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Setyawati DR, Sekaringtyas FC, Pratiwi RD, Rosyidah A, Azhar R, Gustini N, Syahputra G, Rosidah I, Mardliyati E, Tarwadi, El Muttaqien S. Recent updates in applications of nanomedicine for the treatment of hepatic fibrosis. BEILSTEIN JOURNAL OF NANOTECHNOLOGY 2024; 15:1105-1116. [PMID: 39188757 PMCID: PMC11346304 DOI: 10.3762/bjnano.15.89] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 08/07/2024] [Indexed: 08/28/2024]
Abstract
Over recent decades, nanomedicine has played an important role in the enhancement of therapeutic outcomes compared to those of conventional therapy. At the same time, nanoparticle drug delivery systems offer a significant reduction in side effects of treatments by lowering the off-target biodistribution of the active pharmaceutical ingredients. Cancer nanomedicine represents the most extensively studied nanotechnology application in the field of pharmaceutics and pharmacology since the first nanodrug for cancer treatment, liposomal doxorubicin (Doxil®), has been approved by the FDA. The advancement of cancer nanomedicine and its enormous technological success also included various other target diseases, including hepatic fibrosis. This confirms the versatility of nanomedicine for improving therapeutic activity. In this review, we summarize recent updates of nanomedicine platforms for improving therapeutic efficacy regarding liver fibrosis. We first emphasize the challenges of conventional drugs for penetrating the biological barriers of the liver. After that, we highlight design principles of nanocarriers for achieving improved drug delivery of antifibrosis drugs through passive and active targeting strategies.
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Affiliation(s)
- Damai Ria Setyawati
- Research Center for Vaccine and Drugs, National Research and Innovation Agency (BRIN), LAPTIAB 1, PUSPIPTEK, Tangerang Selatan 15314, Indonesia
| | - Fransiska Christydira Sekaringtyas
- Research Center for Vaccine and Drugs, National Research and Innovation Agency (BRIN), LAPTIAB 1, PUSPIPTEK, Tangerang Selatan 15314, Indonesia
| | - Riyona Desvy Pratiwi
- Research Center for Vaccine and Drugs, National Research and Innovation Agency (BRIN), LAPTIAB 1, PUSPIPTEK, Tangerang Selatan 15314, Indonesia
| | - A’liyatur Rosyidah
- Research Center for Vaccine and Drugs, National Research and Innovation Agency (BRIN), LAPTIAB 1, PUSPIPTEK, Tangerang Selatan 15314, Indonesia
| | - Rohimmahtunnissa Azhar
- Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), LAPTIAB 1, PUSPIPTEK, Tangerang Selatan 15314, Indonesia
| | - Nunik Gustini
- Research Center for Vaccine and Drugs, National Research and Innovation Agency (BRIN), LAPTIAB 1, PUSPIPTEK, Tangerang Selatan 15314, Indonesia
| | - Gita Syahputra
- Research Center for Vaccine and Drugs, National Research and Innovation Agency (BRIN), LAPTIAB 1, PUSPIPTEK, Tangerang Selatan 15314, Indonesia
| | - Idah Rosidah
- Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), LAPTIAB 1, PUSPIPTEK, Tangerang Selatan 15314, Indonesia
| | - Etik Mardliyati
- Research Center for Vaccine and Drugs, National Research and Innovation Agency (BRIN), LAPTIAB 1, PUSPIPTEK, Tangerang Selatan 15314, Indonesia
| | - Tarwadi
- Research Center for Vaccine and Drugs, National Research and Innovation Agency (BRIN), LAPTIAB 1, PUSPIPTEK, Tangerang Selatan 15314, Indonesia
| | - Sjaikhurrizal El Muttaqien
- Research Center for Vaccine and Drugs, National Research and Innovation Agency (BRIN), LAPTIAB 1, PUSPIPTEK, Tangerang Selatan 15314, Indonesia
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Du T, Yu B, Luo W. Liver cirrhosis reversal and recompensation: Existing evidence and future prospects. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2024; 32:320-326. [DOI: 10.11569/wcjd.v32.i5.320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
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Dong Y, Wang X, Xu L, Li X, Dai H, Mao X, Chu Y, Yuan X, Liu H. Development of a Chimeric Protein BiPPB-mIFNγ-tTβRII for Improving the Anti-Fibrotic Activity in Vivo by Targeting Fibrotic Liver and Dual Inhibiting the TGF-β1/Smad Signaling Pathway. Protein J 2023; 42:753-765. [PMID: 37690089 DOI: 10.1007/s10930-023-10147-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/02/2023] [Indexed: 09/12/2023]
Abstract
Excessive production of transforming growth factor β1 (TGF-β1) in activated hepatic stellate cells (aHSCs) promotes liver fibrosis by activating the TGF-β1/Smad signaling pathway. Thus, specifically inhibiting the pro-fibrotic activity of TGF-β1 in aHSCs is an ideal strategy for treating liver fibrosis. Overexpression of platelet-derived growth factor β receptor (PDGFβR) has been demonstrated on the surface of aHSCs relative to normal cells in liver fibrosis. Interferon-gamma peptidomimetic (mIFNγ) and truncated TGF-β receptor type II (tTβRII) inhibit the TGF-β1/Smad signaling pathway by different mechanisms. In this study, we designed a chimeric protein by the conjugation of (1) mIFNγ and tTβRII coupled via plasma protease-cleavable linker sequences (FNPKTP) to (2) PDGFβR-recognizing peptide (BiPPB), namely BiPPB-mIFNγ-tTβRII. This novel protein BiPPB-mIFNγ-tTβRII was effectively prepared using Escherichia coli expression system. The active components BiPPB-mIFNγ and tTβRII were slowly released from BiPPB-mIFNγ-tTβRII by hydrolysis using the plasma protease thrombin in vitro. Moreover, BiPPB-mIFNγ-tTβRII highly targeted to fibrotic liver tissues, markedly ameliorated liver morphology and fibrotic responses in chronic liver fibrosis mice by both inhibiting the phosphorylation of Smad2/3 and inducing the expression of Smad7. Meanwhile, BiPPB-mIFNγ-tTβRII markedly reduced the deposition of collagen fibrils and expression of fibrosis-related proteins in acute liver fibrosis mice. Furthermore, BiPPB-mIFNγ-tTβRII showed a good safety performance in both liver fibrosis mice. Taken together, BiPPB-mIFNγ-tTβRII improved the in vivo anti-liver fibrotic activity due to its high fibrotic liver-targeting potential and the dual inhibition of the TGF-β1/Smad signaling pathway, which may be a potential candidate for targeting therapy on liver fibrosis.
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Affiliation(s)
- Yixin Dong
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Xiaohua Wang
- Laboratory of Pathogenic Microbiology and Immunology, Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Liming Xu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Xin Li
- Department of Pediatrics, Hongqi Hospital Affiliated to Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Haibing Dai
- Department of Biology, Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Xu Mao
- Department of Pharmacology, Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Yanhui Chu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, 157011, Mudanjiang, PR China
| | - Xiaohuan Yuan
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, 157011, Mudanjiang, PR China.
| | - Haifeng Liu
- Heilongjiang Province Key Laboratory for Anti-fibrosis Biotherapy, Mudanjiang Medical University, 157011, Mudanjiang, PR China.
- Laboratory of Pathogenic Microbiology and Immunology, Mudanjiang Medical University, 157011, Mudanjiang, PR China.
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Tan Y, Sun X, Xu Y, Tang B, Xu S, Lu D, Ye Y, Luo X, Diao X, Li F, Wang T, Chen J, Xu Q, Wu X. Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis. Nucleic Acids Res 2022; 50:2440-2451. [PMID: 35234905 PMCID: PMC8934652 DOI: 10.1093/nar/gkac139] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 01/21/2022] [Accepted: 02/14/2022] [Indexed: 11/23/2022] Open
Abstract
CUGBP Elav-like family member 1 (CELF1), an RNA-binding protein (RBP), plays important roles in the pathogenesis of diseases such as myotonic dystrophy, liver fibrosis and cancers. However, targeting CELF1 is still a challenge, as RBPs are considered largely undruggable. Here, we discovered that compound 27 disrupted CELF1-RNA binding via structure-based virtual screening and biochemical assays. Compound 27 binds directly to CELF1 and competes with RNA for binding to CELF1. Compound 27 promotes IFN-γ secretion and suppresses TGF-β1-induced hepatic stellate cell (HSC) activation by inhibiting CELF1-mediated IFN-γ mRNA decay. In vivo, compound 27 attenuates CCl4-induced murine liver fibrosis. Furthermore, the structure-activity relationship analysis was performed and compound 841, a derivative of compound 27, was identified as a selective CELF1 inhibitor. In conclusion, targeting CELF1 RNA-binding activity with small molecules was achieved, which provides a novel strategy for treating liver fibrosis and other CELF1-mediated diseases.
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Affiliation(s)
- Yang Tan
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Xueqing Sun
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Yizhu Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Bingjie Tang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Shuaiqi Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Dong Lu
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yan Ye
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xiaomin Luo
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China
| | - Xu Diao
- Department of Pharmacology, Jiangsu Simovay Pharmaceutical Co., Ltd., Nanjing, Jiangsu 210042, China
| | - Fulong Li
- Department of Pharmaceutical Chemistry, Jiangsu Simovay Pharmaceutical Co., Ltd., Nanjing, Jiangsu 210042, China
| | - Tianyi Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Jiayu Chen
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing210023, China
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China
| | - Xingxin Wu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China
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Sripongpun P, Pongpaibul A, Charatcharoenwitthaya P. Value and risk of percutaneous liver biopsy in patients with cirrhosis and clinical suspicion of autoimmune hepatitis. BMJ Open Gastroenterol 2021; 8:bmjgast-2021-000701. [PMID: 34362759 PMCID: PMC8351491 DOI: 10.1136/bmjgast-2021-000701] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/20/2021] [Indexed: 11/03/2022] Open
Abstract
OBJECTIVE The decision regarding whether to perform a liver biopsy in patients with cirrhosis and clinically suspected autoimmune hepatitis (AIH) remains a challenge. This study aimed to assess the utility and complications of percutaneous liver biopsy in cirrhosis for differentiating AIH from other liver conditions. METHODS A clinicopathological database of patients undergoing percutaneous liver biopsies for suspected AIH (unexplained hepatitis with elevated γ-globulin and autoantibody seropositivity) was reviewed to identify patients presenting with cirrhosis. Biopsy slides were reviewed by an experienced hepatopathologist who was blinded to clinical data. RESULTS In 207 patients who underwent liver biopsy for suspected AIH, 59 patients (mean age: 59.0±12.0 years, 83.1% female) had clinically diagnosis of cirrhosis. Mean Child-Turcotte-Pugh score was 6.6±1.6, and 44% of patients had a Child-Turcotte-Pugh score≥7. According to the revised International AIH Group (IAIHG) criteria, histology assessment combined with clinical information facilitated a diagnosis of AIH or overlap syndrome of AIH and primary biliary cholangitis (PBC) in 81.4% of cases. Liver biopsy identified other aetiologies, including PBC (n=2), non-alcoholic steatohepatitis (n=6) and cryptogenic cirrhosis (n=3). A reliable diagnosis of AIH could be made using histological category of the simplified criteria in 69.2% and 81.8% of cases using IAIHG scores before biopsy of <10 and 10-15, respectively. Three patients with cirrhosis (5.1%) experienced bleeding following biopsy, but none of 148 patients with non-cirrhosis had bleeding complication (p=0.022). CONCLUSION Liver biopsy provides important diagnostic information for the management of patients with cirrhosis and suspected AIH, but the procedure is associated with significant risk.
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Affiliation(s)
- Pimsiri Sripongpun
- Medicine, Mahidol University Faculty of Medicine Siriraj Hospital, Bangkok, Thailand.,Medicine, Faculty of Medicine Prince of Songkla University, Hat Yai, Songkla, Thailand
| | - Ananya Pongpaibul
- Pathology, Mahidol University Faculty of Medicine Siriraj Hospital, Bangkok, Thailand
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Abstract
The incidence of alcoholic hepatitis is increasing while the mortality rate remains high. The single current available therapy for severe alcoholic hepatitis is administration of corticosteroids for patients with severe alcoholic hepatitis, which has demonstrated limited benefits, providing a short-term mortality benefit with a marginal response rate. There is a need for developing safe and effective therapies. This article reviews novel therapies targeting various mechanisms in the pathogenesis of alcoholic hepatitis, such as the gut-liver axis, inflammatory cascade, oxidative stress, and hepatic regeneration. Current ongoing clinical trials for alcoholic hepatitis also are described.
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Affiliation(s)
- Ma Ai Thanda Han
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, 185 South Orange Avenue, H-526, Newark, NJ 07103, USA
| | - Nikolaos Pyrsopoulos
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, 185 South Orange Avenue, H-536, Newark, NJ 07103, USA.
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Abstract
Hepatic fibrosis is a complex mechanism defined by the net deposition of the extracellular matrix (ECM) owing to liver injury caused by multiple etiologies such as viral hepatitis and nonalcoholic fatty liver disease. Many cell types are implicated in liver fibrosis development and progression. In general, liver fibrosis starts with the recruitment of inflammatory immune cells to generate cytokines, growth factors, and other activator molecules. Such chemical mediators drive the hepatic stellate cells (HSCs) to activate the production of the ECM component. The activation of HSC is thus a crucial event in the fibrosis initiation, and a significant contributor to collagen deposition (specifically type I). This review explores the causes and mechanisms of hepatic fibrosis and focuses on the roles of key molecules involved in liver fibro genesis, some of which are potential targets for therapeutics to hamper liver fibro genesis.
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Affiliation(s)
- Reham M Dawood
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mai A El-Meguid
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Ghada Maher Salum
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mostafa K El Awady
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
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Frenette CT, Morelli G, Shiffman ML, Frederick RT, Rubin RA, Fallon MB, Cheng JT, Cave M, Khaderi SA, Massoud O, Pyrsopoulos N, Park JS, Robinson JM, Yamashita M, Spada AP, Chan JL, Hagerty DT. Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo. Clin Gastroenterol Hepatol 2019; 17:774-783.e4. [PMID: 29913280 DOI: 10.1016/j.cgh.2018.06.012] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/08/2018] [Accepted: 06/09/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). METHODS We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11-18 (mean, 12.8). Patients were randomly assigned to groups given placebo (N = 42) or Emricasan (25 mg, N = 44), twice daily for 3 months; subjects then received open-label Emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. RESULTS Seventy-four patients completed the 3-month study period (40 given Emricasan and 34 given placebo); 69 patients received open-label Emricasan for 3 months afterward. At the 3-month timepoint, Emricasan significantly reduced mean MELD (P = .003) and Child-Pugh (P = .003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, -0.2882 to -0.0866) and total bilirubin (95% CI, -1.5069 to -0.0823) vs placebo. There were no significant differences between Emricasan and placebo groups in mean MELD (P = .466) or Child-Pugh (P = .124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given Emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P = .02) and caspase 3/7 (P < .001), but not cleaved CK-18 (P = .092), decreased significantly at 3 months in the Emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. CONCLUSIONS In a randomized trial of patients with cirrhosis, we found 3 months treatment with Emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT02230670.
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Affiliation(s)
| | - Giuseppe Morelli
- Department of Medicine, University of Florida, Gainesville, Florida
| | | | - R Todd Frederick
- Division of Hepatology, Department of Transplantation, California Pacific Medical Center, San Francisco, California
| | - Raymond A Rubin
- Piedmont Transplant Institute, Mercer University School of Medicine, Atlanta, Georgia
| | | | - Jason T Cheng
- Loma Linda University Medical Center, Loma Linda, California
| | - Matt Cave
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, Kentucky
| | - Saira A Khaderi
- Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas
| | - Omar Massoud
- Division of Gastroenterology and Hepatology, University of Alabama-Birmingham, Birmingham, Alabama
| | - Nikolaos Pyrsopoulos
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, New Jersey
| | - James S Park
- Division of Gastroenterology and Hepatology, New York University Langone Medical Center, New York, New York
| | | | | | | | - Jean L Chan
- Conatus Pharmaceuticals Inc, San Diego, California
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Feng R, Yuan X, Shao C, Ding H, Liebe R, Weng HL. Are we any closer to treating liver fibrosis (and if no, why not)? J Dig Dis 2018; 19:118-126. [PMID: 29389083 DOI: 10.1111/1751-2980.12584] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/26/2018] [Indexed: 12/11/2022]
Abstract
This review provides a personal view on anti-fibrosis therapy in the liver. The worst clinical consequence of liver fibrosis is the development of liver cirrhosis and portal hypertension. Etiology is a decisive factor which determines patterns of fibrous septa and subsequent vascular remodeling, which is essential for the development of portal hypertension. Removing or controlling the disease-causing agent, i.e. anti-viral treatment for hepatitis, is the essential first step for treating chronic liver diseases and can reverse fibrosis in some settings. However, removing etiology is not always sufficient to prevent fibrosis from progressing towards cirrhosis and portal hypertension. In liver diseases such as severe alcoholic hepatitis and massive parenchymal loss, the formation of vascular anastomoses between portal to central veins based on bridging fibrosis results in cirrhosis and portal hypertension. For these patients, anti-fibrotic treatment is crucial and urgent. Unfortunately, a lack of understanding how fibrosis contributes to vascular remodeling caused by and combined with a lack of suitable experimental models that recapitulate human liver diseases, has hampered the development of successful anti-fibrotic drugs for clinical use to date.
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Affiliation(s)
- Rilu Feng
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Xiaodong Yuan
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Chen Shao
- Department of Pathology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, China
| | - Huiguo Ding
- Department of Gastroenterology and Hepatology, Beijing You'an Hospital, Affiliated with Capital Medical University, Beijing, China
| | - Roman Liebe
- Department of Medicine II, Saarland University Medical Center, Homburg/Saar, Germany
| | - Hong-Lei Weng
- Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Current Perspectives Regarding Stem Cell-Based Therapy for Liver Cirrhosis. Can J Gastroenterol Hepatol 2018; 2018:4197857. [PMID: 29670867 PMCID: PMC5833156 DOI: 10.1155/2018/4197857] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 01/16/2018] [Indexed: 12/12/2022] Open
Abstract
Liver cirrhosis is a major cause of mortality and a common end of various progressive liver diseases. Since the effective treatment is currently limited to liver transplantation, stem cell-based therapy as an alternative has attracted interest due to promising results from preclinical and clinical studies. However, there is still much to be understood regarding the precise mechanisms of action. A number of stem cells from different origins have been employed for hepatic regeneration with different degrees of success. The present review presents a synopsis of stem cell research for the treatment of patients with liver cirrhosis according to the stem cell type. Clinical trials to date are summarized briefly. Finally, issues to be resolved and future perspectives are discussed with regard to clinical applications.
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Ramachandran P, Henderson NC. Antifibrotics in chronic liver disease: tractable targets and translational challenges. Lancet Gastroenterol Hepatol 2016; 1:328-340. [PMID: 28404203 DOI: 10.1016/s2468-1253(16)30110-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 07/22/2016] [Accepted: 07/26/2016] [Indexed: 12/30/2022]
Abstract
Chronic liver disease prevalence is increasing globally. Iterative liver damage, secondary to any cause of liver injury, results in progressive fibrosis, disrupted hepatic architecture, and aberrant regeneration, which are defining characteristics of liver cirrhosis. Liver transplantation is an effective treatment for end-stage liver disease; however, demand greatly outweighs donor organ supply, and in many parts of the world liver transplantation is unavailable. Hence, effective antifibrotic therapies are urgently required. In the past decade, rapid progress has been made in our understanding of the pathophysiology of liver fibrosis and a large number of potential cellular and molecular antifibrotic targets have been identified. This has led to numerous clinical trials of antifibrotic agents in patients with chronic liver disease. However, none of these have resulted in a robust and reproducible effect on fibrosis. It is therefore imperative that the ongoing translational challenges are addressed, to convert scientific discoveries into potent antifibrotics and enable bridging of the translational gap between putative therapeutic targets and effective treatments for patients with chronic liver disease.
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Affiliation(s)
- Prakash Ramachandran
- Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Neil C Henderson
- Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
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Lee SB, Kim HG, Kim HS, Lee JS, Im HJ, Kim WY, Son CG. Ethyl Acetate Fraction of Amomum xanthioides Exerts Antihepatofibrotic Actions via the Regulation of Fibrogenic Cytokines in a Dimethylnitrosamine-Induced Rat Model. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2016; 2016:6014380. [PMID: 27594891 PMCID: PMC4995331 DOI: 10.1155/2016/6014380] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 07/08/2016] [Accepted: 07/16/2016] [Indexed: 01/18/2023]
Abstract
Amomum xanthioides has been traditionally used to treat diverse digestive system disorders in the Asian countries. We investigated antihepatofibrotic effects of ethyl acetate fraction of Amomum xanthioides (EFAX). Liver fibrosis is induced by dimethylnitrosamine (DMN) injection (intraperitoneally, 10 mg/kg of DMN for 4 weeks to Sprague-Dawley rats). EFAX (25 or 50 mg/kg), silymarin (50 mg/kg), or distilled water was orally administered every day. The DMN injection drastically altered body and organ mass, serum biochemistry, and platelet count, while EFAX treatment significantly attenuated this alteration. Severe liver fibrosis is determined by trichrome staining and measurement of hydroxyproline contents. EFAX treatment significantly attenuated these symptoms as well as the increase in oxidative by-products of lipid and protein metabolism in liver tissues. DMN induced a dramatic activation of hepatic stellate cells and increases in the levels of protein and gene expression of transforming growth factor-beta (TGF-β), platelet derived growth factor-beta (PDGF-β), and connective tissue growth factor (CTGF). Immunohistochemical analyses revealed increases in the levels of protein and gene expression of α-smooth muscle actin. These alterations were significantly normalized by EFAX treatment. Our findings demonstrate the potent antihepatofibrotic properties of EFAX via modulation of fibrogenic cytokines, especially TGF-β in the liver fibrosis rat model.
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Affiliation(s)
- Sung-Bae Lee
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
| | - Hyeong-Geug Kim
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
| | - Hyo-Seon Kim
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
| | - Jin-Seok Lee
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
| | - Hwi-Jin Im
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
| | - Won-Yong Kim
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
| | - Chang-Gue Son
- Liver and Immunology Research Center, Daejeon Oriental Hospital of Oriental Medical College of Daejeon University, 176-9 Daeheung-ro, Jung-gu, Daejeon 301-724, Republic of Korea
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14
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Abstract
Liver regeneration has been studied for many decades and the mechanisms underlying regeneration of the normal liver following resection or moderate damage are well described. A large number of factors extrinsic (such as bile acids and circulating growth factors) and intrinsic to the liver interact to initiate and regulate liver regeneration. Less well understood, and more clinically relevant, are the factors at play when the abnormal liver is required to regenerate. Fatty liver disease, chronic scarring, prior chemotherapy and massive liver injury can all inhibit the normal programme of regeneration and can lead to liver failure. Understanding these mechanisms could enable the rational targeting of specific therapies to either reduce the factors inhibiting regeneration or directly stimulate liver regeneration. Although animal models of liver regeneration have been highly instructive, the clinical relevance of some models could be improved to bridge the gap between our in vivo model systems and the clinical situation. Likewise, modern imaging techniques such as spectroscopy will probably improve our understanding of whole-organ metabolism and how this predicts the liver's regenerative capacity. This Review describes briefly the mechanisms underpinning liver regeneration, the models used to study this process, and discusses areas in which failed or compromised liver regeneration is clinically relevant.
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Affiliation(s)
- Stuart J Forbes
- MRC Centre for Regenerative Medicine, 5 Little France Drive, University of Edinburgh, Edinburgh EH16 4UU, UK
| | - Philip N Newsome
- Birmingham National Institute for Health Research (NIHR) Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Vincent Drive Birmingham, B15 2TT, UK
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15
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Mehal W, To U. New approaches for fibrosis regression in alcoholic cirrhosis. Hepatol Int 2016; 10:773-8. [PMID: 27460408 DOI: 10.1007/s12072-016-9752-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 06/21/2016] [Indexed: 01/18/2023]
Abstract
Liver fibrosis is a dynamic process of fibrinogenesis and fibrinolysis. It is sequelae of recurrent injury and inflammation to the liver. Only recently has there been significant progress in understanding the pathophysiology behind liver fibrosis. This has allowed for the development of identifiable targets for potential therapies. In this article we will discuss the underlying general cellular mechanisms that play a key role in the pathway of fibrinogenesis and fibrinolysis and then focus on the mechanisms that are key in alcohol-induced liver fibrosis. Challenges in formulating potential fibrosis therapies as well as current potential targets for liver fibrosis will be reviewed as well.
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Affiliation(s)
- Wajahat Mehal
- Section of Digestive Diseases, Department of Veterans Affairs Connecticut Healthcare, West Haven, CT, 06516, USA. .,Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, 06520, USA.
| | - Uyen To
- Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT, 06520, USA
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16
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Huang SS, Chen DZ, Wu H, Chen RC, Du SJ, Dong JJ, Liang G, Xu LM, Wang XD, Yang YP, Yu ZP, Feng WK, Chen YP. Cannabinoid receptors are involved in the protective effect of a novel curcumin derivative C66 against CCl4-induced liver fibrosis. Eur J Pharmacol 2016; 779:22-30. [PMID: 26945822 DOI: 10.1016/j.ejphar.2016.02.067] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 02/26/2016] [Accepted: 02/29/2016] [Indexed: 12/26/2022]
Abstract
Liver fibrosis is one of the major causes of morbidity and mortality worldwide and lacks efficient therapy. Recent studies suggest the curcumin protects liver from fibrosis. However, curcumin itself is in low bioavailable concentration when administered orally, and the protective mechanism remains poorly understood. The current study aimed to investigate whether a more stable derivative of curcumin, C66, protects against CCl4-inudced liver fibrosis and examine the underlying mechanism involving cannabinoid receptor (CB receptor). At a dose lower than curcumin itself, C66 displayed a superior anti-fibrotic effect. C66 significantly reduced collagen deposition, pro-inflammatory cytokine expression, and liver enzyme activities. Mechanistic study revealed that C66 treatment decreased CCl4-induced cannabinoid receptor 1 (CB1 receptor) expression and increased cannabinoid receptor 2 (CB2 receptor) expression, along with an inhibition of JNK/NF-κB-mediated inflammatory signaling. In conclusion, this curcumin derivative attenuates liver fibrosis likely involving a CB/JNK/NF-κB-mediated pathway.
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Affiliation(s)
- Si-Si Huang
- Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Da-zhi Chen
- Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Zhejiang University, Hangzhou, China
| | - He Wu
- Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Rui-Cong Chen
- Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shan-Jie Du
- Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jia-Jia Dong
- Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lan-Man Xu
- Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiao-Dong Wang
- Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yong-Ping Yang
- Liver Cancer Therapy and Research Center, People's Liberation Army 302 Hospital, Beijing 100039, China
| | - Zhen-Ping Yu
- Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wen-Ke Feng
- Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA.
| | - Yong-Ping Chen
- Hepatology Institute of Wenzhou Medical University, Wenzhou Key Laboratory of Hepatology, Department of Infectious Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
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17
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Abstract
While simple to recommend, diet and lifestyle measures as a first-line therapy for nonalcoholic steatohepatitis (NASH) are hardly a model of successful therapy, as most clinicians can testify. They can be complex to implement, hard to sustain, and of limited efficacy in advanced stages of the disease. The need for specific pharmacotherapy is now acknowledged by practitioners, the pharmaceutical industry, and regulators and is largely expected by patients. The result is a clear move away from products developed second hand for NASH (such as pioglitazone or metformin) or from generic, non-specific hepatoprotectors (such as pentoxifylline, ursodeoxycholic acid, or antioxidants) toward molecules developed and tested specifically for NASH that aim to correct one or several of the pathways of liver injury in this disease. The two most advanced molecules, obeticholic acid and elafibranor, have shown encouraging data on improving hepatic histology. Both compounds appear to clear NASH, with obeticholic acid improving liver fibrosis and elafibranor improving the glycemic and lipid profile. Much larger trials, currently ongoing, will need to confirm these preliminary data and better characterize the safety and tolerability profile. Meanwhile, other compounds are being tested, a few in phase 2b studies (cenicriviroc, aramchol for NASH, and simtuzumab for NASH fibrosis) and many more in earlier, smaller trials. Most of these drug candidates target different pathways, which speaks to the diversity and dynamism of the NASH pipeline.
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Affiliation(s)
- Vlad Ratziu
- Institute for Cardiometabolism and Nutrition (ICAN), Hôpital Pitié Salpêtrière, Service d'hépatogastroentérologie, Université Pierre et Marie Curie, 47-83 Bd de l'Hôpital, 75013, Paris, France.
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18
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Sheiko MA, Rosen HR. Hepatic Fibrosis in Hepatitis C. HEPATITIS C VIRUS II 2016:79-108. [DOI: 10.1007/978-4-431-56101-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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19
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Abstract
Significant progress has been made in understanding the principles underlying the development of liver fibrosis. This includes appreciating its dynamic nature, the importance of active fibrolysis in fibrosis regression, and the plasticity of cell populations endowing them with fibrogenic or fibrolytic properties. This is complemented by an increasing array of therapeutic targets with known roles in the progression or regression of fibrosis. With a key role for fibrosis in determining clinical outcomes and encouraging data from recently Food and Drug Administration-approved antifibrotics for pulmonary fibrosis, the development and validation of antifibrotic therapies has taken center stage in translational hepatology. In addition to summarizing the recent progress in antifibrotic therapies, the authors discuss some of the challenges ahead, such as achieving a better understanding of the interindividual heterogeneity of the fibrotic response, how to match interventions with the ideal patient population, and the development of better noninvasive methods to assess the dynamics of fibrogenesis and fibrolysis. Together, these advances will permit a better targeting and dose titration of individualized therapies. Finally, the authors discuss combination therapy with different antifibrotics as possibly the most potent approach for treating fibrosis in the liver.
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Affiliation(s)
- W. Z. Mehal
- Section of Digestive Diseases, Yale University, New Haven, Connecticut,West Haven Veterans Medical Center, West Haven, Connecticut
| | - D. Schuppan
- Department of Medicine, Institute of Translational Immunology and Research Center for Immunotherapy, University of Mainz Medical Center, Mainz, Germany,Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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20
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21
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Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 2015; 61:1066-79. [PMID: 25066777 PMCID: PMC4306641 DOI: 10.1002/hep.27332] [Citation(s) in RCA: 714] [Impact Index Per Article: 71.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023]
Abstract
Inflammation is one of the most characteristic features of chronic liver disease of viral, alcoholic, fatty, and autoimmune origin. Inflammation is typically present in all disease stages and associated with the development of fibrosis, cirrhosis, and hepatocellular carcinoma. In the past decade, numerous studies have contributed to improved understanding of the links between hepatic inflammation and fibrosis. Here, we review mechanisms that link inflammation with the development of liver fibrosis, focusing on the role of inflammatory mediators in hepatic stellate cell (HSC) activation and HSC survival during fibrogenesis and fibrosis regression. We will summarize the contributions of different inflammatory cells, including hepatic macrophages, T and B lymphocytes, natural killer cells and platelets, as well as key effectors, such as cytokines, chemokines, and damage-associated molecular patterns. Furthermore, we will discuss the relevance of inflammatory signaling pathways for clinical liver disease and for the development of antifibrogenic strategies.
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Affiliation(s)
- Ekihiro Seki
- Department of Medicine, University of California, San Diego, School
of Medicine, La Jolla, CA 92093, USA,Surgery, University of California, San Diego, School of Medicine, La
Jolla, CA 92093, USA
| | - Robert F. Schwabe
- Department of Medicine, Columbia University, College of Physicians
and Surgeons, New York, NY 10032, USA,Institute of Human Nutrition, Columbia University, College of
Physicians and Surgeons, New York, NY 10032, USA
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22
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Berardis S, Sattwika PD, Najimi M, Sokal EM. Use of mesenchymal stem cells to treat liver fibrosis: Current situation and future prospects. World J Gastroenterol 2015; 21:742-758. [PMID: 25624709 PMCID: PMC4299328 DOI: 10.3748/wjg.v21.i3.742] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/05/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Progressive liver fibrosis is a major health issue for which no effective treatment is available, leading to cirrhosis and orthotopic liver transplantation. However, organ shortage is a reality. Hence, there is an urgent need to find alternative therapeutic strategies. Cell-based therapy using mesenchymal stem cells (MSCs) may represent an attractive therapeutic option, based on their immunomodulatory properties, their potential to differentiate into hepatocytes, allowing the replacement of damaged hepatocytes, their potential to promote residual hepatocytes regeneration and their capacity to inhibit hepatic stellate cell activation or induce their apoptosis, particularly via paracrine mechanisms. The current review will highlight recent findings regarding the input of MSC-based therapy for the treatment of liver fibrosis, from in vitro studies to pre-clinical and clinical trials. Several studies have shown the ability of MSCs to reduce liver fibrosis and improve liver function. However, despite these promising results, some limitations need to be considered. Future prospects will also be discussed in this review.
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23
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Bartneck M, Warzecha KT, Tacke F. Therapeutic targeting of liver inflammation and fibrosis by nanomedicine. Hepatobiliary Surg Nutr 2015; 3:364-76. [PMID: 25568860 DOI: 10.3978/j.issn.2304-3881.2014.11.02] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 10/17/2014] [Indexed: 12/25/2022]
Abstract
Nanomedicine constitutes the emerging field of medical applications for nanotechnology such as nanomaterial-based drug delivery systems. This technology may hold exceptional potential for novel therapeutic approaches to liver diseases. The specific and unspecific targeting of macrophages, hepatic stellate cells (HSC), hepatocytes, and liver sinusoidal endothelial cells (LSEC) using nanomedicine has been developed and tested in preclinical settings. These four major cell types in the liver are crucially involved in the complex sequence of events that occurs during the initiation and maintenance of liver inflammation and fibrosis. Targeting different cell types can be based on their capacity to ingest surrounding material, endocytosis, and specificity for a single cell type can be achieved by targeting characteristic structures such as receptors, sugar moieties or peptide sequences. Macrophages and especially the liver-resident Kupffer cells are in the focus of nanomedicine due to their highly efficient and unspecific uptake of most nanomaterials as well as due to their critical pathogenic functions during inflammation and fibrogenesis. The mannose receptor enables targeting macrophages in liver disease, but macrophages can also become activated by certain nanomaterials, such as peptide-modified gold nanorods (AuNRs) that render them proinflammatory. HSC, the main collagen-producing cells during fibrosis, are currently targeted using nanoconstructs that recognize the mannose 6-phosphate and insulin-like growth factor II, peroxisome proliferator activated receptor 1, platelet-derived growth factor (PDGF) receptor β, or integrins. Targeting of the major liver parenchymal cell, the hepatocyte, has only recently been achieved with high specificity by mimicking apolipoproteins, naturally occurring nanoparticles of the body. LSEC were found to be targeted most efficiently using carboxy-modified micelles and their integrin receptors. This review will summarize important functions of these cell types in healthy and diseased livers and discuss current strategies of cell-specific targeting for liver diseases by nanomedicine.
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Affiliation(s)
- Matthias Bartneck
- Department of Medicine III, University Hospital Aachen, 52074 Aachen, Germany
| | | | - Frank Tacke
- Department of Medicine III, University Hospital Aachen, 52074 Aachen, Germany
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24
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Inagaki Y, Sumiyoshi H. [111th Scientific Meeting of the Japanese Society of Internal Medicine: Symposium: 3. Fibrosis of the viscera and its treatment; 1) Reversibility and treatment of liver fibrosis]. ACTA ACUST UNITED AC 2014; 103:2171-5. [PMID: 27522771 DOI: 10.2169/naika.103.2171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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25
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Bansal R, Prakash J, De Ruiter M, Poelstra K. Targeted recombinant fusion proteins of IFNγ and mimetic IFNγ with PDGFβR bicyclic peptide inhibits liver fibrogenesis in vivo. PLoS One 2014; 9:e89878. [PMID: 24587093 PMCID: PMC3933682 DOI: 10.1371/journal.pone.0089878] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Accepted: 01/24/2014] [Indexed: 01/17/2023] Open
Abstract
Hepatic stellate cells (HSCs), following transdifferentiation to myofibroblasts plays a key role in liver fibrosis. Therefore, attempts to attenuate this myofibroblastic phenotype would be a promising therapeutic approach. Interferon gamma (IFNγ) is a potent anti-fibrotic cytokine, but its pleiotropic receptor expression leading to severe adverse effects has limited its clinical application. Since, activated HSC express high-level of platelet derived growth factor beta receptor (PDGFβR), we investigated the potential of PDGFβR-specific targeting of IFNγ and its signaling peptide that lacks IFNγR binding site (mimetic IFNγ or mimIFNγ) in liver fibrosis. We prepared DNA constructs expressing IFNγ, mimIFNγ or BiPPB (PDGFβR-specific bicyclic peptide)-IFNγ, BiPPB-mimIFNγ fusion proteins. Both chimeric proteins alongwith IFNγ and mimIFNγ were produced in E.coli. The expressed proteins were purified and analyzed for PDGFβR-specific binding and in vitro effects. Subsequently, these recombinant proteins were investigated for the liver uptake (pSTAT1α signaling pathway), for anti-fibrotic effects and adverse effects (platelet counts) in CCl4-induced liver fibrogenesis in mice. The purified HSC-targeted IFNγ and mimIFNγ fusion proteins showed PDGFβR-specific binding and significantly reduced TGFβ-induced collagen-I expression in human HSC (LX2 cells), while mouse IFNγ and mimIFNγ did not show any effect. Conversely, mouse IFNγ and BiPPB-IFNγ induced activation and dose-dependent nitric oxide release in mouse macrophages (express IFNγR while lack PDGFβR), which was not observed with mimIFNγ and BiPPB-mimIFNγ, due to the lack of IFNγR binding sites. In vivo, targeted BiPPB-IFNγ and BiPPB-mimIFNγ significantly activated intrahepatic IFNγ-signaling pathway compared to IFNγ and mimIFNγ suggesting increased liver accumulation. Furthermore, the targeted fusion proteins ameliorated liver fibrogenesis in mice by significantly reducing collagen and α-SMA expression and potentiating collagen degradation. IFNγ also induced reduction in fibrogenesis but showed significant decrease in platelet counts, which was restored with targeted proteins. These results suggest that these rationally designed proteins can be further developed as novel anti-fibrotic therapeutics.
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Affiliation(s)
- Ruchi Bansal
- Department of Controlled Drug Delivery (Targeted Therapeutics), MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
- Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands
- * E-mail:
| | - Jai Prakash
- Department of Controlled Drug Delivery (Targeted Therapeutics), MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
- Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands
| | - Marieke De Ruiter
- Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands
| | - Klaas Poelstra
- Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands
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26
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Sahin H, Berres ML, Wasmuth HE. Therapeutic potential of chemokine receptor antagonists for liver disease. Expert Rev Clin Pharmacol 2014; 4:503-13. [DOI: 10.1586/ecp.11.24] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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27
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Luo XY, Takahara T, Kawai K, Fujino M, Sugiyama T, Tsuneyama K, Tsukada K, Nakae S, Zhong L, Li XK. IFN-γ deficiency attenuates hepatic inflammation and fibrosis in a steatohepatitis model induced by a methionine- and choline-deficient high-fat diet. Am J Physiol Gastrointest Liver Physiol 2013; 305:G891-9. [PMID: 24136786 DOI: 10.1152/ajpgi.00193.2013] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cytokines play important roles in all stages of steatohepatitis, including hepatocyte injury, the inflammatory response, and the altered function of sinusoidal cells. This study examined the involvement of a major inflammatory cytokine, interferon-γ (IFN-γ), in the progression of steatohepatitis. In a steatohepatitis model by feeding a methionine- and choline-deficient high-fat (MCDHF) diet to both wild-type and IFN-γ-deficient mice, the liver histology, expression of genes encoding inflammatory cytokines, and fibrosis-related markers were examined. To analyze the effects of IFN-γ on Kupffer cells in vitro, we examined the tumor necrosis factor-α (TNF-α) production by a mouse macrophage cell line. Forty two days of MCDHF diet resulted in weight loss, elevated aminotransferases, liver steatosis, and inflammation in wild-type mice. However, the IFN-γ-deficient mice exhibited less extensive changes. RT-PCR revealed that the expression of tumor necrosis factor-α (TNF-α), transforming growth factor-β, inducible nitric oxide synthase, interleukin-4 and osteopontin were increased in wild-type mice, although they were suppressed in IFN-γ-deficient mice. Seventy days of MCDHF diet induced much more liver fibrosis in wild-type mice than in IFN-γ-deficient mice. The expression levels of fibrosis-related genes, α-smooth muscle actin, type I collagen, tissue inhibitor of matrix metalloproteinase-1, and matrix metalloproteinase-2, were dramatically increased in wild-type mice, whereas they were significantly suppressed in IFN-γ-deficient mice. Moreover, in vitro experiments showed that, when RAW 264.7 macrophages were treated with IFN-γ, they produced TNF-α in a dose-dependent manner. The present study showed that IFN-γ deficiency might inhibit the inflammatory response of macrophages cells and subsequently suppress stellate cell activation and liver fibrosis. These findings highlight the critical role of IFN-γ in the progression of steatohepatitis.
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Affiliation(s)
- Xiao-Yu Luo
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535 Japan.
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28
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Yi HS, Jeong WI. Interaction of hepatic stellate cells with diverse types of immune cells: foe or friend? J Gastroenterol Hepatol 2013; 28 Suppl 1:99-104. [PMID: 23855303 DOI: 10.1111/jgh.12017] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/10/2013] [Indexed: 12/13/2022]
Abstract
Activated hepatic stellate cells (HSCs) have been considered as a major type of cells in liver fibrosis by producing a huge amount of extracellular matrix, especially collagen fibers, and profibrotic mediators such as transforming growth factor-beta, interleukin-6 and monocyte chemoattractant protein-1. Recently, accumulated evidence suggests that the liver is an immunologic organ because of enrichment of diverse types of immune cells and that their interactions with HSCs are closely related with the progression of liver fibrosis. However, the underlying mechanisms of interaction between HSCs and immune cells remain largely unknown. Recently, several studies have demonstrated that natural killer cells, M2 macrophages, regulatory T cells, and bone marrow derived CD11b(+) Gr1(+) immature cells ameliorate liver fibrosis, whereas neutrophils, M1 macrophages, CD8 T cells, natural killer T cells and interleukin-17-producing cells accelerate liver fibrosis. However, there are still controversial issues about their functions during liver fibrogenesis. In this review, we summarize the diversity roles of immune cells (e.g. profibrotic/antifibrotic or both) in regulating the activation of HSCs during hepatic fibrogenesis, in which several producible mediators by HSCs play important roles in the interaction with them. Moreover, the current cell-based therapies using immune cells against liver fibrosis are discussed.
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Affiliation(s)
- Hyon-Seung Yi
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
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29
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Koretz RL. Interferon for hepatitis C: where it has been and where it is going. Immunotherapy 2013; 5:673-5. [PMID: 23829615 DOI: 10.2217/imt.13.55] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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30
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Berenguer M, Schuppan D. Progression of liver fibrosis in post-transplant hepatitis C: mechanisms, assessment and treatment. J Hepatol 2013; 58:1028-41. [PMID: 23262248 DOI: 10.1016/j.jhep.2012.12.014] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 12/10/2012] [Accepted: 12/10/2012] [Indexed: 12/12/2022]
Abstract
Liver fibrosis results from an excessive wound healing response in most chronic liver diseases, such as hepatitis C. Despite great advances in antiviral therapy in recent years, progressive liver fibrosis remains a major problem for patients with recurrent hepatitis C after liver transplantation. Liver biopsy remains a central tool in the management of HCV-positive liver transplant recipients, but reliable non-invasive methods for the assessment of liver fibrosis, such as ultrasound elastography, are increasingly being incorporated in the management of post-transplant patients, helping predict prognosis, guide treatment decisions, and stratify patients for emerging antifibrotic therapies. In this manuscript, we will review the natural history as well as tools to monitor fibrosis progression in the HCV-positive liver transplant recipient, the mechanisms underlying rapid fibrosis progression in up to 30% of these patients, the effect of antiviral therapies and highlight promising antifibrotic approaches.
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Affiliation(s)
- Marina Berenguer
- University Valencia, Dept. of Medicine, Hepatology & Liver Transplantation Unit, La Fe Hospital and CIBEREHD, National Network Center for Hepatology and Gastroenterology Research, Instituto de Salud Carlos III, Spain.
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31
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Abstract
Fibrosis is an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. With protracted damage, fibrosis can progress toward excessive scarring and organ failure, as in liver cirrhosis. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development, with enormous potential but also high risks. Preclinical research has yielded numerous targets for antifibrotic agents, some of which have entered early-phase clinical studies, but progress has been hampered due to the relative lack of sensitive and specific biomarkers to measure fibrosis progression or reversal. Here we focus on antifibrotic approaches for liver that address specific cell types and functional units that orchestrate fibrotic wound healing responses and have a sound preclinical database or antifibrotic activity in early clinical trials. We also touch upon relevant clinical study endpoints, optimal study design, and developments in fibrosis imaging and biomarkers.
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Affiliation(s)
- Detlef Schuppan
- Institute of Molecular and Translational Medicine and Department of Medicine I, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
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32
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Antonelli A, Fallahi P, Ferrari SM, Corrado A, Sebastiani M, Giuggioli D, Miccoli M, Zignego AL, Sansonno D, Marchi S, Ferri C. Parallel increase of circulating CXCL11 and CXCL10 in mixed cryoglobulinemia, while the proinflammatory cytokine IL-6 is associated with high serum Th2 chemokine CCL2. Clin Rheumatol 2013; 32:1147-54. [DOI: 10.1007/s10067-013-2246-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 01/29/2013] [Accepted: 03/20/2013] [Indexed: 12/15/2022]
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Villanueva A, Hernandez-Gea V, Llovet JM. Medical therapies for hepatocellular carcinoma: a critical view of the evidence. Nat Rev Gastroenterol Hepatol 2013; 10:34-42. [PMID: 23147664 DOI: 10.1038/nrgastro.2012.199] [Citation(s) in RCA: 253] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The management of hepatocellular carcinoma (HCC) has substantially changed in the past few decades. Improvements in patient stratification (for example, using the Barcelona Clinic Liver Cancer staging system) and the introduction of novel therapies (such as sorafenib) have improved patient survival. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. Decision-making largely relies on evidence-based criteria, as depicted in the US and European clinical practice guidelines, which endorse five therapeutic recommendations: resection; transplantation; radiofrequency ablation; chemoembolization; and sorafenib. However, areas still exist in which uncertainty precludes a strong recommendation, such as the role of adjuvant therapies after resection, radioembolization with yttrium-90 or second-line therapies for advanced HCC. Many clinical trials that are currently ongoing aim to answer these questions. The first reported studies, however, failed to identify novel therapeutic alternatives (that is, sunitinib, erlotinib or brivanib). Moreover, genomic profiling has enabled patient classification on the basis of molecular parameters, and has facilitated the development of new effective drugs. However, no oncogene addiction loops have been identified so far, as has been the case with other cancers such as melanoma, lung or breast cancer. Efforts that focus on the implementation of personalized medicine approaches in HCC will probably dominate research in the next decade.
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Affiliation(s)
- Augusto Villanueva
- Hepatocellular Carcinoma Translational Research Laboratory, Barcelona Clinic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Liver Unit, Hospital Clínic, Villarroel 170, Barcelona 08036, Catalonia, Spain
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Sharma AD, Iacob R, Cantz T, Manns MP, Ott M. Liver. Regen Med 2013. [DOI: 10.1007/978-94-007-5690-8_37] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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Antonelli A, Fallahi P, Ferrari S, Frascerra S, Mancusi C, Colaci M, Manfredi A, Sansonno D, Zignego A, Ferri C. High Circulating Chemokines (C-X-C Motif) Ligand 9, and (C-X-C Motif) Ligand 11, in Hepatitis C-Associated Cryoglobulinemia. Int J Immunopathol Pharmacol 2013; 26:49-57. [DOI: 10.1177/039463201302600105] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
(C-X-C motif) ligand 9 and (C-X-C motif) ligand 11 (CXCL9 and CXCL11), are potent chemoattractants for activated T cells, and play an important role in T helper 1 (Th) 1 cell recruitment in chronic hepatitis C. No study has evaluated CXCL9, together with CXCL11, circulating levels in patients with mixed cryoglobulinemia and hepatitis C (MC+HCV-p). The aim of the present study therefore was to measure serum CXCL9, and CXCL11 levels, in MC+HCV-p, and to relate the findings to the clinical phenotype. Serum CXCL9 and CXCL11 were measured in 71 MC+HCV-p and in matched controls. MC+HCV-p showed significantly higher mean CXCL9 and CXCL11 levels than controls (P < 0.001, for both), in particular, in 32 patients with active vasculitis (P < 0.001). By defining high CXCL9 or CXCL11 level as a value of at least 2 SD above the mean value of the control group (> 100 pg/mL): 89% MC+HCV-p and 5% controls had high CXCL9 (P < 0.0001, chi-square); 90% MC+HCV-p and 6% controls had high CXCL11 (P < 0.0001, chi-square). In a multiple linear regression model of CXCL9 vs age, ALT, CXCL11, only CXCL11 was significantly (r = 0.452, P < 0.0001) and independently related to CXCL9. Our study demonstrates in MC+HCV-p vs controls: (i) high serum CXCL9, and CXCL11, significantly associated with the presence of active vasculitis; (ii) a strong relationship between circulating CXCL9 and CXCL11. Future studies on a larger cohort of patients are needed to evaluate the relevance of serum CXCL9 and CXCL11 determination as clinico-prognostic marker of MC+HCV.
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Affiliation(s)
- A. Antonelli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - P. Fallahi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - S.M. Ferrari
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - S. Frascerra
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - C. Mancusi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - M. Colaci
- Department of Medical, Surgical, Maternal, Pediatric and Adult Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - A. Manfredi
- Department of Medical, Surgical, Maternal, Pediatric and Adult Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - D. Sansonno
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Policlinico, Bari, Italy
| | - A.L. Zignego
- Center for Systemic Manifestations of Hepatitis Viruses, University of Florence, Florence, Italy
| | - C. Ferri
- Department of Medical, Surgical, Maternal, Pediatric and Adult Sciences, University of Modena and Reggio Emilia, Modena, Italy
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The innate immune response to hepatitis B virus infection: Implications for pathogenesis and therapy. Antiviral Res 2012; 96:405-13. [DOI: 10.1016/j.antiviral.2012.10.001] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2012] [Revised: 10/02/2012] [Accepted: 10/05/2012] [Indexed: 02/07/2023]
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Guo F, Mead J, Aliya N, Wang L, Cuconati A, Wei L, Li K, Block TM, Guo JT, Chang J. RO 90-7501 enhances TLR3 and RLR agonist induced antiviral response. PLoS One 2012; 7:e42583. [PMID: 23056170 PMCID: PMC3463586 DOI: 10.1371/journal.pone.0042583] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Accepted: 07/09/2012] [Indexed: 12/20/2022] Open
Abstract
Recognition of virus infection by innate pattern recognition receptors (PRRs), including membrane-associated toll-like receptors (TLR) and cytoplasmic RIG-I-like receptors (RLR), activates cascades of signal transduction pathways leading to production of type I interferons (IFN) and proinflammatory cytokines that orchestrate the elimination of the viruses. Although it has been demonstrated that PRR-mediated innate immunity plays an essential role in defending virus from infection, it also occasionally results in overwhelming production of proinflammatory cytokines that cause severe inflammation, blood vessel leakage and tissue damage. In our efforts to identify small molecules that selectively enhance PRR-mediated antiviral, but not the detrimental inflammatory response, we discovered a compound, RO 90-7501 ('2'-(4-Aminophenyl)-[2,5'-bi-1H-benzimidazol]-5-amine), that significantly promoted both TLR3 and RLR ligand-induced IFN-β gene expression and antiviral response, most likely via selective activation of p38 mitogen-activated protein kinase (MAPK) pathway. Our results thus imply that pharmacological modulation of PRR signal transduction pathways in favor of the induction of a beneficial antiviral response can be a novel therapeutic strategy.
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Affiliation(s)
- Fang Guo
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America
| | - Jennifer Mead
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America
| | - Nishat Aliya
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America
| | - Lijuan Wang
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America
| | - Andrea Cuconati
- Institute for Hepatitis Virus Research, Hepatitis B Foundation, Doylestown, Pennsylvania, United States of America
| | - Lai Wei
- Institute of Hepatology, Peking University, Beijing, China
| | - Kui Li
- Department of Microbiology, Immunology and Biochemistry, The University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
| | - Timothy M. Block
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America
- Institute for Hepatitis Virus Research, Hepatitis B Foundation, Doylestown, Pennsylvania, United States of America
| | - Ju-Tao Guo
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America
| | - Jinhong Chang
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America
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Antonelli A, Fallahi P, Ferrari S, Frascerra S, Corrado A, Colaci M, Manfredi A, Maccheroni M, Sansonno D, Zignego A, Centanni M, Ferri C. Patients with Mixed Cryoglobulinemia and HCV Infection, in Presence or Absence of Autoimmune Thyroiditis, Have High Serum Levels of (CXC MOTIF) Ligand (CXCL)9 and CXCL11 Chemokines. EUR J INFLAMM 2012. [DOI: 10.1177/1721727x1201000319] [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] Open
Abstract
No data are present in the literature regarding chemokine (CXC motif) ligand (CXCL)9 and CXCL11 circulating levels in cryoglobulinemia associated with hepatitis C (MC+HCV), in presence/absence of autoimmune thyroiditis (AT). Serum CXCL9 and CXCL11 have been measured in 38 MC+HCV patients without AT (MCo), 38 MC+HCV patients with AT (MC+AT), and in matched controls without (control 1) or with thyroiditis (control 2). Serum CXCL9 and CXCL11 were significantly higher: in control 2 than control 1 ( p<0.05); in MCo than control 1 and control 2 ( p<0.001, for both); in MC+AT than control 1 and control 2 ( p<0.0001, for both), and than MCo ( p=0.01, for both). Our study demonstrates markedly high serum levels of CXCL9 and CXCL11 in patients with MC+HCV compared to healthy controls; in MC+HCV patients increased CXCL9 and CXCL11 levels were significantly associated with the presence of AT. Moreover, a strong relation between circulating CXCL9 and CXCL11 in MC+HCV has been shown.
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Affiliation(s)
- A. Antonelli
- Department of Internal Medicine, Metabolism Unit, University of Pisa School of Medicine, Pisa, Italy
| | - P. Fallahi
- Department of Internal Medicine, Metabolism Unit, University of Pisa School of Medicine, Pisa, Italy
| | - S.M. Ferrari
- Department of Internal Medicine, Metabolism Unit, University of Pisa School of Medicine, Pisa, Italy
| | - S. Frascerra
- Department of Internal Medicine, Metabolism Unit, University of Pisa School of Medicine, Pisa, Italy
| | - A. Corrado
- Department of Internal Medicine, Metabolism Unit, University of Pisa School of Medicine, Pisa, Italy
| | - M. Colaci
- Department of Internal Medicine, Rheumatology Unit, University of Modena and Reggio E. School of Medicine, Modena, Italy
| | - A. Manfredi
- Department of Internal Medicine, Rheumatology Unit, University of Modena and Reggio E. School of Medicine, Modena, Italy
| | - M. Maccheroni
- Endocrinological Laboratory, Azienda Ospedaliera Pisana, Pisa, Italy
| | - D. Sansonno
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - A.L. Zignego
- Department of Internal Medicine, University of Florence, Florence, Italy
| | - M. Centanni
- Endocrinology Unit, Department of Medico-Surgical Sciences and Biotechnologies, “Sapienza” University of Rome, Latina, Italy
| | - C. Ferri
- Department of Internal Medicine, Rheumatology Unit, University of Modena and Reggio E. School of Medicine, Modena, Italy
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Bansal R, Tomar T, Ostman A, Poelstra K, Prakash J. Selective targeting of interferon γ to stromal fibroblasts and pericytes as a novel therapeutic approach to inhibit angiogenesis and tumor growth. Mol Cancer Ther 2012; 11:2419-28. [PMID: 22933708 DOI: 10.1158/1535-7163.mct-11-0758] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
New approaches to block the function of tumor stromal cells such as cancer-associated fibroblasts and pericytes is an emerging field in cancer therapeutics as these cells play a crucial role in promoting angiogenesis and tumor growth via paracrine signals. Because of immunomodulatory and other antitumor activities, IFNγ, a pleiotropic cytokine, has been used as an anticancer agent in clinical trials. Unfortunately only modest beneficial effects, but severe side effects, were seen. In this study, we delivered IFNγ to stromal fibroblasts and pericytes, considering its direct antifibrotic activity, using our platelet-derived growth factor-beta receptor (PDGFβR)-binding carrier (pPB-HSA), as these cells abundantly express PDGFβR. We chemically conjugated IFNγ to pPB-HSA using a heterobifunctional PEG linker. In vitro in NIH3T3 fibroblasts, pPB-HSA-IFNγ conjugate activated IFNγ-signaling (pSTAT1α) and inhibited their activation and migration. Furthermore, pPB-HSA-IFNγ inhibited fibroblasts-induced tube formation of H5V endothelial cells. In vivo in B16 tumor-bearing mice, pPB-HSA-IFNγ rapidly accumulated in tumor stroma and pericytes and significantly inhibited the tumor growth while untargeted IFNγ and pPB-HSA carrier were ineffective. These antitumor effects of pPB-HSA-IFNγ were attributed to the inhibition of tumor vascularization, as shown with α-SMA and CD-31 staining. Moreover, pPB-HSA-IFNγ induced MHC-II expression specifically in tumors compared with untargeted IFNγ, indicating the specificity of this approach. This study thus shows the impact of drug targeting to tumor stromal cells in cancer therapy as well as provides new opportunities to use cytokines for therapeutic application.
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Affiliation(s)
- Ruchi Bansal
- Department of Targeted Therapeutics, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
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Abstract
Fibrosis is a pathological feature of most chronic inflammatory diseases. Fibrosis, or scarring, is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Fibrosis affects nearly every tissue in the body. Here we discuss how key components of the innate and adaptive immune response contribute to the pathogenesis of fibrosis. We also describe how cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix-producing myofibroblasts. Finally, we highlight some of the key mechanisms and pathways of fibrosis that are being targeted as potential therapies for a variety of important human diseases.
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Abstract
Fibrosis is a pathological feature of most chronic inflammatory diseases. Fibrosis, or scarring, is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Fibrosis affects nearly every tissue in the body. Here we discuss how key components of the innate and adaptive immune response contribute to the pathogenesis of fibrosis. We also describe how cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix-producing myofibroblasts. Finally, we highlight some of the key mechanisms and pathways of fibrosis that are being targeted as potential therapies for a variety of important human diseases.
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Affiliation(s)
- Thomas A Wynn
- Immunopathogenesis Section, Program in Barrier Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
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Abstract
While preclinical development of potential anti-fibrotics is far advanced, with numerous pharmacological targets and promising agents, almost none has entered clinical validation. Reasons are manifold, including the usually slow progression of liver fibrosis, requiring high numbers of well-stratified patients undergoing long-term treatment when conventional liver biopsy based parameters or hard liver-related endpoints are used. Importantly, there is a notorious lack of sensitive and specific surrogate markers or imaging technologies for liver fibrosis progression or regression that would permit a rapid clinical screening for potential anti-fibrotics. Nonetheless, in view of an urgent need for anti-fibrotics that positively impact morbidity and mortality from chronic liver diseases, the field is now moving more quickly towards clinical translation. This development is driven by thoughtful preclinical validation, a better study design and improved surrogate readouts using currently available methodologies. Moreover, upcoming novel biomarkers and imaging technologies will soon permit a more exact and efficient assessment of fibrosis progression and regression.
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Kong X, Horiguchi N, Mori M, Gao B. Cytokines and STATs in Liver Fibrosis. Front Physiol 2012; 3:69. [PMID: 22493582 PMCID: PMC3318231 DOI: 10.3389/fphys.2012.00069] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2012] [Accepted: 03/11/2012] [Indexed: 12/14/2022] Open
Abstract
Liver fibrosis, or cirrhosis, is a common end-stage condition of many chronic liver diseases after incomplete recovery from hepatocyte damage. During fibrosis progression, hepatocellular damage and inflammation trigger complex cellular events that result in collagen deposition and the disruption of the normal liver architecture. Hepatic stellate cell activation and transdifferentiation into myofibroblasts are key events in liver fibrogenesis. Research findings from cell culture and animal models have revealed that the Janus kinase-signal transducer and activator of transcription (Jak-STAT) signaling pathway, which can be activated by many cytokines, growth factors, and hormones, plays a critical role in hepatic fibrogenesis. This review summarizes the biological significance of diverse cytokines and their downstream signaling protein STATs in hepatic fibrogenesis.
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Affiliation(s)
- Xiaoni Kong
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Bethesda, MD, USA
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Li F, Li QH, Wang JY, Zhan CY, Xie C, Lu WY. Effects of interferon-gamma liposomes targeted to platelet-derived growth factor receptor-beta on hepatic fibrosis in rats. J Control Release 2011; 159:261-70. [PMID: 22226772 DOI: 10.1016/j.jconrel.2011.12.023] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Revised: 10/11/2011] [Accepted: 12/19/2011] [Indexed: 12/13/2022]
Abstract
No drugs have been approved clinically for the therapy of hepatic fibrosis. Though interferon-γ (IFN-γ) is a highly effective anti-fibrotic agent in vitro and in some animal models in vivo, its anti-fibrotic potential in clinical trials has been disappointing, due to unwanted off-target effects and a short half-life period which results in poor efficacy. The aims of this study are to develop a new targeted drug delivery system to selectively deliver IFN-γ to hepatic stellate cells (HSCs) and to investigate whether it will improve the anti-fibrotic effect of IFN-γ and reduce its side effects in fibrotic livers. Sterically stable liposomes (SSLs) were modified by cyclic peptides (pPB) with a specific affinity for platelet-derived growth factor receptor-β (PDGFR-β), and then IFN-γ was encapsulated in the targeted liposomes (pPB-SSL-IFN-γ). In vitro, pPB-SSL was found to be taken up and internalized by cultured activated HSCs. The binding of FITC-labeled pPB-SSL to activated HSCs was in a time-dependent and concentration-dependent manner, which could be inhibited by excess unlabelled pPB-SSL, PDGF-BB, suramin or monensin. The inhibitory effect of pPB-SSL-IFN-γ on the proliferation of activated HSCs was respectively 7.24-fold and 2.95-fold higher than that of free IFN-γ and IFN-γ encapsulated in untargeted SSLs. In healthy rats, the tissue distribution, living-body tracing image analyses and pharmacokinetics study showed that pPB-SSL-IFN-γ accumulated mainly in the livers and had a longer half-life than free IFN-γ (3.98±0.52h vs. 0.21±0.03h). Furthermore, in rats with hepatic fibrosis induced by thioacetamide injection, FITC-labeled pPB-SSL was found to predominantly localize in activated HSCs by immunofluorescent double staining for FITC and albumin or α-smooth muscle actin (α-SMA). The enhanced anti-fibrotic effect of pPB-SSL-IFN-γ treatnment was indicated by significant decreases in the histologic Ishak stage, collagen I-staining positive areas, and α-SMA expression levels in fibrotic livers. In addition, pPB-SSL-IFN-γ treatment improved the leukopenia caused by low- and high-dosage free IFN-γ treatments. In conclusion, IFN-γ encapsulated in pPB-SSL had an extended circulation half-life and was selectively delivered to activated HSCs, which enhanced the anti-fibrotic effect of IFN-γ and reduced its side-effects in rats with hepatic fibrosis. Thus, pPB-SSL-IFN-γ may be an effective agent for the therapy of hepatic fibrosis.
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Affiliation(s)
- Feng Li
- Department of Gastroenterology, Zhongshan Hospital affiliated to Fudan University, Shanghai, China
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Antonelli A, Fallahi P, Ferrari SM, Sebastiani M, Manfredi A, Mazzi V, Fabiani S, Centanni M, Marchi S, Ferri C. Circulating CXCL11 and CXCL10 are increased in hepatitis C-associated cryoglobulinemia in the presence of autoimmune thyroiditis. Mod Rheumatol 2011; 22:659-67. [PMID: 22160826 DOI: 10.1007/s10165-011-0565-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Accepted: 11/15/2011] [Indexed: 12/18/2022]
Abstract
OBJECTIVE No data are available about circulating levels of the CXCL11 chemokine in hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) patients with or without autoimmune thyroiditis (AT). The aim of the present study, therefore, was to evaluate serum CXCL11 levels in these patients. DESIGN Serum CXCL11 (and for comparison, CXCL10) was measured in 45 patients with MC, 45 patients with MC and AT (MC + AT), 45 sex- and age-matched controls without AT (control 1), 45 sex- and age-matched patients with AT without cryoglobulinemia (control 2), and in 45 sex- and age-matched patients with hepatitis C chronic infection without MC (HCV+). RESULTS Serum CXCL11 and CXCL10 levels were significantly higher in control 2 than in control 1 (p < 0.01). MC patients had CXCL11 and CXCL10 significantly higher than control 1 (p < 0.01). MC + AT patients had CXCL11 and CXCL10 higher than control 2 (p < 0.01) and MC patients (p = 0.02). Serum CXCL11 levels were not associated with any of the clinical features of cryoglobulinemia in patients with MC and MC + AT, which was the same for CXCL10. CXCL10 and CXCL11 in HCV+ patients were significantly higher than in controls 1 and 2, but lower than in MC or MC+AT patients. CONCLUSION Our study first demonstrates higher serum levels of CXCL11 chemokine in patients with MC than in HCV+ patients, and in particular in the presence of AT.
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Affiliation(s)
- Alessandro Antonelli
- Department of Internal Medicine, University of Pisa, School of Medicine, Via Roma, 67, 56100 Pisa, Italy.
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Bissell DM. Therapy for hepatic fibrosis: revisiting the preclinical models. Clin Res Hepatol Gastroenterol 2011; 35:521-5. [PMID: 21536514 DOI: 10.1016/j.clinre.2011.03.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Accepted: 03/16/2011] [Indexed: 02/04/2023]
Affiliation(s)
- D Montgomery Bissell
- University of California, Box 0538, 513, Parnassus Avenue, San Francisco, CA 94143, USA.
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Bansal R, Prakash J, de Ruijter M, Beljaars L, Poelstra K. Peptide-modified albumin carrier explored as a novel strategy for a cell-specific delivery of interferon gamma to treat liver fibrosis. Mol Pharm 2011; 8:1899-909. [PMID: 21800888 DOI: 10.1021/mp200263q] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Excessive accumulation of the extracellular matrix proteins primarily produced by activated hepatic stellate cells (HSC) leads to liver fibrosis. To date, no successful therapeutic intervention is available for the treatment of this disease. Platelet derived growth factor beta receptor (PDGFβR) is highly upregulated on disease-inducing activated HSC and thus can be used for delivery of antifibrotic drugs to increase therapeutic efficacy with reduced adverse effects. Interferon gamma (IFNγ) has been recognized as a potent antifibrotic cytokine; however, poor pharmacokinetics and side effects due to frequent administration have limited its clinical use. For HSC-specific delivery, a PDGFβR-specific drug delivery carrier (PPB-HSA) was developed by modifying albumin with PDGFβR-recognizing cyclic peptides. Subsequently, IFNγ was conjugated to PPB-HSA via bifunctional PEG linkers to synthesize PPB-HSA-PEG-IFNγ. In vitro, PPB-HSA-PEG-IFNγ retained complete biological activity similar to unmodified IFNγ and showed PDGFβR-specific binding to human HSC and primary culture-activated rat HSC. In TGFβ-stimulated mouse fibroblasts and human HSC, PPB-HSA-PEG-IFNγ induced significant reduction in crucial fibrotic parameters. In vivo, the conjugate rapidly accumulated into PDGFβR-expressing HSC in fibrotic livers and activated IFNγ-mediated pstat1α signaling pathway. Furthermore, in a CCl(4)-induced acute liver injury model in mice, treatment with HSC-targeted IFNγ strongly ameliorated hepatic fibrogenesis by inducing significant reduction (about 60%; p < 0.01) in collagen I and α-SMA expression as well as enhanced fibrolysis (increased MMP/TIMP ratio; p < 0.05) while free unmodified IFNγ was ineffective. Furthermore, in contrast to free native IFNγ, the conjugate did not induce macrophage infiltration and IL-1β expression in the liver. In conclusion, these data demonstrate the enhanced antifibrotic efficacy and reduced off-target effects of PPB-HSA-PEG-IFNγ conjugate showing the potential of cell-specific targeting of IFNγ for the treatment of liver fibrosis.
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Affiliation(s)
- Ruchi Bansal
- Department of Pharmacokinetics, Toxicology and Targeting, Graduate School for Drug Exploration, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
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Bansal R, Prakash J, Post E, Beljaars L, Schuppan D, Poelstra K. Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice. Hepatology 2011; 54:586-96. [PMID: 21538439 DOI: 10.1002/hep.24395] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Accepted: 04/19/2011] [Indexed: 01/13/2023]
Abstract
UNLABELLED Liver fibrogenesis is a process tightly controlled by endogenous anti- and pro-fibrogenic factors. Interferon gamma (IFNγ) is a potent antifibrogenic cytokine in vitro and might therefore represent a powerful therapeutic entity. However, its poor pharmacokinetics and adverse effects, due to the presence of IFNγ receptors on nearly all cells, prevented its clinical application so far. We hypothesized that delivery of IFNγ specifically to the disease-inducing cells and concurrently avoiding its binding to nontarget cells might increase therapeutic efficacy and avoid side effects. We conjugated IFNγ to a cyclic peptide recognizing the platelet-derived growth factor beta receptor (PDGFβR) which is strongly up-regulated on activated hepatic stellate cells (HSC), the key effector cells responsible for hepatic fibrogenesis. The IFNγ conjugates were analyzed in vitro for PDGFβR-specific binding and biological effects and in vivo in acute (early) and chronic (progressive and established) carbon-tetrachloride-induced liver fibrosis in mice. The targeted-IFNγ construct showed PDGFβR-specific binding to fibroblasts and HSC and inhibited their activation in vitro. In vivo, the targeted-IFNγ construct attenuated local HSC activation in an acute liver injury model. In the established liver fibrosis model, it not only strongly inhibited fibrogenesis but also induced fibrolysis. In contrast, nontargeted IFNγ was ineffective in both models. Moreover, in contrast to unmodified IFNγ, our engineered targeted-IFNγ did not induce IFNγ-related side effects such as systemic inflammation, hyperthermia, elevated plasma triglyceride levels, and neurotropic effects. CONCLUSION This study presents a novel HSC-targeted engineered-IFNγ, which in contrast to systemic IFNγ, blocked liver fibrogenesis and is devoid of side effects, by specifically acting on the key pathogenic cells within the liver.
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Affiliation(s)
- Ruchi Bansal
- Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands.
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ANTONELLI ALESSANDRO, FERRI CLODOVEO, FERRARI SILVIAMARTINA, RUFFILLI ILARIA, COLACI MICHELE, FRASCERRA SILVIA, MICCOLI MARIO, FRANZONI FERDINANDO, GALETTA FABIO, FALLAHI POUPAK. High Serum Levels of CXCL11 in Mixed Cryoglobulinemia Are Associated with Increased Circulating Levels of Interferon-γ. J Rheumatol 2011; 38:1947-52. [DOI: 10.3899/jrheum.110133] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Objective.No study has evaluated circulating chemokine C-X-C motif ligand (CXCL)11 in patients with “mixed cryoglobulinemia and chronic hepatitis C infection” (MC+HCV). We measured CXCL11, and correlated this measurement to the clinical phenotype.Methods.Serum CXCL11, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were assayed in 97 MC+HCV patients and in 97 sex- and age-matched controls.Results.MC+HCV patients showed significantly higher mean CXCL11 serum levels than controls (254 ± 295, 68 ± 16 pg/ml, respectively; p = 0.0002; ANOVA). CXCL11 was significantly increased in 36 cryoglobulinemic patients with compared to those without active vasculitis (303 ± 208 vs 179 ± 62 pg/ml, respectively; p < 0.001; ANOVA). IFN-γ levels were significantly higher in MC+HCV than in controls [6.1 (range 0.8–114.5), 1.4 (range 0.7–2.4) pg/ml, respectively; p < 0.05; Mann-Whitney U test]. Serum TNF-α mean levels were significantly higher in MC+HCV than in controls [13.4 (range 1.8–369), 1.1 (range 0.7–3.2) pg/ml, respectively; p < 0.0001; Mann-Whitney U test]. A multiple regression analysis considering CXCL11 as a dependent variable, and age, alanine aminotransferase, IFN-γ, and TNF-α as independent variables, showed in MC+HCV patients a significant association only with IFN-γ (p < 0.0001).Conclusion.Our study demonstrates markedly high serum levels of CXCL11 in patients with MC+HCV compared to healthy controls overall in the presence of active vasculitis. A strong relationship between circulating IFN-γ and CXCL11 was shown, strongly supporting the role of a T helper 1 immune response in the pathogenesis of MC+HCV.
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