg with a positive predictive value of 0.99. CONCLUSIONS Circulating sCD163 originating from activated Kupffer cells is increased in cirrhosis with increasing Child-Pugh score and with increasing HVPG, and it is an independent predictor for HVPG. These findings support a primary role of macrophage activation in portal hypertension, and may indicate a target for biological intervention.
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Affiliation(s)
- H Grønbaek
- Department of Medicine V, Aarhus University Hospital, Denmark
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Poelstra K, Prakash J, Beljaars L. Drug targeting to the diseased liver. J Control Release 2012; 161:188-97. [PMID: 22370583 DOI: 10.1016/j.jconrel.2012.02.011] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2011] [Revised: 02/08/2012] [Accepted: 02/11/2012] [Indexed: 02/07/2023]
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