|
1
|
Samuvel DJ, Lemasters JJ, Chou CJ, Zhong Z. LP340, a novel histone deacetylase inhibitor, decreases liver injury and fibrosis in mice: role of oxidative stress and microRNA-23a. Front Pharmacol 2024; 15:1386238. [PMID: 38828459 PMCID: PMC11140137 DOI: 10.3389/fphar.2024.1386238] [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: 02/14/2024] [Accepted: 04/24/2024] [Indexed: 06/05/2024] Open
Abstract
Effective therapy for liver fibrosis is lacking. Here, we examined whether LP340, the lead candidate of a new-generation of hydrazide-based HDAC1,2,3 inhibitors (HDACi), decreases liver fibrosis. Liver fibrosis was induced by CCl4 treatment and bile duct ligation (BDL) in mice. At 6 weeks after CCl4, serum alanine aminotransferase increased, and necrotic cell death and leukocyte infiltration occurred in the liver. Tumor necrosis factor-α and myeloperoxidase markedly increased, indicating inflammation. After 6 weeks, α-smooth muscle actin (αSMA) and collagen-1 expression increased by 80% and 575%, respectively, indicating hepatic stellate cell (HSC) activation and fibrogenesis. Fibrosis detected by trichrome and Sirius-red staining occurred primarily in pericentral regions with some bridging fibrosis in liver sections. 4-Hydroxynonenal adducts (indicator of oxidative stress), profibrotic cytokine transforming growth factor-β (TGFβ), and TGFβ downstream signaling molecules phospho-Smad2/3 also markedly increased. LP340 attenuated indices of liver injury, inflammation, and fibrosis markedly. Moreover, Ski-related novel protein-N (SnoN), an endogenous inhibitor of TGFβ signaling, decreased, whereas SnoN expression suppressor microRNA-23a (miR23a) increased markedly. LP340 (0.05 mg/kg, ig., daily during the last 2 weeks of CCl4 treatment) decreased 4-hydroxynonenal adducts and miR23a production, blunted SnoN decreases, and inhibited the TGFβ/Smad signaling. By contrast, LP340 had no effect on matrix metalloproteinase-9 expression. LP340 increased histone-3 acetylation but not tubulin acetylation, indicating that LP340 inhibited Class-I but not Class-II HDAC in vivo. After BDL, focal necrosis, inflammation, ductular reactions, and portal and bridging fibrosis occurred at 2 weeks, and αSMA and collagen-1 expression increased by 256% and 560%, respectively. LP340 attenuated liver injury, ductular reactions, inflammation, and liver fibrosis. LP340 also decreased 4-hydroxynonenal adducts and miR23a production, prevented SnoN decreases, and inhibited the TGFβ/Smad signaling after BDL. In vitro, LP340 inhibited immortal human hepatic stellate cells (hTERT-HSC) activation in culture (αSMA and collagen-1 expression) as well as miR23a production, demonstrating its direct inhibitory effects on HSC. In conclusions, LP340 is a promising therapy for both portal and pericentral liver fibrosis, and it works by inhibiting oxidative stress and decreasing miR23a.
Collapse
Affiliation(s)
- Devadoss J. Samuvel
- Departments of Drug Discovery and Biomedical Sciences, Charleston, SC, United States
| | - John J. Lemasters
- Departments of Drug Discovery and Biomedical Sciences, Charleston, SC, United States
- Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States
| | - C. James Chou
- Departments of Drug Discovery and Biomedical Sciences, Charleston, SC, United States
- Lydex Pharmaceuticals, Mount Pleasant, SC, United States
| | - Zhi Zhong
- Departments of Drug Discovery and Biomedical Sciences, Charleston, SC, United States
| |
Collapse
|
|
2
|
Al-Dhamin Z, Liu LD, Li DD, Zhang SY, Dong SM, Nan YM. Therapeutic efficiency of bone marrow-derived mesenchymal stem cells for liver fibrosis: A systematic review of in vivo studies. World J Gastroenterol 2020; 26:7444-7469. [PMID: 33384547 PMCID: PMC7754546 DOI: 10.3748/wjg.v26.i47.7444] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 10/31/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Although multiple drugs are accessible for recovering liver function in patients, none are considered efficient. Liver transplantation is the mainstay therapy for end-stage liver fibrosis. However, the worldwide shortage of healthy liver donors, organ rejection, complex surgery, and high costs are prompting researchers to develop novel approaches to deal with the overwhelming liver fibrosis cases. Mesenchymal stem cell (MSC) therapy is an emerging alternative method for treating patients with liver fibrosis. However, many aspects of this therapy remain unclear, such as the efficiency compared to conventional treatment, the ideal MSC sources, and the most effective way to use it. Because bone marrow (BM) is the largest source for MSCs, this paper used a systematic review approach to study the therapeutic efficiency of MSCs against liver fibrosis and related factors. We systematically searched multiple published articles to identify studies involving liver fibrosis and BM-MSC-based therapy. Analyzing the selected studies showed that compared with conventional treatment BM-MSC therapy may be more efficient for liver fibrosis in some cases. In contrast, the cotreatment presented a more efficient way. Nevertheless, BM-MSCs are lacking as a therapy for liver fibrosis; thus, this paper also reviews factors that affect BM-MSC efficiency, such as the implementation routes and strategies employed to enhance the potential in alleviating liver fibrosis. Ultimately, our review summarizes the recent advances in the BM-MSC therapy for liver fibrosis. It is grounded in recent developments underlying the efficiency of BM-MSCs as therapy, focusing on the preclinical in vivo experiments, and comparing to other treatments or sources and the strategies used to enhance its potential while mentioning the research gaps.
Collapse
Affiliation(s)
- Zaid Al-Dhamin
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Ling-Di Liu
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Dong-Dong Li
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Si-Yu Zhang
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Shi-Ming Dong
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| | - Yue-Min Nan
- Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Key Laboratory of Mechanism of Liver Fibrosis in Chronic Liver Disease, Shijiazhuang 050051, Hebei Province, China
| |
Collapse
|
|
3
|
Yang Z, Peng Y, Yang S. MicroRNA-146a regulates the transformation from liver fibrosis to cirrhosis in patients with hepatitis B via interleukin-6. Exp Ther Med 2019; 17:4670-4676. [PMID: 31086599 DOI: 10.3892/etm.2019.7490] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 10/08/2017] [Indexed: 12/13/2022] Open
Abstract
The aim of the present study was to measure the expression of microRNA (miR)-146a in liver tissues, peripheral blood mononuclear cells (PMBC) and serum from patients with Hepatitis B and either liver fibrosis or cirrhosis, as well as to determine the regulatory mechanism of miR-146a. A total of 36 patients with Hepatitis B and liver fibrosis and 25 patients with hepatitis B and liver cirrhosis admitted to Linyi People's Hospital (Shandong, China) between June 2012 and February 2016 were included in the present study. Reverse transcription-quantitative polymerase chain reaction was performed to determine the expression of miR-146a and interleukin (IL)-6 mRNA in the liver tissue, PBMCs and serum. Western blotting was used to assess the expression of IL-6 in liver tissues and PBMCs. An enzyme-linked immunosorbent assay was conducted to measure IL-6 levels in serum. To identify the direct interaction between IL-6 and miR-146a, a dual luciferase reporter assay was performed. IL-6 mRNA expression in liver tissues, PBMCs and serum from patients with liver cirrhosis was significantly higher than that from patients with liver fibrosis (P<0.05). Furthermore, IL-6 expression in liver tissues and PBMCs from patients with liver cirrhosis was enhanced and levels of IL-6 protein in the serum of patients with liver cirrhosis were significantly elevated compared with patients with liver fibrosis (P<0.05). By contrast, levels of miR-146a in liver tissues, PBMCs and serum from patients with liver cirrhosis were significantly downregulated (P<0.05) compared with patients with liver fibrosis. miR-146a regulated the expression of IL-6 by binding to its 3'-untranslated region. Thus, in the transformation from liver fibrosis to cirrhosis, the upregulation of IL-6 in liver tissues, PBMCs and serum may be associated with the downregulation of miR-146a. miR-146a directly targets IL-6, which may regulate the occurrence and immune responses of Hepatitis B.
Collapse
Affiliation(s)
- Zhaohui Yang
- Department of Infection, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
| | - Yulong Peng
- Department of Infection, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
| | - Suxian Yang
- Department of Infection, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
| |
Collapse
|
|
4
|
Zhao Y, Leng S, Li D, Feng S, Wang Z, Tao C. Pulmonary function impairment predicted poor prognosis of patients with hepatocellular carcinoma after hepatectomy. Oncotarget 2017; 8:75326-75335. [PMID: 29088868 PMCID: PMC5650423 DOI: 10.18632/oncotarget.20850] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 08/17/2017] [Indexed: 02/05/2023] Open
Abstract
Tumor hypoxia can influence the progression and metastasis of various cancers, including hepatocellular carcinoma (HCC). Clinical studies have indicated that hyperbaric oxygen may improve the prognosis and reduce complications in HCC patients; however, whether pulmonary function can influence the prognosis of HCC remains unknown. In this study, we found that pulmonary function was associated with clinicopathological features, including smoking, liver cirrhosis, tumor size Edmondson-Steiner grade, total operative blood loss and perioperative blood transfusion. Through Cox proportional hazard regression analysis, smoking, tumor number, tumor size, liver cirrhosis, total operative blood loss and pulmonary function were independent risk factors for overall survival (OS) and disease-free survival (DFS). In addition, poor pulmonary function was independently associated with shorter survival and increased HCC recurrence in patients. Notably, we also found that HCC with liver cirrhosis predicted worse prognosis. In summary, our study found pulmonary function could influence HCC progression. Improve pulmonary function may enhance the OS and DFS of patients with HCC.
Collapse
Affiliation(s)
- Yanhua Zhao
- Department of Laboratory Medicine/Clinical Research Center of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Shusheng Leng
- General Surgery Department, Affiliated Hospital/Clinical Medical College of Chengdu University, Chengdu 610081, China
| | - Dongdong Li
- Department of Laboratory Medicine/Clinical Research Center of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Shu Feng
- Department of Laboratory Medicine/Clinical Research Center of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Zhonghao Wang
- Department of Laboratory Medicine/Clinical Research Center of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Chuanmin Tao
- Department of Laboratory Medicine/Clinical Research Center of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu 610041, China
| |
Collapse
|
|
5
|
Chen Y, Yang S, Peng Y, Yang Z. The regulatory role of IL-6R in hepatitis B-associated fibrosis and cirrhosis. ACTA ACUST UNITED AC 2017; 50:e6246. [PMID: 28953986 PMCID: PMC5609599 DOI: 10.1590/1414-431x20176246] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 04/19/2017] [Indexed: 02/07/2023]
Abstract
This study investigated the expression and regulation of IL-6R in hepatitis B-associated moderate hepatic fibrosis and cirrhosis. Liver tissues, peripheral blood monocytes (PBMs) and serum were collected from 26 hepatitis B patients with liver fibrosis and 35 hepatitis B patients with liver cirrhosis. The levels of Il-6r mRNA expression in these samples were examined by quantitative real-time PCR and IL-6R protein levels were analyzed by western blot and ELISA. MiRNAs that regulate IL-6R expression were predicted by bioinformatics analysis, and validated by dual luciferase reporter assay. Compared with the hepatic fibrosis group, IL-6R was significantly upregulated at both mRNA and protein levels in liver tissues, PBMs and serum samples from the hepatic cirrhosis group (P<0.05). The 3'UTR of Il-6r mRNA was predicted to contain a miR-30b binding site and IL-6R was identified as a possible target of miR-30b. MiR-30b expression was significantly downregulated in samples from hepatic cirrhosis patients compared with hepatic fibrosis patients (P<0.05). In conclusion, IL-6R was upregulated while miR-30b was decreased in patients with liver cirrhosis. The miR-30 can directly regulate the expression of IL-6R.
Collapse
Affiliation(s)
- Y Chen
- Department of Infectious Diseases, Linyi People's Hospital, Linyi, Shandong, China
| | - S Yang
- Department of Infectious Diseases, Linyi People's Hospital, Linyi, Shandong, China
| | - Y Peng
- Department of Infectious Diseases, Linyi People's Hospital, Linyi, Shandong, China
| | - Z Yang
- Department of Infectious Diseases, Linyi People's Hospital, Linyi, Shandong, China
| |
Collapse
|
|
6
|
Kan F, Ye L, Yan T, Cao J, Zheng J, Li W. Proteomic and transcriptomic studies of HBV-associated liver fibrosis of an AAV-HBV-infected mouse model. BMC Genomics 2017; 18:641. [PMID: 28830339 PMCID: PMC5568174 DOI: 10.1186/s12864-017-3984-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 08/01/2017] [Indexed: 01/05/2023] Open
Abstract
Background Human hepatitis B virus (HBV) infection is an important public health issue in the Asia-Pacific region and is associated with chronic hepatitis, liver fibrosis, cirrhosis and even liver cancer. However, the underlying mechanisms of HBV-associated liver fibrosis remain incompletely understood. Results In the present study, proteomic and transcriptomic approaches as well as biological network analyses were performed to investigate the differentially expressed molecular signature and key regulatory networks that were associated with HBV-mediated liver fibrosis. RNA sequencing and 2DE-MALDI-TOF/TOF were performed on liver tissue samples obtained from HBV-infected C57BL/6 mouse generated via AAV8-HBV virus. The results showed that 322 genes and 173 proteins were differentially expressed, and 28 HBV-specific proteins were identified by comprehensive proteomic and transcriptomic analysis. GO analysis indicated that the differentially expressed proteins were predominantly involved in oxidative stress, which plays a key role in HBV-related liver fibrosis. Importantly, CAT, PRDX1, GSTP1, NXN and BLVRB were shown to be associated with oxidative stress among the differentially expressed proteins. The most striking results were validated by Western blot and RT-qPCR. The RIG-I like receptor signaling pathway was found to be the major signal pathway that changed during HBV-related fibrosis. Conclusions This study provides novel insights into HBV-associated liver fibrosis and reveals the significant role of oxidative stress in liver fibrosis. Furthermore, CAT, BLVRB, NXN, PRDX1, and IDH1 may be candidates for detection of liver fibrosis or therapeutic targets for the treatment of liver fibrosis. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3984-z) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Fangming Kan
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Lei Ye
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Tao Yan
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jiaqi Cao
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jianhua Zheng
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
| | - Wuping Li
- MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
| |
Collapse
|
|
7
|
Koneru M, Sahu BD, Kumar JM, Kuncha M, Kadari A, Kilari EK, Sistla R. Fisetin protects liver from binge alcohol-induced toxicity by mechanisms including inhibition of matrix metalloproteinases (MMPs) and oxidative stress. J Funct Foods 2016. [DOI: 10.1016/j.jff.2016.02.019] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
|
|
8
|
Serum YKL-40 in young patients with β-thalassemia major: Relation to hepatitis C virus infection, liver stiffness by transient elastography and cardiovascular complications. Blood Cells Mol Dis 2016; 56:1-8. [DOI: 10.1016/j.bcmd.2015.09.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Revised: 09/22/2015] [Accepted: 09/24/2015] [Indexed: 01/19/2023]
|
|
9
|
Serum YKL-40 levels and chitotriosidase activity in patients with beta-thalassemia major. DISEASE MARKERS 2014; 2014:965971. [PMID: 24808626 PMCID: PMC3997983 DOI: 10.1155/2014/965971] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 01/29/2014] [Indexed: 01/29/2023]
Abstract
BACKGROUND YKL-40 association with human disease has been the object of many years of investigation. β-thalassemia patients are affected by hepatic siderosis, which determines a fibrotic process and tissue remodelling. Chitotriosidase has been found to be increased in thalassemic patients returning to normal in patients submitted to bone marrow transplantation. YKL-40 is associated with macrophage activation in liver and in other tissues. The aim of the study was to analyse the level of serum YKL-40 and plasma chitotriosidase activity of patients with beta-thalassemia to assess whether their expression correlates with liver disease and degree of liver siderosis. METHODS Expression of YKL-40 and chitotriosidase as a marker of inflammation in 69 thalassemic patients were evaluated. We sought to investigate whether these two chitinases could be considered as a significant biomarker to evaluate therapy effectiveness. RESULTS Surprisingly we found normal value of YKL-40. We, also, analysed chitotriosidase activity in the same patients that was slightly increased as a consequence of macrophage activation. CONCLUSIONS These data would suggest a good treatment for these patients.
Collapse
|
|
10
|
Abdulaziz Bardi D, Halabi MF, Abdullah NA, Rouhollahi E, Hajrezaie M, Abdulla MA. In vivo evaluation of ethanolic extract of Zingiber officinale rhizomes for its protective effect against liver cirrhosis. BIOMED RESEARCH INTERNATIONAL 2013; 2013:918460. [PMID: 24396831 PMCID: PMC3874366 DOI: 10.1155/2013/918460] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 10/25/2013] [Accepted: 10/29/2013] [Indexed: 12/20/2022]
Abstract
Zingiber officinale is a traditional medicine against various disorders including liver diseases.The aim of this study was to assess the hepatoprotective activity of the ethanolic extract of rhizomes of Z. officinale (ERZO) against thioacetamide-induced hepatotoxicity in rats. Five groups of male Sprague Dawley have been used. In group 1 rats received intraperitoneal (i.p.) injection of normal saline while groups 2-5 received thioacetamide (TAA, 200 mg/kg; i.p.) for induction of liver cirrhosis, thrice weekly for eight weeks. Group 3 received 50 mg/kg of silymarin. The rats in groups 4 and 5 received 250 and 500 mg/kg of ERZO (dissolved in 10% Tween), respectively. Hepatic damage was assessed grossly and microscopically for all of the groups. Results confirmed the induction of liver cirrhosis in group 2 whilst administration of silymarin or ERZO significantly reduced the impact of thioacetamide toxicity. These groups decreased fibrosis of the liver tissues. Immunohistochemistry assessment against proliferating cell nuclear antigen did not show remarkable proliferation in the ERZO-treated rats when compared with group 2. Moreover, factions of the ERZO extract were tested on Hep-G2 cells and showed antiproliferative activity (IC50 38-60 μ g/mL). This study showed hepatoprotective effect of ERZO.
Collapse
Affiliation(s)
- Daleya Abdulaziz Bardi
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Mohammed Farouq Halabi
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Nor Azizan Abdullah
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Elham Rouhollahi
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Maryam Hajrezaie
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
- Institute of Biological Science, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Mahmood Ameen Abdulla
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| |
Collapse
|
|
11
|
Yoshida K, Matsuzaki K. Differential Regulation of TGF-β/Smad Signaling in Hepatic Stellate Cells between Acute and Chronic Liver Injuries. Front Physiol 2012. [PMID: 22457652 DOI: 10.3389/fphys]] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Current evidence suggests that regulation of extracellular matrix (ECM) accumulation by fibrogenic transforming growth factor (TGF)-β and platelet-derived growth factor (PDGF) signals involves different mechanisms in acute and chronic liver injuries, even though hepatic stellate cells (HSC) are the principal effecter in both cases. As a result of chronic liver damage, HSC undergo progressive activation to become myofibroblasts (MFB)-like cells. Our current review will discuss the differential regulation of TGF-β signaling between HSC and MFB in vitro and in vivo. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between conserved Mad-homology (MH) 1 and MH2 domains. TGF-β type I receptor and Ras-associated kinases differentially phosphorylate Smad2 and Smad3 to create COOH-terminally (C), linker (L), or dually (L/C) phosphorylated (p) isoforms. After acute liver injury, TGF-β and PDGF synergistically promote collagen synthesis in the activated HSC via pSmad2L/C and pSmad3L/C pathways. To avoid unlimited ECM deposition, Smad7 induced by TGF-β negatively regulates the fibrogenic TGF-β signaling. In contrast, TGF-β and PDGF can transmit the fibrogenic pSmad2L/C and mitogenic pSmad3L signals in MFB throughout chronic liver injury, because Smad7 cannot be induced by the pSmad3L pathway. This lack of Smad7 induction might lead to constitutive fibrogenesis in MFB, which eventually develop into accelerated liver fibrosis.
Collapse
Affiliation(s)
- Katsunori Yoshida
- Department of Gastroenterology and Hepatology, Kansai Medical University Moriguchi, Osaka, Japan
| | | |
Collapse
|
|
12
|
Yoshida K, Matsuzaki K. Differential Regulation of TGF-β/Smad Signaling in Hepatic Stellate Cells between Acute and Chronic Liver Injuries. Front Physiol 2012; 3:53. [PMID: 22457652 PMCID: PMC3307138 DOI: 10.3389/fphys.2012.00053] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Accepted: 02/26/2012] [Indexed: 12/13/2022] Open
Abstract
Current evidence suggests that regulation of extracellular matrix (ECM) accumulation by fibrogenic transforming growth factor (TGF)-β and platelet-derived growth factor (PDGF) signals involves different mechanisms in acute and chronic liver injuries, even though hepatic stellate cells (HSC) are the principal effecter in both cases. As a result of chronic liver damage, HSC undergo progressive activation to become myofibroblasts (MFB)-like cells. Our current review will discuss the differential regulation of TGF-β signaling between HSC and MFB in vitro and in vivo. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between conserved Mad-homology (MH) 1 and MH2 domains. TGF-β type I receptor and Ras-associated kinases differentially phosphorylate Smad2 and Smad3 to create COOH-terminally (C), linker (L), or dually (L/C) phosphorylated (p) isoforms. After acute liver injury, TGF-β and PDGF synergistically promote collagen synthesis in the activated HSC via pSmad2L/C and pSmad3L/C pathways. To avoid unlimited ECM deposition, Smad7 induced by TGF-β negatively regulates the fibrogenic TGF-β signaling. In contrast, TGF-β and PDGF can transmit the fibrogenic pSmad2L/C and mitogenic pSmad3L signals in MFB throughout chronic liver injury, because Smad7 cannot be induced by the pSmad3L pathway. This lack of Smad7 induction might lead to constitutive fibrogenesis in MFB, which eventually develop into accelerated liver fibrosis.
Collapse
Affiliation(s)
- Katsunori Yoshida
- Department of Gastroenterology and Hepatology, Kansai Medical University Moriguchi, Osaka, Japan
| | | |
Collapse
|
|
13
|
Ji H, Meng Y, Zhang X, Luo W, Wu P, Xiao B, Zhang Z, Li X. Aldosterone induction of hepatic stellate cell contraction through activation of RhoA/ROCK-2 signaling pathway. REGULATORY PEPTIDES 2011; 169:13-20. [PMID: 21545816 DOI: 10.1016/j.regpep.2011.04.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2010] [Revised: 03/21/2011] [Accepted: 04/16/2011] [Indexed: 12/30/2022]
Abstract
The RhoA/ROCK-2 signaling pathway is necessary for activated hepatic stellate cell (HSC) contraction. HSC contraction plays an important role in the pathogenesis of cirrhosis and portal hypertension. This study investigated whether aldosterone contributes to HSC contraction by activation of the RhoA/ROCK-2 signaling pathway. Primary HSCs were isolated from Sprague-Dawley rats via in situ pronase/collagenase perfusion. We found that aldosterone enhanced the contraction of a collagen lattice seeded with HSCs. This induced contraction was suppressed by the mineralcorticoid receptor (MR) inhibitor spironolactone, the ROCK-2 inhibitor Y27632, and the angiotensin II type 1 receptor (AT(1)R) inhibitor irbesartan. Moreover, actin fiber staining showed that aldosterone significantly increased actin fiber formation in HSCs. Pre-incubating with spironolactone, Y27632, or irbesartan inhibited the aldosterone-induced actin fiber reorganization. Molecularly, the effect of aldosterone on activation of HSC contraction was mediated by phosphorylated myosin light chain (P-MLC) through the RhoA/ROCK-2 signaling pathway. All these inhibitors had the ability to block aldosterone-induced protein expressions in the RhoA/ROCK-2/P-MLC cascade in HSCs. Taken together, our current study suggests that aldosterone induces contraction of activated HSCs through the activation of the RhoA/ROCK-2 signaling pathway. This finding may provide a potential therapeutic target for control of cirrhosis and portal hypertension.
Collapse
Affiliation(s)
- Hongli Ji
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Affiliation(s)
- J K Dowman
- Centre for Liver Research, Institute of Biomedical Research, University of Birmingham, B15 2TT, Birmingham, UK.
| | | | | |
Collapse
|
|
15
|
|
|
16
|
Parola M, Pinzani M. Hepatic wound repair. FIBROGENESIS & TISSUE REPAIR 2009; 2:4. [PMID: 19781064 PMCID: PMC2760508 DOI: 10.1186/1755-1536-2-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2009] [Accepted: 09/25/2009] [Indexed: 02/08/2023]
Abstract
Background Human chronic liver diseases (CLDs) with different aetiologies rely on chronic activation of wound healing that represents the driving force for fibrogenesis progression (throughout defined patterns of fibrosis) to the end stage of cirrhosis and liver failure. Issues Fibrogenesis progression has a major worldwide clinical impact due to the high number of patients affected by CLDs, increasing mortality rate, incidence of hepatocellular carcinoma and shortage of organ donors for liver transplantation. Basic science advances Liver fibrogenesis is sustained by a heterogeneous population of profibrogenic hepatic myofibroblasts (MFs), the majority being positive for α smooth muscle actin (αSMA), that may originate from hepatic stellate cells and portal fibroblasts following a process of activation or from bone marrow-derived cells recruited to damaged liver and, in a method still disputed, by a process of epithelial to mesenchymal transition (EMT) involving cholangiocytes and hepatocytes. Recent experimental and clinical data have identified, at tissue, cellular and molecular level major profibrogenic mechanisms: (a) chronic activation of the wound-healing reaction, (b) oxidative stress and related reactive intermediates, and (c) derangement of epithelial-mesenchymal interactions. Clinical care relevance Liver fibrosis may regress following specific therapeutic interventions able to downstage or, at least, stabilise fibrosis. In cirrhotic patients, this would lead to a reduction of portal hypertension and of the consequent clinical complications and to an overall improvement of liver function, thus extending the complication-free patient survival time and reducing the need for liver transplantation. Conclusion Emerging mechanisms and concepts related to liver fibrogenesis may significantly contribute to clinical management of patients affected by CLDs.
Collapse
Affiliation(s)
- Maurizio Parola
- Department of Experimental Medicine and Oncology and Interuniversity Center for Liver Pathophysiology, University of Torino, Torino, Italy.
| | | |
Collapse
|
|
17
|
Specific siRNA targeting the receptor for advanced glycation end products inhibits experimental hepatic fibrosis in rats. Int J Mol Sci 2008; 9:638-661. [PMID: 19325776 PMCID: PMC2635697 DOI: 10.3390/ijms9040638] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2008] [Revised: 04/17/2008] [Accepted: 04/22/2008] [Indexed: 12/13/2022] Open
Abstract
Receptor for advanced glycation end products (RAGE) was studied in different stages of carbon tetrachloride induced hepatic fibrosis (HF), and effect of its gene silencing in the HF development was evaluated in rats. Silencing RAGE expression by specific siRNA effectively suppressed NF-κB activity, hepatic stellate cell activation, and accumulation of extracellular matrix proteins in the fibrotic liver, and also greatly improved the histopathology and the ultrastructure of liver cells. These effects may be partially mediated by the inhibition on IκBα degradation. RAGE gene silencing effectively prevented liver from fibrosis, therefore it offers a potential pharmacological tool for anti-HF gene therapy.
Collapse
|
|
18
|
Parola M, Marra F, Pinzani M. Myofibroblast - like cells and liver fibrogenesis: Emerging concepts in a rapidly moving scenario. Mol Aspects Med 2007; 29:58-66. [PMID: 18022682 DOI: 10.1016/j.mam.2007.09.002] [Citation(s) in RCA: 132] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2007] [Accepted: 09/28/2007] [Indexed: 02/06/2023]
Abstract
Fibrotic progression of chronic liver diseases of different aetiology to the common advanced-stage of cirrhosis can be envisaged as a dynamic and highly integrated cellular response to chronic liver injury. Liver fibrosis is accompanied by perpetuation of liver injury, chronic hepatitis and persisting activation of tissue repair mechanisms, leading eventually to excess deposition of ECM components. Liver fibrogenesis (i.e., the process) is sustained by populations of highly proliferative, pro-fibrogenic and contractile MFs that, according to current literature, originate by a process of activation involving perisinusoidal HSC, portal fibroblasts and even bone marrow-derived MSC. In this short review emerging concepts in hepatic fibrogenesis and related molecular mechanisms, as provided by recent experimental and clinical studies, are presented.
Collapse
Affiliation(s)
- Maurizio Parola
- Dipartimento di Medicina e Oncologia Sperimentale, University of Torino, Corso Raffaello 30, 10125 Torino, Italy.
| | | | | |
Collapse
|
|
19
|
Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 2006; 10:76-99. [PMID: 16563223 PMCID: PMC3933103 DOI: 10.1111/j.1582-4934.2006.tb00292.x] [Citation(s) in RCA: 604] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatic fibrosis is a scarring process that is associated with an increased and altered deposition of extracellular matrix in liver. At the cellular and molecular level, this progressive process is mainly characterized by cellular activation of hepatic stellate cells and aberrant activity of transforming growth factor-beta1 and its downstream cellular mediators. Although the cellular responses to this cytokine are complex, the signalling pathways of this pivotal cytokine during the fibrogenic response and its connection to other signal cascades are now understood in some detail. Based on the current advances in understanding the pleiotropic reactions during fibrogenesis, various inhibitors of transforming growth factor-beta were developed and are now being investigated as potential drug candidates in experimental models of hepatic injury. Although it is too early to favour one of these antagonists for the treatment of hepatic fibrogenesis in human, the experimental results obtained yet provide stimulatory impulses for the development of an effective treatment of choice in the not too distant future. The present review summarises the actual knowledge on the pathogenesis of hepatic fibrogenesis, the role of transforming growth factor-beta and its signalling pathways in promoting the fibrogenic response, and the therapeutic modalities that are presently in the spotlight of many investigations and are already on the way to take the plunge into clinical studies.
Collapse
Affiliation(s)
- A M Gressner
- Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University - HospitalAachen, Germany
- *Correspondence to: A. M. GRESSNER/R. WEISKIRCHEN Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University Hospital, D-52074 Aachen, Germany. Tel.: +49-241-8088678/9 Fax: +49-241-8082512 E-mails:
| | - R Weiskirchen
- Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University - HospitalAachen, Germany
| |
Collapse
|
|
20
|
Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 2006. [PMID: 16563223 DOI: 10.1634/stemcells.2007-0252"> [doi: 10.1111/j.1582-4934.2006.tb00292.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatic fibrosis is a scarring process that is associated with an increased and altered deposition of extracellular matrix in liver. At the cellular and molecular level, this progressive process is mainly characterized by cellular activation of hepatic stellate cells and aberrant activity of transforming growth factor-beta1 and its downstream cellular mediators. Although the cellular responses to this cytokine are complex, the signalling pathways of this pivotal cytokine during the fibrogenic response and its connection to other signal cascades are now understood in some detail. Based on the current advances in understanding the pleiotropic reactions during fibrogenesis, various inhibitors of transforming growth factor-beta were developed and are now being investigated as potential drug candidates in experimental models of hepatic injury. Although it is too early to favour one of these antagonists for the treatment of hepatic fibrogenesis in human, the experimental results obtained yet provide stimulatory impulses for the development of an effective treatment of choice in the not too distant future. The present review summarises the actual knowledge on the pathogenesis of hepatic fibrogenesis, the role of transforming growth factor-beta and its signalling pathways in promoting the fibrogenic response, and the therapeutic modalities that are presently in the spotlight of many investigations and are already on the way to take the plunge into clinical studies.
Collapse
Affiliation(s)
- A M Gressner
- Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University--Hospital, D-52074 Aachen, Germany.
| | | |
Collapse
|
|
21
|
Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 2006. [PMID: 16563223 DOI: 10.1111/j.1528-4934.2006.th00292.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Hepatic fibrosis is a scarring process that is associated with an increased and altered deposition of extracellular matrix in liver. At the cellular and molecular level, this progressive process is mainly characterized by cellular activation of hepatic stellate cells and aberrant activity of transforming growth factor-beta1 and its downstream cellular mediators. Although the cellular responses to this cytokine are complex, the signalling pathways of this pivotal cytokine during the fibrogenic response and its connection to other signal cascades are now understood in some detail. Based on the current advances in understanding the pleiotropic reactions during fibrogenesis, various inhibitors of transforming growth factor-beta were developed and are now being investigated as potential drug candidates in experimental models of hepatic injury. Although it is too early to favour one of these antagonists for the treatment of hepatic fibrogenesis in human, the experimental results obtained yet provide stimulatory impulses for the development of an effective treatment of choice in the not too distant future. The present review summarises the actual knowledge on the pathogenesis of hepatic fibrogenesis, the role of transforming growth factor-beta and its signalling pathways in promoting the fibrogenic response, and the therapeutic modalities that are presently in the spotlight of many investigations and are already on the way to take the plunge into clinical studies.
Collapse
Affiliation(s)
- A M Gressner
- Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University--Hospital, D-52074 Aachen, Germany.
| | | |
Collapse
|
|
22
|
Sivak-Callcott JA, Rootman J, Rasmussen SL, Nugent RA, White VA, Paridaens D, Currie Z, Rose G, Clark B, McNab AA, Buffam FV, Neigel JM, Kazim M. Adult xanthogranulomatous disease of the orbit and ocular adnexa: new immunohistochemical findings and clinical review. Br J Ophthalmol 2006; 90:602-8. [PMID: 16622091 PMCID: PMC1857051 DOI: 10.1136/bjo.2005.085894] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/01/2006] [Indexed: 11/04/2022]
Abstract
BACKGROUND/AIMS Adult xanthogranulomatous disease involving the ocular tissues is rare and poorly understood. Adult onset xanthogranuloma (AOX), adult onset asthma and periocular xanthogranuloma (AAPOX), necrobiotic xanthogranuloma (NBX), and Erdheim-Chester disease (ECD) are the four syndromes within this disorder, which is diagnosed by characteristic histopathology. Experience with eight cases prompted a multi-institutional effort to study the histopathology, immunohistochemistry, clinical findings, and systemic associations in this disorder. METHODS 22 cases, including histopathological slides, were compiled. Published reports were identified by an English language Medline search (1966-2005) and review of reference citations. Each case in this series and the literature was classified as one of four syndromes and then analysed for age onset, sex, skin xanthoma, orbital location, immune dysfunction, internal organ and bone lesions, treatment, and outcome. The histopathology in each of these cases was reviewed by two pathologists. Immunhistochemical stains (CD3, CD4, CD8, L26) were performed in 14 cases where unstained slides were available. RESULTS 137 cases were compiled. There was no sex or age difference between syndromes. AOX, AAPOX, NBX affect the anterior orbit, ECD tends to be diffuse and intraconal. Skin lesions are found in all the syndromes. Immune dysfunction was noted in all cases of AAPOX and NBX; 11% of NBX and all ECD patients had internal organ disease. Treatment included surgery, corticosteroids, other chemotherapeutic agents, radiotherapy, and combinations of these. No AOX or AAPOX deaths occurred; 66% of ECD patients died. All 22 cases had xanthoma cells; most had Touton giant cells. Lymphocytes were present in all cases and occurred as aggregates (mostly in AAPOX) or diffuse populations mixed with fibroblasts (mostly in ECD). Immunohistochemistry revealed the majority of these to be CD8+. Necrosis was most marked in NBX. CONCLUSION Adult xanthogranuloma of the orbit is rare, making prospective evaluation or meta-analysis impossible. The best treatment is unknown but seems to be with multiagent chemotherapy guided by histopathological, immunohistochemical, and systemic findings.
Collapse
Affiliation(s)
- J A Sivak-Callcott
- Department of Ophthalmology, West Virginia University Eye Institute, Morgantown, 26505, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Yoshida K, Matsuzaki K, Mori S, Tahashi Y, Yamagata H, Furukawa F, Seki T, Nishizawa M, Fujisawa J, Okazaki K. Transforming growth factor-beta and platelet-derived growth factor signal via c-Jun N-terminal kinase-dependent Smad2/3 phosphorylation in rat hepatic stellate cells after acute liver injury. THE AMERICAN JOURNAL OF PATHOLOGY 2005; 166:1029-39. [PMID: 15793284 PMCID: PMC1602385 DOI: 10.1016/s0002-9440(10)62324-3] [Citation(s) in RCA: 133] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
After liver injury, transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF) regulate the activation of hepatic stellate cells (HSCs) and tissue remodeling. Mechanisms of PDGF signaling in the TGF-beta-triggered cascade are not completely understood. TGF-beta signaling involves phosphorylation of Smad2 and Smad3 at linker and C-terminal regions. Using antibodies to distinguish Smad2/3 phosphorylated at linker regions from those phosphorylated at C-terminal regions, we investigated Smad2/3-mediated signaling in rat liver injured by CCl(4) administration and in cultured HSCs. In acute liver injury, Smad2/3 were transiently phosphorylated at both regions. Although linker-phosphorylated Smad2 remained in the cytoplasm of alpha-smooth muscle actin-immunoreactive mesenchymal cells adjacent to necrotic hepatocytes in centrilobular areas, linker-phosphorylated Smad3 accumulated in the nuclei. c-Jun N-terminal kinase (JNK) in the activated HSCs directly phosphorylated Smad2/3 at linker regions. Co-treatment of primary cultured HSCs with TGF-beta and PDGF activated the JNK pathway, subsequently inducing endogenous linker phosphorylation of Smad2/3. The JNK pathway may be involved in migration of resident HSCs within the space of Disse to the sites of tissue damage because the JNK inhibitor SP600125 inhibited HSC migration induced by TGF-beta and PDGF signals. Moreover, treatment of HSCs with both TGF-beta and PDGF increased transcriptional activity of plasminogen activator inhibitor-1 through linker phosphorylation of Smad3. In conclusion, TGF-beta and PDGF activate HSCs by transmitting their signals through JNK-mediated Smad2/3 phosphorylation at linker regions, both in vivo and in vitro.
Collapse
Affiliation(s)
- Katsunori Yoshida
- Third Department of Internal Medicine, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka 570-8507, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Abstract
Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.
Collapse
Affiliation(s)
- Ramón Bataller
- Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clinic, Institut d'Investigació Biomèdiques August Pi i Sunyer (IDIBAPS),Barcelona, Catalonia, Spain
| | | |
Collapse
|
|
25
|
Abstract
Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.
Collapse
Affiliation(s)
- Ramón Bataller
- Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clinic, Institut d'Investigació Biomèdiques August Pi i Sunyer (IDIBAPS),Barcelona, Catalonia, Spain
| | | |
Collapse
|
|
26
|
Abstract
Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.
Collapse
Affiliation(s)
- Ramón Bataller
- Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clinic, Institut d'Investigació Biomèdiques August Pi i Sunyer (IDIBAPS),Barcelona, Catalonia, Spain
| | | |
Collapse
|
|
27
|
Abstract
Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.
Collapse
Affiliation(s)
- Ramón Bataller
- Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clinic, Institut d'Investigació Biomèdiques August Pi i Sunyer (IDIBAPS),Barcelona, Catalonia, Spain
| | | |
Collapse
|
|
28
|
Abstract
Liver fibrosis is the hallmark of every chronic liver disease. It is also the major factor of morbidity and mortality due to the development of cirrhosis and its complications including hepatocellular carcinoma. But even at the beginning of the process of liver fibrosis and due to the strategic position of the extracellular matrix at the interface between blood flow and epithelial compartment, any quantitative or qualitative modification of extracellular matrix will rapidly affect structure and function of the liver. The development of several animal models of liver fibrosis as well as isolation and cultivation of hepatic stellate cells, the major fibrogenic cell type in the liver, led to the gathering of recent knowledge on the mechanism of liver fibrosis. Activation of hepatic stellate cells is a key event in this process and many details on this finely tuned mechanism are now available. In addition to these experimental data, experience from chronic hepatitis C now allows the development of new concepts and perspectives such as liver fibrosis regression and antifibrotic therapies.
Collapse
Affiliation(s)
- Pierre Bedossa
- Service d'Anatomie Pathologique, CNRS FRE2443, Hôpital de Bicêtre, 78 Avenue Géneral Leclerc, 94275 Le Kremlin-Bicêtre, France.
| | | |
Collapse
|
|
29
|
Mazzocca A, Carloni V, Sciammetta S, Cordella C, Pantaleo P, Caldini A, Gentilini P, Pinzani M. Expression of transmembrane 4 superfamily (TM4SF) proteins and their role in hepatic stellate cell motility and wound healing migration. J Hepatol 2002; 37:322-30. [PMID: 12175627 DOI: 10.1016/s0168-8278(02)00175-7] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND/AIMS Migration of activated hepatic stellate cells (HSC) is a key event in the progression of liver fibrosis. Little is known about transmembrane proteins involved in HSC motility. Tetraspanins (TM4SF) have been implicated in cell development, differentiation, motility and tumor cell invasion. We evaluated the expression and function of four TM4SF, namely CD9, CD81, CD63 and CD151, and their involvement in HSC migration, adhesion, and proliferation. METHODS/RESULTS All TM4SF investigated were highly expressed at the human HSC surface with different patterns of intracellular distribution. Monoclonal antibodies directed against the four TM4SF inhibited HSC migration induced by extracellular matrix proteins in both wound healing and haptotaxis assays. This inhibition was independent of the ECM substrates employed (collagen type I or IV, laminin), and was comparable to that obtained by incubating the cells with an anti-beta1 blocking mAb. Importantly, cell adhesion was unaffected by the incubation with the same antibodies. Co-immunoprecipitation studies revealed different patterns of association between the four TM4SF studied and beta1 integrin. Finally, anti-TM4SF antibodies did not affect HSC growth. CONCLUSIONS These findings provide the first characterization of tetraspanins expression and of their role in HSC migration, a key event in liver tissue wound healing and fibrogenesis.
Collapse
Affiliation(s)
- Antonio Mazzocca
- Dipartimento di Medicina Interna, Università degli Studi di Firenze, Viale Morgagni, 85, Florence, Italy.
| | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Gewaltig J, Mangasser-Stephan K, Gartung C, Biesterfeld S, Gressner AM. Association of polymorphisms of the transforming growth factor-beta1 gene with the rate of progression of HCV-induced liver fibrosis. Clin Chim Acta 2002; 316:83-94. [PMID: 11750277 DOI: 10.1016/s0009-8981(01)00738-0] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND The objective of the present study was to elucidate possible relationships between four polymorphisms of the TGF-beta1 gene (-800G>A; -509C>T; Leu10Pro; Arg25Pro) and stage, histological activity grade and progression rate of liver fibrosis, classified according to the METAVIR-score. METHODS Three study groups, i.e. 48 patients with hepatic fibrosis (26 with known duration of hepatitis C virus infection), 47 patients with non-fibrotic diseases and 50 healthy blood donors, were analyzed for TGF-beta1 polymorphisms using ARMS-PCR and sequence analysis. The concentrations of total TGF-beta1 in plasma and of hyaluronan, P-III-NP and activities of transminases in serum were measured. RESULTS The presence of proline at codons 10 and/or 25 was associated with a faster progression of fibrosis than other polymorphisms. Patients with the genotype (25)ArgPro developed fibrosis significantly faster (0.23 units/year) than those having (25)ArgArg (0.08 units/year). Similarly, the fibrosis progression rate of patients with genotypes (10)LeuPro and (10)ProPro was almost three times as fast as of those having genotype (10)LeuLeu. Stage and histological activity grade of fibrosis in (25)ArgPro in comparison to (25)ArgArg were higher. Also (10)LeuPro showed a higher average stage of fibrosis than (10)LeuLeu. The TGF-beta1 plasma concentrations of patients with hepatic fibrosis were not significantly different between carriers of (25)ArgArg and (25)ArgPro genotypes. The frequency of the genotype (25)ArgPro in liver fibrotic patients was about three times that of the control group whereas the frequency distribution of the genotype (25)ArgArg tended to lower frequency in the fibrosis group. TGF-beta1-promoter polymorphisms did not show any correlation with stage, grade or progression of liver fibrosis. CONCLUSION Our results indicate that the heterozygous ArgPro of codon 25 predicts significantly faster fibrotic progression of chronic hepatitis C than the homozygous (25)ArgArg genotype. The homozygous LeuLeu genotype of codon 10 showed a slow progression of fibrosis.
Collapse
Affiliation(s)
- Jan Gewaltig
- Institute of Clinical Chemistry and Pathobiochemistry, Central Laboratory, RWTH-University Hospital Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
| | | | | | | | | |
Collapse
|
|
31
|
|