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Modifications of liver stiffness and CXCL4, TGF-β1 and HGF are similar in HCV- and HIV/HCV-infected patients after DAAs. Sci Rep 2021; 11:9824. [PMID: 33972651 PMCID: PMC8110591 DOI: 10.1038/s41598-021-89370-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/26/2021] [Indexed: 01/11/2023] Open
Abstract
The objective of this work was to identify predictive factors of fibrosis regression after direct antiviral agents (DAAs) in HCV-monoinfected and HIV/HCV-coinfected patients. This was a prospective study of HCV-monoinfected (n = 20), HIV/HCV-co-infected (n = 66) patients and healthy controls (n = 15). Patients had started DAAs and achieved sustained virological response. Liver stiffness (LS) and serum concentrations of profibrotic transforming growth factor (TGF)-β1 and CXC chemokine ligand 4 (CXCL4) and antifibrotic HGF hepatocyte growth factor (HGF) were analyzed at baseline (M0) and 12 months after starting DAAs (M12). A M12 LS achievement of ≤ 9.5 kPa was considered the cutoff point to discharge from a liver clinic. The LS decrease from M0 to M12 was 34%. No significant differences were observed in LS decline between HCV- and HIV/HCV-infected individuals. Changes of serum CXCL4, TGF-β1 and HGF levels did not correlate with LS improvement. 16 out from 56 patients (28%) with a baseline LS > 9.5 achieved a M12 LS ≤ 9.5. HCV-monoinfected and HIV/HCV coinfected patients experienced a significant reduction of LS after sustained virological response. This improvement did not correlate with changes in serum profibrotic or antifibrotic markers. A 29% of those with a baseline LS > 9.5 achieved a LS under this cutoff point.
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Zhang S, Li G, Liu C, Lu S, Jing Q, Chen X, Zheng H, Ma H, Zhang D, Ren S, Shen Z, Wang Y, Lu Z, Huang D, Tan P, Chen J, Zhang X, Qiu Y, Liu Y. miR-30e-5p represses angiogenesis and metastasis by directly targeting AEG-1 in squamous cell carcinoma of the head and neck. Cancer Sci 2020; 111:356-368. [PMID: 31778279 PMCID: PMC7004514 DOI: 10.1111/cas.14259] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/08/2019] [Accepted: 11/18/2019] [Indexed: 02/06/2023] Open
Abstract
Metastasis is a critical determinant for the treatment strategy and prognosis in patients with squamous cell carcinoma of the head and neck (SCCHN). However, the mechanisms underlying SCCHN metastasis are poorly understood. Our study sought to determine the key microRNA and their functional mechanisms involved in SCCHN metastasis. For The Cancer Genome Atlas (TCGA) data analysis, quantitative PCR was used to quantify the level of miR-30e-5p in SCCHN and its clinical significance was further analyzed. A series of in vitro and in vivo experiments were applied to determine the effects of miR-30e-5p and its target AEG-1 on SCCHN metastasis. A mechanism investigation further revealed that AEG-1 was implicated in the angiogenesis and metastasis mediated by miR-30e-5p. Overall, our study confirms that miR-30e-5p is a valuable predictive biomarker and potential therapeutic target in SCCHN metastasis.
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Affiliation(s)
- Shuiting Zhang
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Guo Li
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Chao Liu
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Shanhong Lu
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Qiancheng Jing
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
- Department of Otolaryngology Head and Neck SurgeryChangsha Central HospitalUniversity of South ChinaChangshaChina
| | - Xiyu Chen
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Hua Zheng
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Huiling Ma
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Diekuo Zhang
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Shuling Ren
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Zhe Shen
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Yunyun Wang
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Zhaoyi Lu
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Donghai Huang
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Pingqing Tan
- Department of Head and Neck SurgeryHunan Cancer HospitalThe Affiliated Tumor Hospital of Xiangya Medical SchoolCentral South UniversityChangshaChina
| | - Jie Chen
- Department of Head and Neck SurgeryHunan Cancer HospitalThe Affiliated Tumor Hospital of Xiangya Medical SchoolCentral South UniversityChangshaChina
| | - Xin Zhang
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Yuanzheng Qiu
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
| | - Yong Liu
- Department of Otolaryngology Head and Neck SurgeryXiangya HospitalCentral South UniversityChangshaChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaChina
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Villani R, Vendemiale G, Serviddio G. Molecular Mechanisms Involved in HCC Recurrence after Direct-Acting Antiviral Therapy. Int J Mol Sci 2018; 20:ijms20010049. [PMID: 30583555 PMCID: PMC6337751 DOI: 10.3390/ijms20010049] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/18/2018] [Accepted: 12/19/2018] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis C is associated with a high risk of developing hepatocellular carcinoma (HCC) because of a direct effect of the Hepatitis C Virus (HCV) proteins and an indirect oncogenic effect of chronic inflammation and impaired immune response. The treatment of chronic hepatitis C markedly reduces all-cause mortality; in fact, interferon-based treatment has shown a reduction of HCC incidence of more than 70%. The recent introduction of the highly effective direct-acting antivirals (DAAs) has completely changed the scenario of chronic hepatitis C (CHC) with rates of HCV cure over 90%. However, an unexpectedly high incidence of HCC recurrence was observed in patients after DAA treatment (27% versus 0.4–2% in patients who received interferon treatment). The mechanism that underlies the high rate of tumor relapse is currently unknown and is one of the main issues in hepatology. We reviewed the possible mechanisms involved in HCC recurrence after DAA treatment.
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MESH Headings
- Animals
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/virology
- Hepacivirus/drug effects
- Hepacivirus/immunology
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/virology
- Humans
- Incidence
- Interferons/therapeutic use
- Liver Neoplasms/drug therapy
- Liver Neoplasms/epidemiology
- Liver Neoplasms/immunology
- Liver Neoplasms/virology
- Macrophages/drug effects
- Monocytes/drug effects
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/virology
- Neutrophils/drug effects
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Affiliation(s)
- Rosanna Villani
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| | - Gianluigi Vendemiale
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| | - Gaetano Serviddio
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
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Ni Y, Li JM, Liu MK, Zhang TT, Wang DP, Zhou WH, Hu LZ, Lv WL. Pathological process of liver sinusoidal endothelial cells in liver diseases. World J Gastroenterol 2017; 23:7666-7677. [PMID: 29209108 PMCID: PMC5703927 DOI: 10.3748/wjg.v23.i43.7666] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Revised: 09/13/2017] [Accepted: 09/28/2017] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis develops from liver fibrosis and is the severe pathological stage of all chronic liver injury. Cirrhosis caused by hepatitis B virus and hepatitis C virus infection is especially common. Liver fibrosis and cirrhosis involve excess production of extracellular matrix, which is closely related to liver sinusoidal endothelial cells (LSECs). Damaged LSECs can synthesize transforming growth factor-beta and platelet-derived growth factor, which activate hepatic stellate cells and facilitate the synthesis of extracellular matrix. Herein, we highlight the angiogenic cytokines of LSECs related to liver fibrosis and cirrhosis at different stages and focus on the formation and development of liver fibrosis and cirrhosis. Inhibition of LSEC angiogenesis and antiangiogenic therapy are described in detail. Targeting LSECs has high therapeutic potential for liver diseases. Further understanding of the mechanism of action will provide stronger evidence for the development of anti-LSEC drugs and new directions for diagnosis and treatment of liver diseases.
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MESH Headings
- Angiogenesis Inhibitors/pharmacology
- Angiogenesis Inhibitors/therapeutic use
- Animals
- Cytokines/metabolism
- Disease Models, Animal
- Endothelial Cells/drug effects
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Endothelial Cells/virology
- Extracellular Matrix/metabolism
- Extracellular Matrix/pathology
- Hepacivirus/pathogenicity
- Hepatic Stellate Cells/metabolism
- Hepatic Stellate Cells/pathology
- Hepatic Stellate Cells/virology
- Hepatitis B virus/pathogenicity
- Hepatitis, Viral, Human/diagnosis
- Hepatitis, Viral, Human/drug therapy
- Hepatitis, Viral, Human/pathology
- Hepatitis, Viral, Human/virology
- Humans
- Liver/blood supply
- Liver/cytology
- Liver/pathology
- Liver/virology
- Liver Cirrhosis/diagnosis
- Liver Cirrhosis/drug therapy
- Liver Cirrhosis/pathology
- Liver Cirrhosis/virology
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/pathology
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Affiliation(s)
- Yao Ni
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Juan-Mei Li
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ming-Kun Liu
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ting-Ting Zhang
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Dong-Ping Wang
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Wen-Hui Zhou
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ling-Zi Hu
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Wen-Liang Lv
- Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
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Chen HY, Chen YM, Wu J, Yang FC, Lv Z, Qian YG, Zheng SS. Effects of HGF gene polymorphisms and protein expression on transhepatic arterial chemotherapeutic embolism efficacy and prognosis in patients with primary liver cancer. Onco Targets Ther 2017; 10:803-810. [PMID: 28243116 PMCID: PMC5315352 DOI: 10.2147/ott.s115035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE To investigate the correlations of two hepatocyte growth factor (HGF) gene polymorphisms (rs5745652 and rs2074725) and their protein expression levels with the efficacy of transhepatic arterial chemotherapeutic embolism (TACE) and prognosis in patients with primary liver cancer (PLC). METHODS From March 2011 to June 2012, 109 PLC patients (the case group) who chose TACE as primary treatment and 80 healthy people (the control group) who had undergone physical examination in The First Affiliated Hospital, Zhejiang University were selected during the same period. Gene polymorphisms of HGF rs5745652 and HGF rs2074725 were detected. Serum HGF level, treating efficacy, survival quality, and 3-year survival rate for PLC patients who received TACE were observed. RESULTS There were significant differences in genotype and allele frequencies of HGF rs5745652 and HGF rs2074725, between the case and control groups (all P<0.05). Compared with CT+TT genotype of HGF rs5745652, patients carrying CC genotype had lower serum HGF levels, higher efficacy, better survival quality, and prolonged 3-year survival rate (all P<0.05). In rs2074725, patients carrying CA+AA genotype had lower serum HGF levels, higher efficacy, better survival quality, and prolonged 3-year survival rate compared with patients carrying rs2074725 CC genotype (all P<0.05). Gene polymorphisms of HGF rs5745652 and HGF rs2074725, tumor size, and Barcelona Clinic Liver Cancer stage were independent prognostic factors for PLC (P<0.05). CONCLUSION Our results indicated that HGF gene polymorphisms affect TACE efficacy and survival quality of PLC patients. Patients with HGF CC genotype of rs5745652 and CA+AA genotype of rs2074725 had decreased HGF level, better curative effect, high survival quality, and a good prognosis after TACE treatment.
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Affiliation(s)
- Hai-Yong Chen
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases
| | - Yao-Min Chen
- Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China
| | - Jian Wu
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases
| | - Fu-Chun Yang
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases
| | - Zhen Lv
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases
| | - Yi-Gang Qian
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases
| | - Shu-Sen Zheng
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases
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Prystupa A, Kiciński P, Sak J, Boguszewska-Czubara A, Toruń-Jurkowska A, Załuska W. Proinflammatory Cytokines (IL-1α, IL-6) and Hepatocyte Growth Factor in Patients with Alcoholic Liver Cirrhosis. Gastroenterol Res Pract 2015; 2015:532615. [PMID: 26448742 PMCID: PMC4558446 DOI: 10.1155/2015/532615] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 08/06/2015] [Indexed: 02/07/2023] Open
Abstract
Background. The aim of the study was to assess the activity of interleukin-1α, interleukin-6, and hepatocyte growth factor protein (HGF) in serum of patients with alcoholic liver cirrhosis. Materials and Methods. Sixty patients with alcoholic liver cirrhosis treated in various hospitals were randomly enrolled. The stage of cirrhosis was assessed according to the Child-Turcotte-Pugh scoring system. The control group consisted of ten healthy persons without liver disease, who did not drink alcohol. Additionally, the group of alcoholics without liver cirrhosis was included in the study. The activity of interleukin-1α, interleukin-6, and HGF in blood plasma of patients and controls was measured using the sandwich enzyme immunoassay technique with commercially available quantitative ELISA test kits. Results. Higher concentrations of HGF protein were demonstrated in patients with Child class B and Child class C liver cirrhosis, compared to controls and alcoholics without liver cirrhosis. Moreover, significantly higher concentrations of HGF protein were found in patients with Child class C liver cirrhosis compared to patients with Child class A liver cirrhosis (p < 0.05). The concentrations of interleukin-1α in patients with Child class B and Child class C liver cirrhosis were significantly higher in comparison with controls. Significantly higher concentrations of interleukin-6 were demonstrated in Child class C, compared to Child class A.
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Affiliation(s)
- Andrzej Prystupa
- Department of Internal Medicine, Medical University of Lublin, Staszica 16, 20-081 Lublin, Poland
| | - Paweł Kiciński
- Department of Family Medicine, Medical University of Lublin, Staszica 11, 20-081 Lublin, Poland
| | - Jarosław Sak
- Department of Ethics and Human Philosophy, Medical University of Lublin, Staszica 4/6, 20-059 Lublin, Poland
- Department of Nephrology, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
| | - Anna Boguszewska-Czubara
- Department of Medical Chemistry, Medical University of Lublin, Chodźki 4a, 20-093 Lublin, Poland
| | - Anna Toruń-Jurkowska
- Department of Mathematics and Medical Biostatistics, Medical University of Lublin, Jaczewskiego 4, 20-954 Lublin, Poland
| | - Wojciech Załuska
- Department of Nephrology, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
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Abstract
Recent data indicate that hepatic angiogenesis, regardless of the etiology, takes place in chronic liver diseases (CLDs) that are characterized by inflammation and progressive fibrosis. Because anti-angiogenic therapy has been found to be efficient in the prevention of fibrosis in experimental models of CLDs, it is suggested that blocking angiogenesis could be a promising therapeutic option in patients with advanced fibrosis. Consequently, efforts are being directed to revealing the mechanisms involved in angiogenesis during the progression of liver fibrosis. Literature evidences indicate that hepatic angiogenesis and fibrosis are closely related in both clinical and experimental conditions. Hypoxia is a major inducer of angiogenesis together with inflammation and hepatic stellate cells. These profibrogenic cells stand at the intersection between inflammation, angiogenesis and fibrosis and play also a pivotal role in angiogenesis. This review mainly focuses to give a clear view on the relevant features that communicate angiogenesis with progression of fibrosis in CLDs towards the-end point of cirrhosis that may be translated into future therapies. The pathogenesis of hepatic angiogenesis associated with portal hypertension, viral hepatitis, non-alcoholic fatty liver disease and alcoholic liver disease are also discussed to emphasize the various mechanisms involved in angiogenesis during liver fibrogenesis.
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Affiliation(s)
- Gülsüm Özlem Elpek
- Gülsüm Özlem Elpek, Department of Pathology, Akdeniz University Medical School, 07070 Antalya, Turkey
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Pathophysiology of Portal Hypertension. PANVASCULAR MEDICINE 2015. [PMCID: PMC7153457 DOI: 10.1007/978-3-642-37078-6_144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The bases of our current knowledge on the physiology of the hepatic portal system are largely owed to the work of three pioneering vascular researchers from the sixteenth and the seventeenth centuries: A. Vesalius, W. Harvey, and F. Glisson. Vesalius is referred to as the founder of modern human anatomy, and in his influential book, De humani corporis fabrica libri septem, he elaborated the first anatomical atlas of the hepatic portal venous system (Vesalius 2013). Sir William Harvey laid the foundations of modern cardiovascular research with his Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (Harvey 1931) in which he established the nature of blood circulation. Finally, F. Glisson characterized the gastrointestinal-hepatic vascular system (Child 1955). These physiological descriptions were later complemented with clinical observations. In the eighteenth and nineteenth centuries, Morgagni, Puckelt, Cruveilhier, and Osler were the first to make the connection between common hepatic complications – ascites, splenomegaly, and gastrointestinal bleeding – and obstruction of the portal system (Sandblom 1993). These were the foundations that allowed Gilbert, Villaret, and Thompson to establish an early definition of portal hypertension at the beginning of the twentieth century. In this period, Thompson performed the first direct measurement of portal pressure by laparotomy in some patients (Gilbert and Villaret 1906; Thompson et al. 1937). Considering all these milestones, and paraphrasing Sir Isaac Newton, if hepatologists have seen further, it is by standing on the shoulders of giants. Nowadays, our understanding of the pathogenesis of portal hypertension has largely improved thanks to the progress in preclinical and clinical research. However, this field is ever-changing and hepatologists are continually identifying novel pathological mechanisms and developing new therapeutic strategies for this clinical condition. Hence, the aim of this chapter is to summarize the current knowledge about this clinical condition.
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Martín-Vílchez S, Rodríguez-Muñoz Y, López-Rodríguez R, Hernández-Bartolomé Á, Borque-Iñurrita MJ, Molina-Jiménez F, García-Buey L, Moreno-Otero R, Sanz-Cameno P. Inhibition of tyrosine kinase receptor Tie2 reverts HCV-induced hepatic stellate cell activation. PLoS One 2014; 9:e106958. [PMID: 25302785 PMCID: PMC4193738 DOI: 10.1371/journal.pone.0106958] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 08/12/2014] [Indexed: 01/18/2023] Open
Abstract
Background Hepatitis C virus (HCV) infection is a major cause of chronic liver disease (CLD) and is frequently linked to intrahepatic microvascular disorders. Activation of hepatic stellate cells (HSC) is a central event in liver damage, due to their contribution to hepatic renewal and to the development of fibrosis and hepatocarcinoma. During the progression of CLDs, HSC attempt to restore injured tissue by stimulating repair processes, such as fibrosis and angiogenesis. Because HSC express the key vascular receptor Tie2, among other angiogenic receptors and mediators, we analyzed its involvement in the development of CLD. Methods Tie2 expression was monitored in HSC cultures that were exposed to media from HCV-expressing cells (replicons). The effects of Tie2 blockade on HSC activation by either neutralizing antibody or specific signaling inhibitors were also examined. Results Media from HCV-replicons enhanced HSC activation and invasion and upregulated Tie2 expression. Notably, the blockade of Tie2 receptor (by a specific neutralizing antibody) or signaling (by selective AKT and MAPK inhibitors) significantly reduced alpha-smooth muscle actin (α-SMA) expression and the invasive potential of HCV-conditioned HSC. Conclusions These findings ascribe a novel profibrogenic function to Tie2 receptor in the progression of chronic hepatitis C, highlighting the significance of its dysregulation in the evolution of CLDs and its potential as a novel therapeutic target.
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Affiliation(s)
- Samuel Martín-Vílchez
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America
| | - Yolanda Rodríguez-Muñoz
- Unidad de Hepatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-ehd), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Rosario López-Rodríguez
- Unidad de Hepatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-ehd), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Ángel Hernández-Bartolomé
- Unidad de Hepatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
| | - María Jesús Borque-Iñurrita
- Unidad de Biología Molecular, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
| | - Francisca Molina-Jiménez
- Unidad de Biología Molecular, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
| | - Luisa García-Buey
- Unidad de Hepatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-ehd), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Ricardo Moreno-Otero
- Unidad de Hepatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-ehd), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Paloma Sanz-Cameno
- Unidad de Hepatología, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-ehd), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- * E-mail:
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Abstract
It has become increasingly clear that angiogenesis occurring during chronic wound healing and fibrogenesis provides a key contribution to disease progression and complications. The association of fibrogenesis and angiogenesis should be regarded as crucial in the modern evaluation of liver disease progression and in the search for therapeutic targets. Physiological hepatic angiogenesis occurs during liver regeneration, contributing to the formation of new functional sinusoids. Pathological angiogenesis in liver is characterized by intrahepatic vascular remodeling with capillarization of the sinusoids and development of intrahepatic shunts, which lead to increased hepatic resistance and decreased effective hepatocyte perfusion. The problem of angiogenesis in chronic hepatitis C and nonalcoholic fatty liver disease has not been fully resolved. This manuscript briefly describes pathogenesis of new blood vessel formation in chronic hepatitis and potential role of angiogenesis in disease progression.
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Abstract
BACKGROUND Angiogenic factors are involved in the physiopathology of several inflammatory diseases and they probably play a role in the pathogenesis of acute pancreatitis (AP). AIMS To investigate if angiogenic factors are elevated in patients with AP, their relationship with severity and clinical evolution of AP, and their use as prognosis markers of AP. METHODS A case (25)-control (30) study was carried out. Patients with AP were classified according to severity (using Ranson and Glasgow scores) and according to their clinical evolution (taking into account the development of complications during hospital stay). Platelet-derived growth factor (PDGFBB), angiopoietin-1, angiopoietin-2 (Ang-2), angiopoietin tyrosine-kinase receptor, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), VEGF tyrosine-kinase receptor 1, and VEGF tyrosine-kinase receptor 2 were determined at 12 hours and then at 5 days after hospitalization. RESULTS PDGFBB, Ang-2, angiopoietin tyrosine-kinase receptor, and HGF were significantly higher in cases (P<0.001), and in patients with unfavorable clinical evolution (P<0.001). PDGFBB and HGF were significantly higher in patients with severe AP (P<0.05). To predict unfavorable clinical evolution, PDGFBB, Ang-2, and HGF showed an area under receiver operating characteristic curve of 0.97. CONCLUSIONS PDGFBB and HGF are related to severity of AP. These factors along with Ang-2 are related to clinical evolution and are useful in predicting the development of several complications during hospital stay. Therefore, these angiogenic factors could be useful as prognosis markers of AP.
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13
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Vespasiani-Gentilucci U, Galati G, Mazzarelli C, D'Avola D, Spataro S, Gallo P, Rigon A, Pellicelli A, Dicuonzo G, Afeltra A, Picardi A. Angiogenic cytokines in patients undergoing antiviral treatment for chronic hepatitis C virus infection. J Interferon Cytokine Res 2011; 31:207-210. [PMID: 20874229 DOI: 10.1089/jir.2010.0040] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
During chronic liver disease (CLD), angiogenesis participates in the fibrogenic process. Herein, we aimed at verifying the on-treatment kinetics of serum vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) in hepatitis C virus (HCV) patients undergoing antiviral therapy. Forty-three HCV patients treated with pegylated-interferon/ribavirin and 26 controls were studied. Serum VEGF and Ang-2 were determined before treatment, at different time points during treatment, and at follow-up after treatment. Thirty and 13 patients were sustained virological responder (SVR) and No-SVR, respectively. Patients showed increased Ang-2 levels [504 (368-720) versus 449 (389-483) pg/mL, P < 0.05], and equivalent VEGF levels [271 (193-377) versus 274 (199-324) pg/mL, P = 0.6], with respect to controls. By univariate analysis, stage of fibrosis was associated with Ang-2 levels (odds ratio 4.25, P < 0.05). In SVR patients VEGF levels showed a progressive reduction (P < 0.05) but returned to pretherapy levels at follow-up, and Ang-2 levels showed an opposite progressive increase, being significantly reduced at follow-up (P < 0.01). No significant modifications in VEGF and Ang-2 levels were observed in No-SVR. We conclude that, in patients with HCV-CLD, Ang-2 serum levels are associated with fibrosis and reduced at follow-up in SVR patients. On-treatment, VEGF and Ang-2 serum levels undergo different-sided modifications only in SVR patients, possibly expressing the vascular remodeling occurring early after viral clearance.
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14
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Lim AKP, Patel N, Eckersley RJ, Cobbold JFL, Crossey MME, Cosgrove DO, Goldin RD, Thomas HC, Taylor-Robinson SD. Hepatic vein transit times of a microbubble agent in assessing response to antiviral treatment in patients with chronic hepatitis C. J Viral Hepat 2010; 17:778-83. [PMID: 20002308 DOI: 10.1111/j.1365-2893.2009.01234.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Microbubble measurement of hepatic vein transit times (HVTT) may have the potential to assess severity of hepatitis C virus (HCV)-related liver disease, where there is a shorter HVTT with more severe disease. We investigated the utility of this test as a marker of response to antiviral treatment. Thirty-seven patients with biopsy-proven HCV-related disease undergoing antiviral treatment were studied. All had baseline scans and then repeat scans 6 months after the end of treatment. HVTT using Levovist were obtained from the right and middle hepatic veins, and the shorter time was used for analysis. The aspartate aminotransferase to platelet ratio index (APRI) scores were calculated retrospectively. There were seven patients with mild hepatitis, 23 with moderate/severe hepatitis and seven with cirrhosis. The mean baseline HVTT in responders ± SE increased from 27.3 ± 2.29 s to 33.5 ± 2.8 s posttreatment (P = 0.01). In the 10 nonresponders, the HVTT remained the same; 43.3 ± 9 s baseline compared to 44 ± 7.8 s posttreatment (P = 0.84). This trend was also seen with the APRI score where in responders, the mean score decreased from 1.1 ± 0.2 to 0.74 ± 1 (P = 0.03) and in nonresponders, the score remained unchanged; 0.88 ± 0.2 compared to 0.84 ± 0.2 (P = 0.31). HVTT measurement lengthened, while APRI scores decreased in patients who responded to antiviral treatment while both remained the same, shortened (HVTT) or increased (APRI), respectively, in patients who were nonresponders. These results are encouraging and indicate that these tests could be potentially used as markers of response to treatment and could obviate the need for serial biopsies in antiviral future treatment studies.
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Affiliation(s)
- A K P Lim
- Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
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15
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Pinzani M, Macias-Barragan J. Update on the pathophysiology of liver fibrosis. Expert Rev Gastroenterol Hepatol 2010; 4:459-72. [PMID: 20678019 DOI: 10.1586/egh.10.47] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Fibrogenesis represents the main pathophysiological consequence of chronic liver disease and leads to life-threatening clinical consequences. The knowledge in this field has grown exponentially in the past 20 years and, currently, evaluation and treatment of liver fibrosis are central issues in hepatology. Classic mechanisms of liver fibrogenesis have been expanded and consolidated over the past few years. Concomitantly, novel mechanisms have been suggested and demonstrated. The aim of this article is to provide an update on these mechanisms with an attempt to integrate classic and novel pathways responsible for the evolution of the fibrogenic process and, potentially, for its regression.
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Affiliation(s)
- Massimo Pinzani
- Università degli Studi di Firenze, Florence, Italy; Dipartimento di Medicina Interna, Viale GB Morgagni, 85, 50134 Firenze, Italy.
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16
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Angiogenesis: from chronic liver inflammation to hepatocellular carcinoma. JOURNAL OF ONCOLOGY 2010; 2010:272170. [PMID: 20592752 PMCID: PMC2878677 DOI: 10.1155/2010/272170] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Revised: 02/24/2010] [Accepted: 03/16/2010] [Indexed: 02/06/2023]
Abstract
Recently, new information relating to the potential relevance of chronic hepatic inflammation to the development and progression of hepatocellular carcinoma (HCC) has been generated. Persistent hepatocellular injury alters the homeostatic balance within the liver; deregulation of the expression of factors involved in wound healing may lead to the evolution of dysplastic lesions into transformed nodules. Progression of such nodules depends directly on the development and organization of a vascular network, which provides the nutritional and oxygen requirements to an expanding nodular mass. Angiogenic stimulation promotes intense structural and functional changes in liver architecture and physiology, in particular, it facilitates transformation of dysplasia to nodular lesions with carcinogenic potential. HCC depends on the growth and spreading of vessels throughout the tumor. Because these vascular phenomena correlate with disease progression and prognosis, therapeutic strategies are being developed that focus on precluding vascular expansion in these tumors. Accordingly, an in-depth study of factors that promote and support pathological angiogenesis in chronic hepatic diseases may provide insights into methods of preventing the development of HCC and/or stimulating the regression of established HCC.
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17
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Talaat RM. Soluble angiogenesis factors in sera of Egyptian patients with hepatitis C virus infection: correlation with disease severity. Viral Immunol 2010; 23:151-157. [PMID: 20373995 DOI: 10.1089/vim.2009.0089] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hepatitis C virus (HCV) infection causes chronic hepatitis, which gradually progresses to liver cirrhosis and subsequently to hepatocellular carcinoma (HCC). Angiogenesis plays a major role in chronic inflammation and may have prognostic value in disease progression. This study was designed to evaluate vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and tumor necrosis factor-alpha (TNF-alpha) as prognostic factors of disease progression in Egyptian patients with different stages of HCV-related cirrhosis and HCC. VEGF, PDGF, and TNF-alpha were measured using enzyme-linked immunosorbent assay (ELISA) in 82 HCV-infected patients (20 mild, 20 moderate, and 20 severe cirrhosis patients, and 22 HCC patients), and 20 healthy controls. Our results showed comparable increases in VEGF and PDGF levels in those with increasing clinical stages of disease, with maximal production seen in HCC patients. A gradual elevation of TNF-alpha levels was seen also in HCV-infected patients at different stages of disease and HCC. A statistically significantly positive correlation between serum levels of VEGF, PDGF, and TNF-alpha, and grade of disease was recorded. Thus assessment of these parameters in those with different stages of disease may be helpful in choosing the best treatment strategy, and indicate that anti-angiogenic therapy may be useful.
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Affiliation(s)
- Roba M Talaat
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), Menofia University, Sadat City, Egypt.
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18
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Paternostro C, David E, Novo E, Parola M. Hypoxia, angiogenesis and liver fibrogenesis in the progression of chronic liver diseases. World J Gastroenterol 2010; 16:281-8. [PMID: 20082471 PMCID: PMC2807946 DOI: 10.3748/wjg.v16.i3.281] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [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
Angiogenesis is a dynamic, hypoxia-stimulated and growth factor-dependent process, and is currently referred to as the formation of new vessels from pre-existing blood vessels. Experimental and clinical studies have unequivocally reported that hepatic angiogenesis, irrespective of aetiology, occurs in conditions of chronic liver diseases (CLDs) characterized by perpetuation of cell injury and death, inflammatory response and progressive fibrogenesis. Angiogenesis and related changes in liver vascular architecture, that in turn concur to increase vascular resistance and portal hypertension and to decrease parenchymal perfusion, have been proposed to favour fibrogenic progression of the disease towards the end-point of cirrhosis. Moreover, hepatic angiogenesis has also been proposed to modulate the genesis of portal-systemic shunts and increase splanchnic blood flow, thus potentially affecting complications of cirrhosis. Hepatic angiogenesis is also crucial for the growth and progression of hepatocellular carcinoma. Recent literature has identified a number of cellular and molecular mechanisms governing the cross-talk between angiogenesis and fibrogenesis, with a specific emphasis on the crucial role of hypoxic conditions and hepatic stellate cells, particularly when activated to the myofibroblast-like pro-fibrogenic phenotype. Experimental anti-angiogenic therapy has been proven to be effective in limiting the progression of CLDs in animal models. From a clinical point of view, anti-angiogenic therapy is currently emerging as a new pharmacologic intervention in patients with advanced fibrosis and cirrhosis.
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19
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VEGF-A/HGF induce Prox-1 expression in the chick embryo chorioallantoic membrane lymphatic vasculature. Clin Exp Med 2009; 10:169-72. [DOI: 10.1007/s10238-009-0085-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2009] [Accepted: 11/23/2009] [Indexed: 10/20/2022]
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20
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Kitade M, Yoshiji H, Noguchi R, Ikenaka Y, Kaji K, Shirai Y, Yamazaki M, Uemura M, Yamao J, Fujimoto M, Mitoro A, Toyohara M, Sawai M, Yoshida M, Morioka C, Tsujimoto T, Kawaratani H, Fukui H. Crosstalk between angiogenesis, cytokeratin-18, and insulin resistance in the progression of non-alcoholic steatohepatitis. World J Gastroenterol 2009; 15:5193-9. [PMID: 19891019 PMCID: PMC2773899 DOI: 10.3748/wjg.15.5193] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [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
AIM: To elucidate the possible crosstalk between angiogenesis, cytokeratin-18 (CK-18), and insulin resistance (IR) especially in patients with non-alcoholic steatohepatitis (NASH).
METHODS: Twenty-eight patients with NASH and 11 with simple fatty liver disease (FL) were enrolled in this study and underwent clinicopathological examination. The measures of angiogenesis, CK-18, and IR employed were CD34-immunopositive vessels, CK-18-immunopositive cells, and homeostasis model assessment of IR (HOMA-IR), respectively. The correlations of these factors with NASH were elucidated.
RESULTS: Significant development of hepatic neovascularization was observed only in NASH, whereas almost no neovascularization could be observed in FL and healthy liver. The degree of angiogenesis was almost parallel to liver fibrosis development, and both parameters were positively correlated. Similarly, CK-18 expression and HOMA-R were significantly increased in NASH as compared with FL and healthy liver. Furthermore, CK-18 and HOMA-IR were also positively correlated with the degree of neovascularization.
CONCLUSION: These results indicate that the crosstalk between angiogenesis, CK-18, and IR may play an important role in the onset and progression of NASH.
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21
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Gabriel A, Kukla M, Wilk M, Liszka Ł, Petelenz M, Musialik J. Angiogenesis in chronic hepatitis C is associated with inflammatory activity grade and fibrosis stage. Pathol Res Pract 2009; 205:758-64. [PMID: 19592175 DOI: 10.1016/j.prp.2009.06.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2008] [Revised: 03/20/2009] [Accepted: 06/19/2009] [Indexed: 02/06/2023]
Abstract
Data regarding the assessment of angiogenesis in liver tissue in chronic hepatitis C (CHC) are rare. The study was performed to explain the association between the histopathological features and the number of new blood vessels in lobules and portal tracts in CHC. The second aim of the study was to define the localization of sprouting and pattern of formation of new vessels by estimating CD 34 antigen expression in the liver. The study involved 74 patients with CHC, infected with viral genotype 1b before antiviral therapy. The number of new-formatted blood vessels was positively associated with fibrosis stage and inflammatory activity grade in the liver biopsy from CHC patients. The relationship was evident in the portal tract, fibrous septa and periportal zones of lobules. The results suggest that inflammatory hepatocyte injury may promote neo-angiogenesis.
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Affiliation(s)
- Andrzej Gabriel
- Department of Pathomorphology in Zabrze, Medical University of Silesia, Zabrze, Poland.
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22
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Mejias M, Garcia-Pras E, Tiani C, Miquel R, Bosch J, Fernandez M. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology 2009; 49:1245-56. [PMID: 19137587 DOI: 10.1002/hep.22758] [Citation(s) in RCA: 247] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
UNLABELLED Portal hypertension, the most important complication in patients with cirrhosis of the liver, is a serious and life-threatening disease for which there are few therapeutic options. Because angiogenesis is a pathological hallmark of portal hypertension, the goal of this study was to determine the effects of sorafenib-a potent inhibitor of proangiogenic vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-beta), and Raf kinases-on splanchnic, intrahepatic, systemic, and portosystemic collateral circulations in two different experimental models of portal hypertension: rats with prehepatic portal hypertension induced by partial portal vein ligation and rats with intrahepatic portal hypertension and secondary biliary cirrhosis induced by bile duct ligation. Such a comprehensive approach is necessary for any translational research directed toward defining the efficacy and potential clinical application of new therapeutic agents. Sorafenib administered orally once a day for 2 weeks in experimental models of portal hypertension and cirrhosis effectively inhibited VEGF, PDGF, and Raf signaling pathways, and produced several protective effects by inducing an approximately 80% decrease in splanchnic neovascularization and a marked attenuation of hyperdynamic splanchnic and systemic circulations, as well as a significant 18% decrease in the extent of portosystemic collaterals. In cirrhotic rats, sorafenib treatment also resulted in a 25% reduction in portal pressure, as well as a remarkable improvement in liver damage and intrahepatic fibrosis, inflammation, and angiogenesis. Notably, beneficial effects of sorafenib against tissue damage and inflammation were also observed in splanchnic organs. CONCLUSION Taking into account the limitations of translating animal study results into humans, we believe that our findings will stimulate consideration of sorafenib as an effective therapeutic agent in patients suffering from advanced portal hypertension.
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Affiliation(s)
- Marc Mejias
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Ciberehd, Barcelona, Spain
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23
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Chaparro M, González Moreno L, Trapero-Marugán M, Medina J, Moreno-Otero R. Review article: pharmacological therapy for hepatocellular carcinoma with sorafenib and other oral agents. Aliment Pharmacol Ther 2008; 28:1269-77. [PMID: 18808443 DOI: 10.1111/j.1365-2036.2008.03857.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Unresectable disease patients have median survival of few months. There is a substantial need for novel treatments for patients with advanced HCC. AIM To provide an update review of mechanism of hepatocarcinigenesis and systemic therapies for HCC and the relevant role of Sorafenib in patients with advanced disease. METHODS A Medline search was performed to identify pertinent original research and review articles. Selected references in these articles were also evaluated. RESULTS Systemic chemotherapy for HCC has been quite ineffective. Preclinical studies demonstrated that Raf/MAPK-ERK kinase (MEK)/Extracellular signal regulated kinase (ERK) pathway has a role in HCC. HCC tumours are highly vascularized and vascular endothelial growth factor (VEGF) augments HCC development and metastasis. Sorafenib blocks tumour cell proliferation by targeting Raf/MEK/ERK signalling and exerts an antiangiogenic effect by targeting VEGF receptors-2/3 and platelet derived growth factor receptor beta tyrosine kinases. CONCLUSIONS Currently available therapies are not effective for patients with advanced HCC. Sorafenib has demonstrated for the first time to prolong survival in patients with advanced HCC, and it is the new reference standard for systemic treatment in these patients.
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Affiliation(s)
- M Chaparro
- Department of Hepatology and Ciberehd, University Hospital La Princesa, Universidad Autónoma de Madrid, Madrid, Spain
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24
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Maeda MDFY, Silva CD, Harima LS, Silva LFFD, Ctenas B, Alves VAF. [Vascularization in hepatic cirrhosis: an immunohistochemical study on necropsies]. ARQUIVOS DE GASTROENTEROLOGIA 2008; 45:38-45. [PMID: 18425227 DOI: 10.1590/s0004-28032008000100008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2007] [Accepted: 08/29/2007] [Indexed: 11/22/2022]
Abstract
BACKGROUND Fibrosis has been the most cited variable in cirrhosis, but major alterations in hepatic vascularization have been pointed as basic elements in the physiopathology of the illness and its complications as portal hypertension, hepatic failure and hepatocellular carcinoma. METHODS The present study aims at assessing microvascular density in 35 cases of necropsies of cirrhotic patients by immunohistochemical detection of endothelial marker CD34, comparing semi-quantification with morphometric quantitative method, also searching for a possible relation of vascular alterations with the main causal agents, injury patterns and major clinical complications. RESULTS A significant association was detected between semi-quantitative and quantitative approach of microvessel density in parenchyma, but not in septa. No significant association was detected between neovascularization and any specific clinical complication of cirrhosis. Under our standpoint, the main achievement of the present study was the demonstration that the vascular neoformation in hepatic parenchyma is significantly higher in cirrhosis associated with chronic hepatitis than in cirrhosis resulting from steatohepatitis. CONCLUSION These findings require further clinical studies to assess the hypothesis that the rearrangement of liver microcirculation through the detection of CD34 might be relevant in prognostic assessment of cirrhotic patients.
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Affiliation(s)
- Mariane de Fátima Yukie Maeda
- Laboratório de Investigação Médica em Patologia Hepática, Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP.
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25
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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: 139] [Impact Index Per Article: 7.7] [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.
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Affiliation(s)
- Maurizio Parola
- Dipartimento di Medicina e Oncologia Sperimentale, University of Torino, Corso Raffaello 30, 10125 Torino, Italy.
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26
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Huang XX, McCaughan GW, Shackel NA, Gorrell MD. Up-regulation of proproliferative genes and the ligand/receptor pair placental growth factor and vascular endothelial growth factor receptor 1 in hepatitis C cirrhosis. Liver Int 2007; 27:960-968. [PMID: 17696935 DOI: 10.1111/j.1478-3231.2007.01542.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIMS Cirrhosis can lead to hepatocellular carcinoma (HCC). Non-diseased liver and hepatitis C virus (HCV)-associated cirrhosis with or without HCC were compared. METHOD Proliferation pathway genes, immune response genes and oncogenes were analysed by a quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and immunostaining. RESULTS Real-time RT-PCR showed up-regulation of genes in HCV cirrhosis including the proliferation-associated genes bone morphogenetic protein 3 (BMP3), placental growth factor 3 (PGF3), vascular endothelial growth factor receptor 1 (VEGFR1) and soluble VEGFR1, the oncogene FYN, and the immune response-associated genes toll-like receptor 9 (TLR9) and natural killer cell transcript 4 (NK4). Expressions of TLR2 and the oncogenes B-cell CLL/lymphoma 9 (BCL9) and PIM2 were decreased in HCV cirrhosis. In addition, PIM2 and TLR2 were increased in HCV cirrhosis with HCC compared with HCV cirrhosis. The ligand/receptor pair PGF and VEGFR1 was intensely expressed by the portal tract vascular endothelium. VEGFR1 was expressed in reactive biliary epithelial structures in fibrotic septum and in some stellate cells and macrophages. CONCLUSION PGF and VEGFR1 may have an important role in the pathogenesis of the neovascular response in cirrhosis.
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MESH Headings
- Adolescent
- Adult
- Bone Morphogenetic Proteins/analysis
- Carcinoma, Hepatocellular/chemistry
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Cell Proliferation
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Female
- Gene Expression Regulation, Neoplastic
- Hepatitis C/complications
- Hepatitis C/genetics
- Hepatitis C/metabolism
- Hepatitis C/pathology
- Hepatocyte Growth Factor/analysis
- Humans
- Liver/chemistry
- Liver/pathology
- Liver/virology
- Liver Cirrhosis/complications
- Liver Cirrhosis/genetics
- Liver Cirrhosis/metabolism
- Liver Cirrhosis/pathology
- Liver Cirrhosis/virology
- Liver Neoplasms/chemistry
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Male
- Middle Aged
- Neoplasm Proteins/analysis
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/virology
- Placenta Growth Factor
- Pregnancy Proteins/analysis
- Pregnancy Proteins/genetics
- Protein Serine-Threonine Kinases/analysis
- Proto-Oncogene Proteins/analysis
- Proto-Oncogene Proteins c-fyn/analysis
- RNA, Messenger/analysis
- Toll-Like Receptors/analysis
- Transcription Factors
- Vascular Endothelial Growth Factor Receptor-1/genetics
- Vascular Endothelial Growth Factor Receptor-1/metabolism
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Affiliation(s)
- Xiao X Huang
- A W Morrow Gastroenterology and Liver Centre at Royal Prince Alfred Hospital, NSW, Australia
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27
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Novo E, Cannito S, Zamara E, Valfrè di Bonzo L, Caligiuri A, Cravanzola C, Compagnone A, Colombatto S, Marra F, Pinzani M, Parola M. Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. THE AMERICAN JOURNAL OF PATHOLOGY 2007; 170:1942-53. [PMID: 17525262 PMCID: PMC1899450 DOI: 10.2353/ajpath.2007.060887] [Citation(s) in RCA: 167] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Pathological angiogenesis is associated with the fibrogenic progression of chronic liver diseases. Experimental data suggest that hypoxia and vascular endothelial growth factor (VEGF) may stimulate proliferation and synthesis of type I collagen in activated, myofibroblast-like rat hepatic stellate cells (HSC/MFs). In this study, we investigated whether hypoxia, recombinant VEGF, or angiopoietin 1 (Ang-1) may affect other crucial profibrogenic features. In human HSC/MFs, which constitutively express VEGF receptor-1 and -2 (VEGFR-1, VEGFR-2) and the Ang-1 receptor Tie-2, exposure to hypoxia, VEGF, or Ang-1 resulted in a Ras/Erk-dependent stimulation of chemokinesis and chemotaxis. Migration of human HSC/MFs under hypoxic conditions involved up-regulation of VEGF-A, Ang-1, and related receptors and was mainly dependent on VEGFR-2 (Flk-1). In specimens from either cirrhotic rat livers or from patients with hepatitis C virus-related cirrhosis, HSC/MFs expressed proangiogenic factors and related receptors in areas of active fibrogenesis (ie, at the leading or lateral edge of developing incomplete fibrotic septa). Data presented herein suggest that VEGF and Ang-1 may contribute to fibrogenesis by acting as hypoxia-inducible, autocrine, and paracrine factors able to recruit myofibroblast-like cells. Moreover, HSC/MFs, in addition to their established profibrogenic role, may also contribute to neoangiogenesis during chronic hepatic wound healing.
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Affiliation(s)
- Erica Novo
- Università degli Studi di Torino, Dipartimento Medicina e Oncologia Sperimentale, Corso Raffaello 30, 10125 Turin, Italy
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28
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Teixeira TF, da Silva TC, Fukumasu H, de Lima CE, Lúcia Zaidan Dagli M, Guerra JL. Histological alterations in the livers of Cx43-deficient mice submitted to a cholestasis model. Life Sci 2007; 81:380-4. [PMID: 17603082 DOI: 10.1016/j.lfs.2007.05.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2006] [Revised: 03/14/2007] [Accepted: 05/29/2007] [Indexed: 10/23/2022]
Abstract
Gap junction intercellular communication capacity and connexin expression are reportedly involved in cell proliferation. To understand the participation of connexins in biliary duct hyperplasia, a cholestasis model was applied to mice with heterologous deletion of Gja 1, the connexin 43 (Cx43) gene. Heterozygous (Cx43+/-) knockout (KO) and wild-type mice (Cx43+/+) (WT) were submitted to bile duct ligation and euthanized at different time points (48 h, 7 days, and 14 days) after surgery. After euthanasia, the macroscopic and microscopic liver alterations were examined. A histomorphometric study of the livers was performed. For this purpose, a grid containing 100 points was applied to each liver section. The volumetric fraction of bile ducts, hepatocytes, arterioles, and terminal hepatic vein were quantified. Cell proliferation was also quantified by western blot PCNA. High mortality was observed in both genotypes. The heterologous deletion of Cx43 did not affect the biliary duct hyperplasia or most of the other parameters analyzed; however, the Cx43-deficient mice showed decrease in hepatic vein angiogenesis in comparison with the wild-type mice 48 h after surgery. In conclusion, our results indicate that the Cx43 gene heterologous deletion does not affect the biliary duct hyperplasia; on the other hand, connexin 43 deficiencies do affect the hepatic vein angiogenesis, although other studies to understand the details of this influence will be necessary.
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Affiliation(s)
- Tarso Felipe Teixeira
- Laboratory of Experimental Oncology, Department of Pathology, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, Brazil
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Kato K, Takada T, Fukusato T. Expression of vascular endothelial-cadherin in human hepatocellular carcinoma tissues. Hepatol Res 2007; 37:444-53. [PMID: 17437529 DOI: 10.1111/j.1872-034x.2007.00051.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Angiogenesis is important in tumor growth and progression to metastasis. Vascular endothelial (VE)-cadherin is an endothelial cell-specific cadherin required for angiogenesis, but its expression in hepatocellular carcinoma (HCC) tissues has not been examined. METHODS Expression of VE-cadherin was analyzed in 31 HCC frozen tissue specimens by immunohistochemical and immunoelectron microscopic procedures. In addition, the association of its expression with clinicopathological parameters was investigated to determine the possible diagnostic or predictive value of VE-cadherin expression in neoplastic and non-neoplastic liver lesions. RESULTS Immunoreactive VE-cadherin expression was faint or barely detectable on sinusoidal endothelial cells of normal liver but was evident on sinusoidal or capillary endothelium of chronic hepatitis, cirrhosis, and HCC tissues. VE-cadherin expression was more intense on capillary endothelium of HCC tissues in 26 (84%) of 31 patients than on sinusoidal endothelium of surrounding non-tumorous liver tissues with chronic liver diseases. The intensity or intracapillary extent of positive stain for VE-cadherin on capillary endothelium of HCC tissues was significantly associated with tumor size, capsular invasion and tumor cell differentiation in HCC. CONCLUSIONS Intense VE-cadherin expression was evident in capillary endothelium of HCC tissues, giving the first indication of association with clinicopathological features of HCC patients.
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Affiliation(s)
- Kenichirou Kato
- Departments of Surgery and Pathology, Teikyo University School of Medicine, Tokyo, Japan
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Michaelis M, Michaelis R, Suhan T, Schmidt H, Mohamed A, Doerr HW, Cinatl J. Ribavirin inhibits angiogenesis by tetrahydrobiopterin depletion. FASEB J 2007; 21:81-7. [PMID: 17135367 DOI: 10.1096/fj.06-6779com] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ribavirin is a broad-spectrum antiviral drug that is used to treat hepatitis C virus (HCV)-infected patients. The virological response after ribavirin treatment appears to be insufficient to fully explain ribavirin-induced beneficial effects. Angiogenesis plays a pathogenic role in HCV-induced liver damage. Here, we investigated the influence of therapeutic ribavirin concentrations on angiogenesis. Ribavirin inhibited endothelial cell tube formation in vitro and vessel formation in the chick chorioallantoic membrane assay in vivo. Ribavirin inhibits inosine monophosphate dehydrogenase, which causes depletion of cellular GTP and in turn reduction of cellular tetrahydrobiopterin levels. The availability of tetrahydrobiopterin limits NO production by endothelial NO synthase. Ribavirin reduced levels of tetrahydrobiopterin (as revealed by HPLC), NO (as revealed by electron spin resonance spectroscopy), and cGMP (as revealed by RIA) in endothelial cells. Addition of tetrahydrobiopterin or NO prevented ribavirin-induced tube formation inhibition. In conclusion, angiogenesis inhibition by ribavirin has not been described before. This inhibition may contribute to ribavirin-induced pharmacological effects including adverse events.
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Affiliation(s)
- Martin Michaelis
- Institut für Medizinische Virologie, Klinikum der Johann Wolfgang Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany
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Lalor PF, Lai WK, Curbishley SM, Shetty S, Adams DH. Human hepatic sinusoidal endothelial cells can be distinguished by expression of phenotypic markers related to their specialised functions in vivo. World J Gastroenterol 2006; 12:5429-39. [PMID: 17006978 PMCID: PMC4088223 DOI: 10.3748/wjg.v12.i34.5429] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2006] [Revised: 05/28/2006] [Accepted: 06/14/2006] [Indexed: 02/06/2023] Open
Abstract
The hepatic sinusoids are lined by a unique population of hepatic sinusoidal endothelial cells (HSEC), which is one of the first hepatic cell populations to come into contact with blood components. However, HSEC are not simply barrier cells that restrict the access of blood-borne compounds to the parenchyma. They are functionally specialised endothelial cells that have complex roles, including not only receptor-mediated clearance of endotoxin, bacteria and other compounds, but also the regulation of inflammation, leukocyte recruitment and host immune responses to pathogens. Thus understanding the differentiation and function of HSEC is critical for the elucidation of liver biology and pathophysiology. This article reviews methods for isolating and studying human hepatic endothelial cell populations using in vitro models. We also discuss the expression and functions of phenotypic markers, such as the presence of fenestrations and expression of VAP-1, Stabilin-1, L-SIGN, which can be used to identify sinusoidal endothelium and to permit discrimination from vascular and lymphatic endothelial cells.
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MESH Headings
- Amine Oxidase (Copper-Containing)/genetics
- Amine Oxidase (Copper-Containing)/metabolism
- Biomarkers/metabolism
- Cell Adhesion Molecules/genetics
- Cell Adhesion Molecules/metabolism
- Cell Adhesion Molecules, Neuronal/genetics
- Cell Adhesion Molecules, Neuronal/metabolism
- Cells, Cultured
- Endothelial Cells/metabolism
- Endothelium, Lymphatic/cytology
- Endothelium, Vascular/cytology
- Gene Expression Regulation/genetics
- Humans
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Liver/blood supply
- Liver/cytology
- Liver/metabolism
- Liver Circulation
- Phenotype
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Receptors, Lymphocyte Homing/genetics
- Receptors, Lymphocyte Homing/metabolism
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Affiliation(s)
- P F Lalor
- Liver Research Group, Institute of Biomedical Research, Division of Medical Science, University of Birmingham, Birmingham B15 2TT, United Kingdom.
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Andrade RJ, González FJ, Vázquez L, Cilvetti A, Camargo R, García-Cortés M, Martos-VanDussen JV, Rosón P, Lucena MI, Clavijo E. Vascular Ophthalmological Side Effects Associated with Antiviral Therapy for Chronic Hepatitis C are Related to Vascular Endothelial Growth Factor Levels. Antivir Ther 2006. [DOI: 10.1177/135965350601100403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
We have screened for the incidence of vascular ophthalmological side effects (VOSE) in chronic hepatitis C (CHC) patients undergoing pegylated interferon (peg-IFN) plus ribavirin (RBV) therapy and sought evidence for angiogenesis activation. Thirty-four CHC patients were prospectively evaluated (18 patients with 180 μg/week of peg-IFN-α2a plus 800 mg/day of RBV and 16 with 1.5μg/kg/week of peg-IFN-α2b plus 800–1,200 mg/day of RBV). Complete ophthalmological evaluation and serum vascular endothelial growth factor (VEGF) levels were assessed before and at the end of therapy. Thirteen patients (38.2%) developed VOSE, eight (23.5%) featured subconjunctival haemorrhage, and five (14.7%) had evidence of retinopathy – all were unrelated to age, sex, genotype, the type of antiviral schedule used and response to therapy. At the end of treatment, the VOSE group had significantly higher serum VEGF levels than the group of patients without detectable side effects (median 281 [range 106–386] vs 117 [83–225] pg/ml, P=0.05). These differences increased when VEGF values were corrected by platelet count. In the VOSE group, baseline VEGF and VEGF/platelet values were also significantly higher (164 [55–260] vs 64 [21–172] pg/ml, P=0.046; and 0.920 [0.217–1.543] vs 0.320 [0.100–0.661] pg/106 platelets, P=0.024, respectively]. In a multivariate model VEGF/platelet values at end of treatment and hepatic fibrosis stage were the only predictors of VOSE development. In 3 out of 13 patients visual acuity was affected and 2 had residual lesions in the follow-up. In this exploratory study, antiviral therapy of CHC frequently induces VOSE, apparently through an activation of angiogenesis.
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Affiliation(s)
- Raúl J Andrade
- Liver Unit, University Hospital and School of Medicine, Málaga, Spain
| | - F Jesús González
- Oncology Unit, University Hospital and School of Medicine, Málaga, Spain
- Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, Granada, Spain
| | - Luis Vázquez
- Liver Unit, University Hospital and School of Medicine, Málaga, Spain
| | - Angel Cilvetti
- Ophthalmology Unit, University Hospital and School of Medicine, Málaga, Spain
| | - Raquel Camargo
- Liver Unit, University Hospital and School of Medicine, Málaga, Spain
| | | | | | - Pedro Rosón
- Liver Unit, University Hospital and School of Medicine, Málaga, Spain
| | - M Isabel Lucena
- Clinical Pharmacology Services, ‘Virgen de la Victoria’ University Hospital and School of Medicine, Málaga Spain
| | - Encarnaciòn Clavijo
- Microbiology Unit, ‘Virgen de la Victoria’ University Hospital and School of Medicine, Málaga Spain
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Salcedo X, Medina J, Sanz-Cameno P, García-Buey L, Martín-Vilchez S, Borque MJ, López-Cabrera M, Moreno-Otero R. The potential of angiogenesis soluble markers in chronic hepatitis C. Hepatology 2005; 42:696-701. [PMID: 16104024 DOI: 10.1002/hep.20828] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Angiogenesis, the formation of new vessels, has been reported to play a significant pathogenic role in liver damage-associated hepatitis C virus infection. Most of our current knowledge derives from immunohistochemical studies of hepatic biopsy samples obtained from chronic hepatitis C (CHC) patients. We evaluated whether CHC is associated with elevated serum levels of angiogenesis markers and whether these are modulated by therapy. Vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), and soluble Tie-2 (sTie-2) were determined in the serum of 36 CHC patients, before and after receiving antiviral combination therapy with pegylated interferon alpha-2b plus ribavirin, and in 15 healthy controls. CHC patients showed elevated baseline VEGF and Ang-2 levels. After treatment, both factors were decreased, whereas antiangiogenic sTie-2 was increased, indicating a shift toward an "anti-angiogenic" profile of serum markers in CHC patients. In conclusion, this suggests that serum VEGF, Ang-2, and sTie-2 levels could be useful as noninvasive, mechanistically based markers of response to therapy and disease progression in CHC.
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Affiliation(s)
- Xamila Salcedo
- Liver and Molecular Biology Units, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Spain
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Salcedo X, Medina J, Sanz-Cameno P, García-Buey L, Martín-Vilchez S, Moreno-Otero R. Review article: angiogenesis soluble factors as liver disease markers. Aliment Pharmacol Ther 2005; 22:23-30. [PMID: 15963076 DOI: 10.1111/j.1365-2036.2005.02532.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Angiogenesis is the formation of new blood vessels from pre-existing ones; it has been studied at the molecular level in different pathologies and is currently considered a promising novel therapeutic target in cancer. Recently, the use of angiogenesis soluble factors as markers of tumour growth has been investigated. The knowledge gained has led to test their use as therapeutic agents. Additionally, angiogenesis soluble factors could be used for the follow-up of pathologies that currently require monitoring with invasive techniques, like chronic viral hepatitis or renal and haematological diseases. The different factors have been described in multiple studies. In some cases, such as hepatocellular carcinoma, a potential use as prognostic markers has been suggested.
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Affiliation(s)
- X Salcedo
- Liver Unit, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Spain
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35
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Medina J, Sanz-Cameno P, García-Buey L, Martín-Vílchez S, López-Cabrera M, Moreno-Otero R. Evidence of angiogenesis in primary biliary cirrhosis: an immunohistochemical descriptive study. J Hepatol 2005; 42:124-31. [PMID: 15629517 DOI: 10.1016/j.jhep.2004.09.024] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2004] [Revised: 09/08/2004] [Accepted: 09/17/2004] [Indexed: 01/01/2023]
Abstract
BACKGROUND/AIMS The intrahepatic inflammatory process occurring during primary biliary cirrhosis contributes to bile duct destruction, but the cellular and molecular pathways involved are largely unknown. Furthermore, additional pathogenetic mechanisms may exist. We aimed at evaluating the cellular infiltrate phenotype; the expression of lymphocyte activation, antigen recognition and cell-adhesion molecules; the occurrence of hepatic angiogenesis and the molecules involved. METHODS Immunohistochemical investigations were performed in frozen liver biopsy sections from primary biliary cirrhosis patients. RESULTS CD8+ and CD69+ T cells were predominant in inflammatory infiltrates around damaged cholangiocytes; beta2-microglobulin conformational epitope and intercellular adhesion molecule-1 expression were enhanced in bile ducts and hepatocytes. Inflamed portal areas showed vascular cell adhesion molecule-1 up-regulation; formation of tubule-like structures (neovessels) by endothelial cells expressing vascular endothelial-cadherin and CD-31; vascular endothelial growth factor expression in surrounding sinusoidal endothelial cells; and enhanced expression of angiopoietins 1 and 2, their receptor Tie-2 and endoglin, suggesting their involvement in new vascular structure formation. CONCLUSIONS The inflammatory infiltrate in primary biliary cirrhosis shows an increased reactivity for lymphocyte activation, antigen recognition and cell- and vascular-adhesion molecules. Additionally, intrahepatic angiogenesis occurs, involving vascular endothelial growth factor, angiopoietins 1 and 2, Tie-2 and endoglin in neovessel formation.
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Affiliation(s)
- Jesús Medina
- Unidad de Hepatología (planta 3), Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Diego de León 62, E-28006 Madrid, Spain
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Abstract
Intrahepatic hypoxia may occur during the inflammatory and fibrotic processes that characterize several chronic liver diseases of viral and autoimmune origin. As a consequence, new vascular structures are formed to provide oxygen and nutrients. Angiogenesis involves a tightly regulated network of cellular and molecular mechanisms that result in the formation of functional vessels. Of particular importance are growth factors, molecules involved in matrix remodeling and cell migration, and vessel maturation-related factors. In recent years, a number of studies have examined the expression and function of many pro- and antiangiogenic molecules in the setting of nontumoral chronic liver diseases and liver regeneration. This review examines the potential pathogenetic role of angiogenesis in the context of viral hepatitis, cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, and alcoholic liver disease. The future perspectives for research in this field are outlined.
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Affiliation(s)
- Jesús Medina
- Liver Unit, Hospital de la Princesa, Universidad Autónoma de Madrid, Spain
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