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Hausmann M, Seuwen K, de Vallière C, Busch M, Ruiz PA, Rogler G. Role of pH-sensing receptors in colitis. Pflugers Arch 2024; 476:611-622. [PMID: 38514581 PMCID: PMC11006753 DOI: 10.1007/s00424-024-02943-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 03/06/2024] [Accepted: 03/06/2024] [Indexed: 03/23/2024]
Abstract
Low pH in the gut is associated with severe inflammation, fibrosis, and colorectal cancer (CRC) and is a hallmark of active inflammatory bowel disease (IBD). Subsequently, pH-sensing mechanisms are of interest for the understanding of IBD pathophysiology. Tissue hypoxia and acidosis-two contributing factors to disease pathophysiology-are linked to IBD, and understanding their interplay is highly relevant for the development of new therapeutic options. One member of the proton-sensing G protein-coupled receptor (GPCR) family, GPR65 (T-cell death-associated gene 8, TDAG8), was identified as a susceptibility gene for IBD in a large genome-wide association study. In response to acidic extracellular pH, GPR65 induces an anti-inflammatory response, whereas the two other proton-sensing receptors, GPR4 and GPR68 (ovarian cancer G protein-coupled receptor 1, OGR1), mediate pro-inflammatory responses. Here, we review the current knowledge on the role of these proton-sensing receptors in IBD and IBD-associated fibrosis and cancer, as well as colitis-associated cancer (CAC). We also describe emerging small molecule modulators of these receptors as therapeutic opportunities for the treatment of IBD.
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Affiliation(s)
- Martin Hausmann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091, Zurich, CH, Switzerland.
| | - Klaus Seuwen
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091, Zurich, CH, Switzerland
| | - Cheryl de Vallière
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091, Zurich, CH, Switzerland
| | - Moana Busch
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091, Zurich, CH, Switzerland
| | - Pedro A Ruiz
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091, Zurich, CH, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091, Zurich, CH, Switzerland
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2
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Vanderstichele S, Vranckx JJ. Anti-fibrotic effect of adipose-derived stem cells on fibrotic scars. World J Stem Cells 2022; 14:200-213. [PMID: 35432731 PMCID: PMC8963379 DOI: 10.4252/wjsc.v14.i2.200] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/01/2021] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Sustained injury, through radiotherapy, burns or surgical trauma, can result in fibrosis, displaying an excessive deposition of extracellular matrix (ECM), persisting inflammatory reaction, and reduced vascularization. The increasing recognition of fibrosis as a cause for disease and mortality, and increasing use of radiotherapy causing fibrosis, stresses the importance of a decent anti-fibrotic treatment.
AIM To obtain an in-depth understanding of the complex mechanisms underlying fibrosis, and more specifically, the potential mechanisms-of-action of adipose-derived stomal cells (ADSCs) in realizing their anti-fibrotic effect.
METHODS A systematic review of the literature using PubMed, Embase and Web of Science was performed by two independent reviewers.
RESULTS The injection of fat grafts into fibrotic tissue, releases ADSC into the environment. ADSCs’ capacity to directly differentiate into key cell types (e.g., ECs, fibroblasts), as well as to secrete multiple paracrine factors (e.g., hepatocyte growth factor, basis fibroblast growth factor, IL-10), allows them to alter different mechanisms underlying fibrosis in a combined approach. ADSCs favor ECM degradation by impacting the fibroblast-to-myofibroblast differentiation, favoring matrix metalloproteinases over tissue inhibitors of metalloproteinases, positively influencing collagen organization, and inhibiting the pro-fibrotic effects of transforming growth factor-β1. Furthermore, they impact elements of both the innate and adaptive immune response system, and stimulate angiogenesis on the site of injury (through secretion of pro-angiogenic cytokines like stromal cell-derived factor-1 and vascular endothelial growth factor).
CONCLUSION This review shows that understanding the complex interactions of ECM accumulation, immune response and vascularization, is vital to fibrosis treatments’ effectiveness like fat grafting. It details how ADSCs intelligently steer this complex system in an anti-fibrotic or pro-angiogenic direction, without falling into extreme dilation or stimulation of a single aspect. Detailing this combined approach, has brought fat grafting one step closer to unlocking its full potential as a non-anecdotal treatment for fibrosis.
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Affiliation(s)
| | - Jan Jeroen Vranckx
- Department of Plastic, Reconstructive Surgery, KU-Leuven University Hospitals, Leuven 3000, Belgium
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3
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Santos MP, Gonçalves-Santos E, Gonçalves RV, Santos EC, Campos CC, Bastos DSS, Marques MJ, Souza RLM, Novaes RD. Doxycycline aggravates granulomatous inflammation and lung microstructural remodeling induced by Schistosoma mansoni infection. Int Immunopharmacol 2021; 94:107462. [PMID: 33611055 DOI: 10.1016/j.intimp.2021.107462] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 01/29/2021] [Accepted: 02/01/2021] [Indexed: 12/20/2022]
Abstract
Although doxycycline exhibits immunomodulatory properties, its effects on pulmonary infection by Schistosoma mansoni remain overlooked. Thus, we investigated the impact of this drug on lung granulomatous inflammation and microstructural remodeling in a murine model of schistosomiasis. Swiss mice were randomized in four groups: (i) uninfected, (ii) infected with S. mansoni and untreated, (iii) infected treated with praziquantel (Pzq; 200 mg/kg), and (iv) infected treated with Dox (50 mg/kg). Pz was administered in a single dose, and Dox for 60 days. S. mansoni induced marked granulomatous lung inflammation, which was associated to cytokines upregulation (IL-2, IL-4, IL-10, IFN-γ, TNF-α, and TGF-β), neutrophils and macrophages recruitment, alveolar collapse, lung fibrosis, and extensive depletion of elastic fibers. These parameters were attenuated by Pzq and aggravated by Dox. Exudative/productive granulomas were predominant in untreated and Dox-treated animals, while fibrotic granulomas were more frequent in Pzq-treated mice. The number and size of granulomas in Dox-treated animals was higher than untreated and Pzq-treated mice. Dox treatment inhibited the increase in MMP-1 and MMP-2 activity but upregulated myeloperoxidase and N-acetylglucosaminidase activity compared to untreated and Pzq-treated animals. Dox and Pzq exerted no effect on elastin depletion and upregulation of elastase activity. Together, our findings indicated that Dox aggravated granulomatous inflammation, accelerating lung microstructural remodeling by downregulating MMP-1 and MMP-2 activity without impair neutrophils and macrophages recruitment or elastase activity. Thus, Dox potentiates inflammatory damage associated with lung fibrosis, elastin depletion and massive alveolar collapse, profoundly subverting lung structure in S. mansoni-infected mice.
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Affiliation(s)
- Margarida P Santos
- Institute of Biomedical Sciences, Department of Structural Biology, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil
| | - Elda Gonçalves-Santos
- Institute of Biomedical Sciences, Department of Structural Biology, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil
| | - Reggiani V Gonçalves
- Department of Animal Biology, Federal University of Viçosa, Viçosa, Minas Gerais, Brazil
| | - Eliziária C Santos
- School of Medicine, Federal University of Jequitinhonha and Mucuri Valleys, Diamantina, Minas Gerais, Brazil
| | - Camila C Campos
- Institute of Biomedical Sciences, Department of Structural Biology, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil
| | - Daniel S S Bastos
- Department of General Biology, Federal University of Viçosa, Viçosa, Minas Gerais, Brazil
| | - Marcos J Marques
- Institute of Biomedical Sciences, Department of Pathology and Parasitology, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil
| | - Raquel L M Souza
- Institute of Biomedical Sciences, Department of Pathology and Parasitology, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil
| | - Rômulo D Novaes
- Institute of Biomedical Sciences, Department of Structural Biology, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil.
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4
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Brovold M, Keller D, Soker S. Differential fibrotic phenotypes of hepatic stellate cells within 3D liver organoids. Biotechnol Bioeng 2020; 117:2516-2526. [PMID: 32391915 DOI: 10.1002/bit.27379] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 04/16/2020] [Accepted: 05/07/2020] [Indexed: 02/06/2023]
Abstract
Liver fibrosis occurs in most cases of chronic liver disease, which are somewhat common, but also a potentially deadly group of diseases. In vitro modeling of liver fibrosis relies primarily on the isolation of in vivo activated hepatic stellate cells (aHSCs) and studying them in standard tissue culture dishes (two-dimensional [2D]). In contrast, modeling of fibrosis in a biofabricated three-dimensional (3D) construct allows us to study changes to the environment, such as extracellular matrix (ECM) composition and structure, and tissue rigidity. In the current study, we used aHSCs produced through subcultures in 2D and encapsulated them in a 3D collagen gel to form spherical constructs. In parallel, and as a comparison, we used an established HSC line, LX-2, representing early and less severe fibrosis. Compared with LX-2 cells, the aHSCs created a stiffer environment and expressed higher levels of TIMP1 and LOXL2, all of which are indicative of advanced liver fibrosis. Collectively, this study presents a fibrosis model that could be incorporated with multi-cellular models to more accurately reflect the effects of a severe fibrotic environment on liver function.
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Affiliation(s)
- Matthew Brovold
- Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
| | - Dale Keller
- Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.,School of Medicine, Meharry Medical College, Nashville, Tennessee
| | - Shay Soker
- Wake Forest School of Medicine, Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
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5
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Dupnik KM, Lee MH, Mishra P, Reust MJ, Colombe S, Haider SR, Yao B, Vick K, Zhang T, Xiang J, Miyaye D, Magawa R, Lyimo E, Mukerebe C, Mngara J, Kalluvya SE, de Dood CJ, van Dam GJ, Corstjens PLAM, Downs JA. Altered Cervical Mucosal Gene Expression and Lower Interleukin 15 Levels in Women With Schistosoma haematobium Infection but Not in Women With Schistosoma mansoni Infection. J Infect Dis 2020; 219:1777-1785. [PMID: 30590736 DOI: 10.1093/infdis/jiy742] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Accepted: 12/21/2018] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Schistosomiasis increases the risk of human immunodeficiency virus (HIV) acquisition in women by mechanisms that are incompletely defined. Our objective was to determine how the cervical environment is impacted by Schistosoma haematobium or Schistosoma mansoni infection by quantifying gene expression in the cervical mucosa and cytokine levels in cervicovaginal lavage fluid. METHODS We recruited women with and those without S. haematobium infection and women with and those without S. mansoni infection from separate villages in rural Tanzania with high prevalences of S. haematobium and S. mansoni, respectively. Infection status was determined by urine and stool microscopy and testing for serum circulating anodic antigen. RNA was extracted from cervical cytobrush samples for transcriptome analysis. Cytokine levels were measured by magnetic bead immunoassay. RESULTS In the village where S. haematobium was prevalent, 110 genes were differentially expressed in the cervical mucosa of 18 women with versus 39 without S. haematobium infection. Among the 27 cytokines analyzed in cervicovaginal lavage fluid from women in this village, the level of interleukin 15 was lower in the S. haematobium-infected group (62.8 vs 102.9 pg/mL; adjusted P = .0013). Differences were not observed in the S. mansoni-prevalent villages between 11 women with and 29 without S. mansoni infection. CONCLUSIONS We demonstrate altered cervical mucosal gene expression and lower interleukin 15 levels in women with S. haematobium infection as compared to those with S. mansoni infection, which may influence HIV acquisition and cancer risks. Studies to determine the effects of antischistosome treatment on these mucosal alterations are needed.
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Affiliation(s)
- Kathryn M Dupnik
- Center for Global Health, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Myung Hee Lee
- Center for Global Health, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Pallavi Mishra
- Center for Global Health, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Mary Juliet Reust
- Center for Global Health, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Soledad Colombe
- Center for Global Health, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Syeda Razia Haider
- Center for Global Health, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Benjamin Yao
- Center for Global Health, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Kaitlin Vick
- Center for Global Health, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Tuo Zhang
- Genomics Resources Core Facility, Weill Cornell Medicine, New York, New York
| | - Jenny Xiang
- Genomics Resources Core Facility, Weill Cornell Medicine, New York, New York
| | - Donald Miyaye
- National Institute for Medical Research, Bugando Medical Centre, Mwanza, Tanzania
| | - Ruth Magawa
- National Institute for Medical Research, Bugando Medical Centre, Mwanza, Tanzania
| | - Eric Lyimo
- National Institute for Medical Research, Bugando Medical Centre, Mwanza, Tanzania
| | - Crispin Mukerebe
- National Institute for Medical Research, Bugando Medical Centre, Mwanza, Tanzania
| | - Julius Mngara
- National Institute for Medical Research, Bugando Medical Centre, Mwanza, Tanzania
| | | | | | - Govert J van Dam
- Department of Parasitology, Leiden University, Leiden, the Netherlands
| | | | - Jennifer A Downs
- Center for Global Health, Department of Medicine, Weill Cornell Medicine, New York, New York.,Department of Medicine, Bugando Medical Centre, Mwanza, Tanzania
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6
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Dias MV, Castro AP, Campos CC, Souza-Silva TG, Gonçalves RV, Souza RLM, Marques MJ, Novaes RD. Doxycycline hyclate: A schistosomicidal agent in vitro with immunomodulatory potential on granulomatous inflammation in vivo. Int Immunopharmacol 2019; 70:324-337. [DOI: 10.1016/j.intimp.2019.02.032] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 02/13/2019] [Accepted: 02/19/2019] [Indexed: 02/07/2023]
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7
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El-Khadragy MF, Al-Olayan EM, Elmallah MIY, Alharbi AM, Yehia HM, Abdel Moneim AE. Probiotics and yogurt modulate oxidative stress and fibrosis in livers of Schistosoma mansoni-infected mice. Altern Ther Health Med 2019; 19:3. [PMID: 30606163 PMCID: PMC6318950 DOI: 10.1186/s12906-018-2406-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 12/07/2018] [Indexed: 01/05/2023]
Abstract
Background Considerable morbidity, mortality, and economic loss result from schistosomiasis infection. Deposition of Schistosoma eggs in the hepatic portal vein is considered as the main causative agent for the development of liver fibrosis and subsequent liver cirrhosis. Probiotics are exogenous and beneficial microorganisms to living hosts against the harmful effect of many parasites. Strong evidence suggests the importance of probiotics in the control strategy of helminth. The ultimate goal of this study is to evaluate the protective effect of probiotics and yogurt on Schistosoma mansoni-induced oxidative stress and hepatic fibrosis in mice. Methods Mice were infected by tail immersion of schistosomal cercariae followed by an oral treatment with either probiotics or yogurt for one week before infection and immediately post-infection. Mice were scarified on day 56 following infection with S. mansoni and liver sample were obtained. Results We showed that oral administration of probiotics or yogurt revealed a significant reduction in worm number, egg load, and granuloma size in liver tissue, which is mainly assigned to the decreased expression level of matrix metalloproteinases 9 (MMP-9) in liver tissue. A significant reduction in the oxidative stress markers-induced by S. mansoni infection including lipid peroxidation and nitrite/nitrate was also detected. The level of some antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase) and reduced glutathione was greatly enhanced. Furthermore, treatment with probiotics or yogurt inhibited apoptosis in hepatic tissue, which is mainly assigned to the decreased expression level of caspases-3 in liver tissue. Conclusion Our findings represent the promising anti-schistosomal activities of probiotics and yogurt. Electronic supplementary material The online version of this article (10.1186/s12906-018-2406-3) contains supplementary material, which is available to authorized users.
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8
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Hutter S, van Haaften WT, Hünerwadel A, Baebler K, Herfarth N, Raselli T, Mamie C, Misselwitz B, Rogler G, Weder B, Dijkstra G, Meier CF, de Vallière C, Weber A, Imenez Silva PH, Wagner CA, Frey-Wagner I, Ruiz PA, Hausmann M. Intestinal Activation of pH-Sensing Receptor OGR1 [GPR68] Contributes to Fibrogenesis. J Crohns Colitis 2018; 12:1348-1358. [PMID: 30165600 DOI: 10.1093/ecco-jcc/jjy118] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS pH-sensing ovarian cancer G-protein coupled receptor-1 [OGR1/GPR68] is regulated by key inflammatory cytokines. Patients suffering from inflammatory bowel diseases [IBDs] express increased mucosal levels of OGR1 compared with non-IBD controls. pH-sensing may be relevant for progression of fibrosis, as extracellular acidification leads to fibroblast activation and extracellular matrix remodelling. We aimed to determine OGR1 expression in fibrotic lesions in the intestine of Crohn's disease [CD] patients, and the effect of Ogr1 deficiency in fibrogenesis. METHODS Human fibrotic and non-fibrotic terminal ileum was obtained from CD patients undergoing ileocaecal resection due to stenosis. Gene expression of fibrosis markers and pH-sensing receptors was analysed. For the initiation of fibrosis in vivo, spontaneous colitis by Il10-/-, dextran sodium sulfate [DSS]-induced chronic colitis and the heterotopic intestinal transplantation model were used. RESULTS Increased expression of fibrosis markers was accompanied by an increase in OGR1 [2.71 ± 0.69 vs 1.18 ± 0.03, p = 0.016] in fibrosis-affected human terminal ileum, compared with the non-fibrotic resection margin. Positive correlation between OGR1 expression and pro-fibrotic cytokines [TGFB1 and CTGF] and pro-collagens was observed. The heterotopic animal model for intestinal fibrosis transplanted with terminal ileum from Ogr1-/- mice showed a decrease in mRNA expression of fibrosis markers as well as a decrease in collagen layer thickness and hydroxyproline compared with grafts from wild-type mice. CONCLUSIONS OGR1 expression was correlated with increased expression levels of pro-fibrotic genes and collagen deposition. Ogr1 deficiency was associated with a decrease in fibrosis formation. Targeting OGR1 may be a potential new treatment option for IBD-associated fibrosis.
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Affiliation(s)
- Senta Hutter
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Wouter T van Haaften
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Anouk Hünerwadel
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Katharina Baebler
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Neel Herfarth
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Tina Raselli
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Céline Mamie
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Benjamin Misselwitz
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.,Institute of Physiology, University of Zürich, Zürich, Switzerland
| | - Bruce Weder
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Chantal Florence Meier
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Cheryl de Vallière
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Achim Weber
- Department of Pathology and Molecular Pathology, University Hospital Zürich, Zürich, Switzerland
| | - Pedro H Imenez Silva
- Institute of Physiology, University of Zürich, Zürich, Switzerland.,Kidney Control of Homeostasis, Swiss National Centre of Competence in Research, Zürich, Switzerland
| | - Carsten A Wagner
- Institute of Physiology, University of Zürich, Zürich, Switzerland
| | - Isabelle Frey-Wagner
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Pedro A Ruiz
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Martin Hausmann
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
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9
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Weder B, Mamie C, Rogler G, Clarke S, McRae B, Ruiz PA, Hausmann M. BCL2 Regulates Differentiation of Intestinal Fibroblasts. Inflamm Bowel Dis 2018; 24:1953-1966. [PMID: 29796658 DOI: 10.1093/ibd/izy147] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Fibrosis in patients with Crohn's disease (CD) results from an imbalance toward excessive fibrous tissue formation driven by fibroblasts. Activation of fibroblasts is linked to the B-cell lymphoma 2 (BCL2) family, which is involved in the induction of apoptosis. We investigated the impact of BCL2 repression on fibrogenesis. METHODS The model of dextran sodium sulfate (DSS)-induced chronic colitis and the heterotopic transplantation model of fibrosis were used. Following the administration of the BCL2 antagonist (ABT-737, 50 mg/kg/d), collagen layer thickness and hydroxyproline (HYP) content were determined. Fibroblasts were stimulated with the BCL2 antagonist (0.01-100 µM). BCL2, alpha smooth muscle actin (αSMA), and collagen I (COL1A1) were determined by quantitative polymerase chain reaction (qPCR), immunofluorescence microscopy (IF), and western blot (WB). mRNA expression pattern was determined by next-generation sequencing (NGS). RESULTS Collagen layer thickness was significantly decreased in both DSS-induced chronic colitis and the transplantation model of fibrosis upon BCL2 antagonist administration compared with vehicle. Decreased HYP content confirmed the preventive effects of the BCL2 antagonist on fibrosis. In vitro, a significant increase in PI+/annexin V+ human colonic fibroblasts was determined by fluorescence-activated cell sorting upon treatment with high-dose BCL2 antagonist; at a lower dose, αSMA, COL1A1, and TGF were decreased. NGS, IF, and qPCR revealed decreased expression and nuclear translocation of GATA6 and SOX9, known for reprogramming fibroblasts. CONCLUSION BCL2 antagonist administration partially prevented fibrogenesis in both fibrosis models. The BCL2 antagonist reduced the expression of TGFβ-induced factors involved in differentiation of myofibroblasts, and therefore might represent a potential treatment option against CD-associated fibrosis.
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Affiliation(s)
- Bruce Weder
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Céline Mamie
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Stephen Clarke
- AbbVie Bioresearch Center, AbbVie, Worcester, Massachusetts
| | - Bradford McRae
- AbbVie Bioresearch Center, AbbVie, Worcester, Massachusetts
| | - Pedro A Ruiz
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Martin Hausmann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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10
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Lutz C, Weder B, Hünerwadel A, Fagagnini S, Lang B, Beerenwinkel N, Rossel JB, Rogler G, Misselwitz B, Hausmann M. Myeloid differentiation primary response gene (MyD) 88 signalling is not essential for intestinal fibrosis development. Sci Rep 2017; 7:17678. [PMID: 29247242 PMCID: PMC5732165 DOI: 10.1038/s41598-017-17755-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 11/29/2017] [Indexed: 01/15/2023] Open
Abstract
Dysregulation of the immune response to microbiota is associated with inflammatory bowel disease (IBD), which can trigger intestinal fibrosis. MyD88 is a key component of microbiota signalling but its influence on intestinal fibrosis has not been clarified. Small bowel resections from donor-mice were transplanted subcutaneously into the neck of recipients C57BL/6 B6-MyD88tm1 Aki (MyD88-/-) and C57BL/6-Tg(UBC-green fluorescence protein (GFP))30Scha/J (GFP-Tg). Grafts were explanted up to 21 days after transplantation. Collagen layer thickness was determined using Sirius Red stained slides. In the mouse model of fibrosis collagen deposition and transforming growth factor-beta 1 (TGF-β1) expression was equal in MyD88+/+ and MyD88-/-, indicating that MyD88 was not essential for fibrogenesis. Matrix metalloproteinase (Mmp)9 expression was significantly decreased in grafts transplanted into MyD88-/- recipients compared to MyD88+/+ recipients (0.2 ± 0.1 vs. 153.0 ± 23.1, respectively, p < 0.05), similarly recruitment of neutrophils was significantly reduced (16.3 ± 4.5 vs. 25.4 ± 3.1, respectively, p < 0.05). Development of intestinal fibrosis appears to be independent of MyD88 signalling indicating a minor role of bacterial wall compounds in the process which is in contrast to published concepts and theories. Development of fibrosis appears to be uncoupled from acute inflammation.
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Affiliation(s)
- C Lutz
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland
| | - B Weder
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland
| | - A Hünerwadel
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland
| | - S Fagagnini
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland
| | - B Lang
- Department of Biosystems Sciences and Engineering, ETH Zurich, Basel, Switzerland.,SIB Swiss Institute of Bioinformatics, Basel, Switzerland
| | - N Beerenwinkel
- Department of Biosystems Sciences and Engineering, ETH Zurich, Basel, Switzerland.,SIB Swiss Institute of Bioinformatics, Basel, Switzerland
| | - J B Rossel
- Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland
| | - G Rogler
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland
| | - B Misselwitz
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland
| | - M Hausmann
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland.
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Al-Olayan EM, El-Khadragy MF, Alajmi RA, Othman MS, Bauomy AA, Ibrahim SR, Abdel Moneim AE. Ceratonia siliqua pod extract ameliorates Schistosoma mansoni-induced liver fibrosis and oxidative stress. Altern Ther Health Med 2016; 16:434. [PMID: 27821159 PMCID: PMC5100080 DOI: 10.1186/s12906-016-1389-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 10/13/2016] [Indexed: 01/24/2023]
Abstract
Background Schistosomiasis is a prevalent parasitic disease found predominantly in tropical and sub-tropical areas of the developing world, with the second highest socioeconomic and public health burden despite strenuous control efforts. In the present study, we aimed to investigate the ameliorative effects of Ceratonia siliqua pod extract (CPE) on liver fibrosis and oxidative stress in mice infected with Schistosoma mansoni. Methods The schistosomal hepatopathologic mouse model was established by tail immersion with schistosomal cercaria. The extract was given daily for 10 days beginning 42 days post-infection. Liver samples were obtained from mice sacrificed 9 weeks after infection. Liver histopathological changes were observed with hematoxylin-eosin and Masson trichrome staining. Results Typical schistosomal hepatopathologic changes were induced in the untreated mice. However, the oral administration of CPE was effective in reducing worm number and the egg load in the liver. This treatment also decreased granuloma size and collagen deposition by inhibiting tissue inhibitor of metalloproteinases-2 (TIMP-2) expression. Schistosomal infection induced oxidative stress by increasing lipid peroxidation (LPO) and nitrite/nitrate (nitric oxide; NO) production along with concomitant decreases in glutathione (GSH) and various antioxidant enzymes, including superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. However, treatment of mice with CPE at 300 or 600 mg/kg inhibited LPO and NO production, increased GSH content, and restored the activities of the antioxidant enzymes compared with untreated infected mice. Furthermore, treatment with CPE inhibited apoptosis, as indicated by the reduced Bax expression in hepatic tissue. Conclusion These data indicated that extracts from Ceratonia siliqua pods may play an important role in combating schistosomal hepatopathology and may inhibit granuloma formation and liver fibrosis through down-regulation of TIMP-2 expression. Electronic supplementary material The online version of this article (doi:10.1186/s12906-016-1389-1) contains supplementary material, which is available to authorized users.
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Elbakry KA, Abdelaziz MM. Myrrh and artesunate modulate some Th1 and Th2 cytokines secretion in Schistosoma mansoni infected mice. Cent Eur J Immunol 2016; 41:138-42. [PMID: 27536198 PMCID: PMC4967647 DOI: 10.5114/ceji.2016.60986] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 02/10/2016] [Indexed: 11/17/2022] Open
Abstract
The effects of artesunate and myrrh on S. mansoni infection and the levels of some Th1 and Th2 cytokines were evaluated in the present study. Six weeks after infection, a group of mice was treated with 4 mg/kg of artesunate and other group was treated with 10 mg/kg of myrrh for 3 successive days. Worm burden was reduced with a percentage of 53.7% and 58.78% after treatment with myrrh and artesunate respectively as well as the levels of IgG antibodies were significantly reduced compared with infected group. No obvious changes were observed in the level of interferon γ after treatment. After treatment with artesunate, interleukin 2 (IL-2) level was significantly decreased, while no significant difference was observed in myrrh-treated group compared with the infected group. On the other hand, the level of IL-10 was not significantly decreased after treatment with artesunate, but it was significantly increased after treatment with myrrh. However, IL-12 levels were significantly decreased after treatment with artesunate. The results demonstrated that, artesunate or myrrh treatment could give a level of protection against S. mansoni infection and modulate the levels of some Th1 and Th2 cytokines in mice infected with S. mansoni.
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Affiliation(s)
- Kadry A. Elbakry
- Zoology Department, Faculty of Science, Damietta University, Damietta, Egypt
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Ramalingam TR, Gieseck RL, Acciani TH, M Hart K, Cheever AW, Mentink-Kane MM, Vannella KM, Wynn TA. Enhanced protection from fibrosis and inflammation in the combined absence of IL-13 and IFN-γ. J Pathol 2016; 239:344-54. [PMID: 27125685 DOI: 10.1002/path.4733] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 04/12/2016] [Accepted: 04/15/2016] [Indexed: 12/17/2022]
Abstract
Persistent or dysregulated IL-13 responses are key drivers of fibrosis in multiple organ systems, and this identifies this cytokine as an important therapeutic target. Nevertheless, the mechanisms by which IL-13 blockade leads to the amelioration of fibrosis remain unclear. Because IFN-γ exhibits potent anti-fibrotic activity, and IL-4Rα signalling antagonizes IFN-γ effector function, compensatory increases in IFN-γ activity following IL-13/IL-4Rα blockade might contribute to the reduction in fibrosis. To investigate the role of IFN-γ, we developed novel IL-13(-/-) /IFN-γ(-/-) double cytokine-deficient mice and examined disease progression in models of type 2-driven fibrosis. As predicted, we showed that fibrosis in the lung and liver are both highly dependent on IL-13. We also observed increased IFN-γ production and inflammatory activity in the tissues of IL-13-deficient mice. Surprisingly, however, an even greater reduction in fibrosis was observed in IL-13/IFN-γ double deficient mice, most notably in the livers of mice chronically infected with Schistosoma mansoni. The increased protection was associated with marked decreases in Tgfb1, Mmp12, and Timp1 mRNA expression in the tissues; reduced inflammation; and decreased expression of important pro-inflammatory mediators such as TNF-α. Experiments conducted with neutralizing monoclonal antibodies to IL-13 and IFN-γ validated the findings with the genetically deficient mice. Together, these studies demonstrate that the reduction in fibrosis observed when IL-13 signalling is suppressed is not dependent on increased IFN-γ activity. Instead, by reducing compensatory increases in type 1-associated inflammation, therapeutic strategies that block IFN-γ and IL-13 activity simultaneously can confer greater protection from progressive fibrosis than IL-13 blockade alone. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.
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Affiliation(s)
- Thirumalai R Ramalingam
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
| | - Richard L Gieseck
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
| | - Thomas H Acciani
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
| | - Kevin M Hart
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
| | - Allen W Cheever
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
| | | | - Kevin M Vannella
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
| | - Thomas A Wynn
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
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The Effect of rhCygb on CCl4-Induced Hepatic Fibrogenesis in Rat. Sci Rep 2016; 6:23508. [PMID: 27006085 PMCID: PMC4804332 DOI: 10.1038/srep23508] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 03/08/2016] [Indexed: 12/22/2022] Open
Abstract
This study aims to investigate whether the use of recombinant human cytoglobin (rhCygb) impact on hepatic fibrogenesis caused by CCl4. SD (n = 150) rats were randomly divided into three groups of normal, CCl4 model and rhCygb groups. After model establishment, rats in rhCygb groups were administered daily with rhCygb (2 mg/kg, s.c.). Histological lesions were staged according to metavir. Serum parameters including ALT, AST, HA, LN, Col III and Col IV were determined. The liver proteins were separated by 2-DE and identified. As a result, the stage of hepatic damage and liver fibrosis in rhCygb groups were significantly milder than that in CCl4 model groups. Meanwhile, rhCygb dramatically reversed serum levels of ALT and AST, and also markedly decreased the liver fibrosis markers levels of LN, HA, Col III and Col IV. In 2-DE, 33 proteins among three groups with the same changing tendency in normal and rhCygb treated groups compared with CCl4 model group were identified. GO analysis showed that several identified proteins involved in oxidative stress pathway. The study provides new insights and data for administration of rhCygb reversing CCl4-induced liver fibrosis suggesting that rhCygb might be used in the treatment of liver fibrosis.
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15
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Decreased Fibrogenesis After Treatment with Pirfenidone in a Newly Developed Mouse Model of Intestinal Fibrosis. Inflamm Bowel Dis 2016; 22:569-82. [PMID: 26848518 DOI: 10.1097/mib.0000000000000716] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Fibrosis as a common problem in patients with Crohn's disease is a result of an imbalance toward excessive tissue repair. At present, there is no specific treatment option. Pirfenidone is approved for the treatment of idiopathic pulmonary fibrosis with both antifibrotic and anti-inflammatory effects. We subsequently investigated the impact of pirfenidone treatment on development of fibrosis in a new mouse model of intestinal fibrosis. METHODS Small bowel resections from donor mice were transplanted subcutaneously into the neck of recipients. Animals received either pirfenidone (100 mg/kg, three times daily, orally) or vehicle. RESULTS After administration of pirfenidone, a significantly decreased collagen layer thickness was revealed as compared to vehicle (9.7 ± 1.0 versus 13.5 ± 1.5 µm, respectively, **P < 0.001). Transforming growth factor-β and matrix metalloproteinase-9 were significantly decreased after treatment with pirfenidone as confirmed by real-time PCR (0.42 ± 0.13 versus 1.00 ± 0.21 and 0.46 ± 0.24 versus 1.00 ± 0.62 mRNA expression level relative to GAPDH, respectively, *P < 0.05). Significantly decreased transforming growth factor-β after administration of pirfenidone was confirmed by Western blotting. CONCLUSION In our mouse model, intestinal fibrosis can be reliably induced and is developed within 7 days. Pirfenidone partially prevented the development of fibrosis, making it a potential treatment option against Crohn's disease-associated fibrosis.
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Chuah C, Jones MK, McManus DP, Nawaratna SK, Burke ML, Owen HC, Ramm GA, Gobert GN. Characterising granuloma regression and liver recovery in a murine model of schistosomiasis japonica. Int J Parasitol 2016; 46:239-52. [PMID: 26812024 DOI: 10.1016/j.ijpara.2015.12.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 11/30/2015] [Accepted: 12/07/2015] [Indexed: 02/07/2023]
Abstract
For hepatic schistosomiasis the egg-induced granulomatous response and the development of extensive fibrosis are the main pathologies. We used a Schistosoma japonicum-infected mouse model to characterise the multi-cellular pathways associated with the recovery from hepatic fibrosis following clearance of the infection with the anti-schistosomal drug, praziquantel. In the recovering liver splenomegaly, granuloma density and liver fibrosis were all reduced. Inflammatory cell infiltration into the liver was evident, and the numbers of neutrophils, eosinophils and macrophages were significantly decreased. Transcriptomic analysis revealed the up-regulation of fatty acid metabolism genes and the identification of Peroxisome proliferator activated receptor alpha as the upstream regulator of liver recovery. The aryl hydrocarbon receptor signalling pathway which regulates xenobiotic metabolism was also differentially up-regulated. These findings provide a better understanding of the mechanisms associated with the regression of hepatic schistosomiasis.
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Affiliation(s)
- Candy Chuah
- QIMR Berghofer Medical Research Institute, Brisbane, Qld 4006, Australia; School of Veterinary Sciences, The University of Queensland, Gatton, Qld 4343, Australia; School of Medical Sciences, Universiti Sains Malaysia, 16150 Kelantan, Malaysia
| | - Malcolm K Jones
- School of Veterinary Sciences, The University of Queensland, Gatton, Qld 4343, Australia
| | - Donald P McManus
- QIMR Berghofer Medical Research Institute, Brisbane, Qld 4006, Australia
| | | | - Melissa L Burke
- QIMR Berghofer Medical Research Institute, Brisbane, Qld 4006, Australia
| | - Helen C Owen
- School of Veterinary Sciences, The University of Queensland, Gatton, Qld 4343, Australia
| | - Grant A Ramm
- QIMR Berghofer Medical Research Institute, Brisbane, Qld 4006, Australia
| | - Geoffrey N Gobert
- QIMR Berghofer Medical Research Institute, Brisbane, Qld 4006, Australia.
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Borthwick LA, Wynn TA. IL-13 and TGF-β1: Core Mediators of Fibrosis. CURRENT PATHOBIOLOGY REPORTS 2015. [DOI: 10.1007/s40139-015-0091-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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18
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Muti LA, Pârvu AE, Crăciun AM, Miron N, Acalovschi M. Nitro-oxidative stress, VEGF and MMP-9 in patients with cirrhotic and non-cirrhotic portal hypertension. ACTA ACUST UNITED AC 2015; 88:140-5. [PMID: 26528062 PMCID: PMC4576785 DOI: 10.15386/cjmed-458] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 03/03/2015] [Accepted: 03/04/2015] [Indexed: 12/16/2022]
Abstract
Background and aims Nitro-oxidative stress may have pathophysiological consequences. The study aimed to assess the nitro-oxidative stress, the vascular growth factor, and metalloproteinase-9 levels in patients with noncirrohic and cirrhotic portal hypertension. Methods Patients with noncirrhotic portal hypertension (n=50) and cirrhotic portal hypertension (n=50) from the 3rd Medical Clinic in Cluj-Napoca Romania were prospectively enrolled between October 2004 and October 2006. A control group of healthy volunteers (n=50) was also evaluated. Nitro-oxidative stress was assessed by measuring serum concentration of nitrites and nitrate, 3-nitrotyrosine, total oxidative status, total antioxidant reactivity, and oxidative stress index. Serum vascular growth factor and matrix metalloproteinase-9 were also determined. Results Serum nitrites and nitrate levels significantly increased in both noncirrhotic (p<0.001) and cirrhotic portal hypertension (p=0.057). 3-nitrotyrosine also increased in noncirrhotic (p=0.001) and cirrhotic portal hypertension patients (p=0.014). Total oxidative status showed a significant increase in noncirrhotic (p<0.001) and in cirrhotic portal hypertension (p<0.001), but total antioxidant reactivity did not change significantly. The oxidative stress index increased in both noncirrhotic (p <0.001) and cirrhotic portal hypertension (p<0.001), as well as the serum vascular growth factor (p=0.005 and p=0.01, respectively). In NCPHT patients serum MMP-9 was significantly lower than in the healthy controls (p=0.03) and CPHT patients (p=0.05). Conclusion In patients with noncirrhotic and cirrhotic portal hypertension a significant systemic nitro-oxidative stress was found, correlated with an increase of VEGF. MMP-9 decreased in noncirrhotic portal hypertension.
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Affiliation(s)
- Leon Adrian Muti
- 3rd Medical Clinic, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Alina Elena Pârvu
- Pathophysiology Department, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Alexandra M Crăciun
- Biochemistry Department, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Nicolae Miron
- 3rd Medical Clinic, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Monica Acalovschi
- 3rd Medical Clinic, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Giannandrea M, Parks WC. Diverse functions of matrix metalloproteinases during fibrosis. Dis Model Mech 2014; 7:193-203. [PMID: 24713275 PMCID: PMC3917240 DOI: 10.1242/dmm.012062] [Citation(s) in RCA: 385] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Fibrosis--a debilitating condition that can occur in most organs - is characterized by excess deposition of a collagen-rich extracellular matrix (ECM). At first sight, the activities of proteinases that can degrade matrix, such as matrix metalloproteinases (MMPs), might be expected to be under-expressed in fibrosis or, if present, could function to resolve the excess matrix. However, as we review here, some MMPs are indeed anti-fibrotic, whereas others can have pro-fibrotic functions. MMPs modulate a range of biological processes, especially processes related to immunity and tissue repair and/or remodeling. Although we do not yet know precisely how MMPs function during fibrosis--that is, the protein substrate or substrates that an individual MMP acts on to effect a specific process--experiments in mouse models demonstrate that MMP-dependent functions during fibrosis are not limited to effects on ECM turnover. Rather, data from diverse models indicate that these proteinases influence cellular activities as varied as proliferation and survival, gene expression, and multiple aspects of inflammation that, in turn, impact outcomes related to fibrosis.
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20
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Yoshino TP, Brown M, Wu XJ, Jackson CJ, Ocadiz-Ruiz R, Chalmers IW, Kolb M, Hokke CH, Hoffmann KF. Excreted/secreted Schistosoma mansoni venom allergen-like 9 (SmVAL9) modulates host extracellular matrix remodelling gene expression. Int J Parasitol 2014; 44:551-63. [PMID: 24859313 PMCID: PMC4079936 DOI: 10.1016/j.ijpara.2014.04.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 04/15/2014] [Accepted: 04/16/2014] [Indexed: 12/31/2022]
Abstract
Schistosoma mansoni VAL9 (SmVAL9) is a secreted N-linked glycoprotein containing a unique, difucosyl modification. SmVAL9 is found throughout miracidia/sporocyst parenchymal cell inclusions/vesicles and germinal cells. SmVAL9 differentially regulates murine and snail matrix metalloproteinases. The Schistosoma mansoni venom allergen-like (SmVAL) protein family consists of 29 members, each possessing a conserved α-β-α sandwich tertiary feature called the Sperm-coating protein/Tpx-1/Ag5/PR-1/Sc7 (SCP/TAPS) domain. While the SmVALs have been found in both excretory/secretory (E/S) products and in intra/sub-tegumental (non-E/S) fractions, the role(s) of this family in host/parasite relationships or schistosome developmental processes remains poorly resolved. In order to begin quantifying SmVAL functional diversity or redundancy, dissecting the specific activity (ies) of individual family members is necessary. Towards this end, we present the characterisation of SmVAL9; a protein previously found enriched in both miracidia/sporocyst larval transformation proteins and in egg secretions. While our study confirms that SmVAL9 is indeed found in soluble egg products and miracidia/sporocyst larval transformation proteins, we find it to be maximally transcribed/translated in miracidia and subsequently down-regulated during in vitro sporocyst development. SmVAL9 localisation within sporocysts appears concentrated in parenchymal cells/vesicles as well as associated with larval germinal cells. Furthermore, we demonstrate that egg-derived SmVAL9 carries an N-linked glycan containing a schistosome-specific difucosyl element and is an immunogenic target during chronic murine schistosomiasis. Finally, we demonstrate that recombinant SmVAL9 affects the expression of extracellular matrix, remodelling matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP) gene products in both Biomphalaria glabrata embryonic cell (BgMMP1) and Mus musculus bone marrow-derived macrophage (MmMMP2, MmMMP9, MmMMP12, MmMMP13, MmMMP14, MmMMP28, TIMP1 and TIMP2) in vitro cultures. These findings importantly suggest that excreted/secreted SmVAL9 participates in tissue reorganisation/extracellular matrix remodelling during intra-mammalian egg translocation, miracidia infection and intra-molluscan sporocyst development/migration.
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Affiliation(s)
- Timothy P Yoshino
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA
| | - Martha Brown
- Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Room 3.31, Edward Llwyd Building, Penglais Campus, Aberystwyth SY23 3DA, UK
| | - Xiao-Jun Wu
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA
| | - Colin J Jackson
- Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Room 3.31, Edward Llwyd Building, Penglais Campus, Aberystwyth SY23 3DA, UK
| | - Ramon Ocadiz-Ruiz
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA
| | - Iain W Chalmers
- Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Room 3.31, Edward Llwyd Building, Penglais Campus, Aberystwyth SY23 3DA, UK
| | - Marlen Kolb
- Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Room 3.31, Edward Llwyd Building, Penglais Campus, Aberystwyth SY23 3DA, UK
| | - Cornelis H Hokke
- Department of Parasitology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands
| | - Karl F Hoffmann
- Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Room 3.31, Edward Llwyd Building, Penglais Campus, Aberystwyth SY23 3DA, UK.
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Dong H, Liu Y, Zou Y, Li C, Li L, Li X, Zhao X, Zhou L, Liu J, Niu Y. Alteration of the ERK5 pathway by hydroxysafflor yellow A blocks expression of MEF2C in activated hepatic stellate cells in vitro: Potential treatment for hepatic fibrogenesis. PHARMACEUTICAL BIOLOGY 2013; 52:435-443. [PMID: 24192313 DOI: 10.3109/13880209.2013.840850] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Abstract Context: Hepatic fibrosis ultimately leads to cirrhosis if not treated effectively. Hepatic stellate cells (HSC) are a main mediator of hepatic fibrosis through the accumulation of extracellular matrix proteins. Suppression activation of passaged HSC has been proposed as therapeutic strategies for the treatment and prevention of hepatic fibrosis. Objective: To evaluate the effect of hydroxysafflor yellow A (HSYA), an active chemical compound derived from the flowers of Carthamus tinctorius L. (Compositae), on HSC inhibition, and to begin elucidating underlying mechanisms. Materials and methods: Primary HSCs were isolated from rats by in situ pronase/collagenase perfusion. Culture-activated HSCs were treated with or without HSYA at 30 μM in the presence or absence of PD98059 for 48 h, and then cell proliferation was measured by MTS assays. Messenger RNA (mRNA) expression was quantified by polymerase chain reaction, and protein was quantified by Western blots or enzyme-linked immunosorbent assays. Results: HSYA significantly inhibits culture-activated HSC proliferation in a dose-dependent and time-dependent manner with an IC50 value of 112.79 μM. HSYA (30 μM) induce the suppression of HSC activation, as indicated by decreases in contents of type I alpha collagen in HSC-cultured media and expression of α-smooth muscle actin protein in culture-activated HSC by 55 and 71%, respectively. HSYA (30 μM) also caused significant decreases in mRNA expression of type III alpha collagen in HSC by 28%. HSYA (30 μM) suppresses myocyte enhancer factor 2 C (MEF2C) expression both at its mRNA and protein levels by 60 and 61%, respectively. Further study demonstrated that HSYA (30 μM) caused significant decreases in p-ERK5 by 49%. Blocking extracellular signal-regulated protein kinase 5 (ERK5) activity by XMD 8--92, an ERK5 inhibitor, markedly abrogated the inhibitive effects of HSYA on HSC activation, and blocked the HSYA-mediated MEF2C down-regulation. Conclusions: HSYA suppress HSC activation by ERK5-mediated MEF2C down-regulation and makes it a potential candidate for prevention and treatment of hepatic fibrogenesis.
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Affiliation(s)
- Haiying Dong
- The Institute of Medicine, Qiqihar Medical University , Qiqihar , China and
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Deatrick KB, Luke CE, Elfline MA, Sood V, Baldwin J, Upchurch GR, Jaffer FA, Wakefield TW, Henke PK. The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling. J Vasc Surg 2013; 58:1375-1384.e2. [PMID: 23490298 PMCID: PMC3688659 DOI: 10.1016/j.jvs.2012.11.088] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Revised: 11/14/2012] [Accepted: 11/21/2012] [Indexed: 10/27/2022]
Abstract
BACKGROUND Vein wall fibrotic injury following deep venous thrombosis (VT) is associated with elevated matrix metalloproteinases (MMPs). Whether and by what mechanism MMP2 contributes to vein wall remodeling after VT is unknown. METHODS Stasis VT was produced by ligation of the inferior vena cava and tissue was harvested at 2, 8, and 21 days in MMP2 -/- and genetic wild type (WT) mice. Tissue analysis by immunohistochemistry, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and zymography was performed. RESULTS Thrombus resolution was less at 8 days in MMP2 -/- compared with WT, evidenced by a 51% increase in VT size (P < .01), and threefold fewer von Willebrand's factor positive channels (P < .05). In MMP2 -/- mice, the main phenotypic fibrotic differences occurred at 8 days post-VT, with significantly less vein wall collagen content (P = .013), fourfold lower procollagen III gene expression (P < .01), but no difference in procollagen I compared with WT. Decreased inflammation in MMP2 -/- vein walls was suggested by ∼ threefold reduced TNFα and IL-1β at 2 days and 8 days post-VT (P < .05). A fourfold increase in vein wall monocytes (P = .03) with threefold decreased apoptosis (P < .05), but no difference in cellular proliferation at 8 days was found in MMP2 -/- compared with WT. As increased compensatory MMP9 activity was observed in the MMP2 -/-mice, MMP2/9 double null mice had thrombus induced with VT harvest at 8 days. Consistently, twofold larger VT, a threefold decrease in vein wall collagen, and a threefold increase in monocytes were found (all P < .05). Similar findings were observed in MMP9 -/- mice administered an exogenous MMP2 inhibitor. CONCLUSIONS In stasis VT, deletion of MMP2 was associated with less midterm vein wall fibrosis and inflammation, despite an increase in monocytes. Consideration that VT resolution was impaired with MMP2 (and MMP2/9) deletion suggests direct inhibition will likely also require anticoagulant therapy.
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Affiliation(s)
- Kristopher B Deatrick
- Conrad Jobst Vascular Research Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Mich
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Deatrick KB, Obi A, Luke CE, Elfline MA, Sood V, Upchurch GR, Jaffer F, Wakefield TW, Henke PK. Matrix metalloproteinase-9 deletion is associated with decreased mid-term vein wall fibrosis in experimental stasis DVT. Thromb Res 2013; 132:360-6. [PMID: 23978304 PMCID: PMC3777801 DOI: 10.1016/j.thromres.2013.06.027] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 06/26/2013] [Accepted: 06/28/2013] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Post thrombotic syndrome therapy is primarily palliative, and the associated vein wall inflammatory mechanisms are unclear. Vein wall fibrotic injury following deep venous thrombosis (VT) is associated with elevated matrix metalloproteinases (MMPs). Whether and by what mechanism MMP9 directly contributes to vein wall remodeling after VT is unknown. METHODS WT and MMP9 -/- mice underwent stasis VT by ligation of the inferior vena cava (IVC) and tissue was harvested at 2, 8, and 21days. Assessment of thrombus size, and gene, protein and structural vein wall determinations were done. RESULTS VT resolution was increased in MMP9-/- mice as compared with controls at 21d only. The primary phenotypic fibrotic vein wall differences occurred at 8d post VT, with significantly less vein wall collagen content as assessed by Picosirius red staining in MMP9 -/- mice as compared with WT. Increased monocytic vein wall influx with less IL-1b and TGFb was found in MMP9 -/- vein walls as compared with WT. Corresponding levels of PAI-1 were increased in MMP9 -/- compared with WT, and no difference in FSP-1+cells as compared with controls. CONCLUSIONS In stasis VT, MMP9 modulates midterm vein wall collagen content, with an altered local inflammatory and profibrotic environment, likely directed by monocytes. Thus, MMP9 plays a role in both vein wall responses as well as late thrombus resolution.
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Affiliation(s)
- Kristopher B Deatrick
- Conrad Jobst Vascular Research Laboratory, Section of Vascular Surgery, Department of Surgery, University of Michigan Medical School, Boston MA, United States
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Abstract
Asthma affects nearly 300 million people worldwide. The majority respond to inhaled corticosteroid treatment with or without beta-adrenergic agonists. However, a subset of 5 to 10% with severe asthma do not respond optimally to these medications. Different phenotypes of asthma may explain why current therapies show limited benefits in subgroups of patients. Interleukin-13 is implicated as a central regulator in IgE synthesis, mucus hypersecretion, airway hyperresponsiveness, and fibrosis. Promising research suggests that the interleukin-13 pathway may be an important target in the treatment of the different asthma phenotypes.
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Ariel A, Timor O. Hanging in the balance: endogenous anti-inflammatory mechanisms in tissue repair and fibrosis. J Pathol 2012; 229:250-63. [DOI: 10.1002/path.4108] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Revised: 09/05/2012] [Accepted: 09/12/2012] [Indexed: 02/06/2023]
Affiliation(s)
- Amiram Ariel
- Department of Biology, Faculty of Natural Sciences; University of Haifa; Haifa Israel
| | - Orly Timor
- Department of Biology, Faculty of Natural Sciences; University of Haifa; Haifa Israel
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Zhu CL, Li WT, Li Y, Gao RT. Serum levels of tissue inhibitor of metalloproteinase-1 are correlated with liver fibrosis in patients with chronic hepatitis B. J Dig Dis 2012; 13:558-63. [PMID: 23107442 DOI: 10.1111/j.1751-2980.2012.00629.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate the relationship between tissue inhibitor of metalloproteinase-1 (TIMP-1) expression and the severity of liver fibrosis in chronic hepatitis B (CHB) patients, and to explore the diagnostic value of serum TIMP-1. METHODS A total of 159 CHB patients underwent liver biopsy for the analysis of liver fibrosis stages and inflammation. Serum TIMP-1 was determined by ELISA. Hyaluronic acid (HA), procollagen type III (PCIII), collagen type IV (CIV), laminin (LN), and FIB-4 index were determined and calculated, and diagnostic accuracy was analyzed using receiver operating characteristic (ROC) curve. RESULTS Serum levels of TIMP-1 were associated with the grade of liver inflammation in CHB patients (r = 0.695, P < 0.01), especially in those without fibrosis or with stage 1 fibrosis, and were also positively correlated with liver fibrosis in CHB patients (r = 0.854, P < 0.01), particularly in those with inflammation at grade 1, 2 and 3. The area under the ROC curve (AUROC) of serum TIMP-1 was 0.918 for significant liver fibrosis (≥stage 2), and a sensitivity of 89.4% and specificity of 83.6% were obtained with a cut-off value of ≥174.5 ng/mL of serum TIMP-1, which were higher than that of HA, CIV and FIB-4 index. CONCLUSION TIMP-1 is a valuable single biomarker for the evaluation of significant fibrosis in CHB patients.
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Affiliation(s)
- Chuan Long Zhu
- Department of Infectious Disease, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui Province, China.
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Peng WJ, Yan JW, Wan YN, Wang BX, Tao JH, Yang GJ, Pan HF, Wang J. Matrix Metalloproteinases: A Review of Their Structure and Role in Systemic Sclerosis. J Clin Immunol 2012; 32:1409-14. [DOI: 10.1007/s10875-012-9735-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Accepted: 06/26/2012] [Indexed: 02/04/2023]
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Li Q, Yan Z, Li F, Lu W, Wang J, Guo C. The improving effects on hepatic fibrosis of interferon-γ liposomes targeted to hepatic stellate cells. NANOTECHNOLOGY 2012; 23:265101. [PMID: 22700686 DOI: 10.1088/0957-4484/23/26/265101] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
No satisfactory anti-fibrotic therapies have yet been applied clinically. One of the main reasons is the inability to specifically target the responsible cells to produce an available drug concentration and the side-effects. Exploiting the key role of the activated hepatic stellate cells (HSCs) in both hepatic fibrogenesis and over-expression of platelet-derived growth factor receptor- (PDGFR- ), we constructed targeted sterically stable liposomes (SSLs) modified by a cyclic peptide (pPB) with affinity for the PDGFR- to deliver interferon (IFN)- to HSCs. The pPB-SSL-IFN- showed satisfactory size distribution. In vitro pPB-SSL could be taken up by activated HSCs. The study of tissue distribution via living-body animal imaging showed that the pPB-SSL-IFN- mostly accumulated in the liver until 24 h. Furthermore, the pPB-SSL-IFN- showed more significant remission of hepatic fibrosis. In vivo the histological Ishak stage, the semiquantitative score for collagen in fibrotic liver and the serum levels of collagen type IV-C in fibrotic rats treated with pPB-SSL-IFN- were less than those treated with SSL-IFN- , IFN- and the control group. In vitro pPB-SSL-IFN- was also more effective in suppressing activated HSC proliferation and inducing apoptosis of activated HSCs. Thus the data suggest that pPB-SSL-IFN- might be a more effective anti-fibrotic agent and a new opportunity for clinical therapy of hepatic fibrosis.
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Affiliation(s)
- Qinghua Li
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
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Altered circulating levels of matrix metalloproteinases and inhibitors associated with elevated type 2 cytokines in lymphatic filarial disease. PLoS Negl Trop Dis 2012; 6:e1681. [PMID: 22679524 PMCID: PMC3367978 DOI: 10.1371/journal.pntd.0001681] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Accepted: 04/27/2012] [Indexed: 12/13/2022] Open
Abstract
Background Infection with Wuchereria bancrofti can cause severe disease characterized by subcutaneous fibrosis and extracellular matrix remodeling. Matrix metalloproteinases (MMPs) are a family of enzymes governing extracellular remodeling by regulating cellular homeostasis, inflammation, and tissue reorganization, while tissue-inhibitors of metalloproteinases (TIMPs) are endogenous regulators of MMPs. Homeostatic as well as inflammation-induced balance between MMPs and TIMPs is considered critical in mediating tissue pathology. Methods To elucidate the role of MMPs and TIMPs in filarial pathology, we compared the plasma levels of a panel of MMPs, TIMPs, other pro-fibrotic factors, and cytokines in individuals with chronic filarial pathology with (CP Ag+) or without (CP Ag−) active infection to those with clinically asymptomatic infections (INF) and in those without infection (endemic normal [EN]). Markers of pathogenesis were delineated based on comparisons between the two actively infected groups (CP Ag+ compared to INF) and those without active infection (CP Ag− compared to EN). Results and Conclusion Our data reveal that an increase in circulating levels of MMPs and TIMPs is characteristic of the filarial disease process per se and not of active infection; however, filarial disease with active infection is specifically associated with increased ratios of MMP1/TIMP4 and MMP8/TIMP4 as well as with pro-fibrotic cytokines (IL-5, IL-13 and TGF-β). Our data therefore suggest that while filarial lymphatic disease is characterized by a non-specific increase in plasma MMPs and TIMPs, the balance between MMPs and TIMPs is an important factor in regulating tissue pathology during active infection. Lymphatic filariasis afflicts over 120 million people worldwide. While the infection is mostly clinically asymptomatic, approximately 40 million people suffer from overt, morbid clinical pathology characterized by swelling of the scrotal area and lower limbs (hydrocele and lymphedema). Host immunologic factors that influence the pathogenesis of disease in these individuals are not completely understood. Matrix metalloproteinases are a family of circulating and tissue proteins that influence the development of tissue fibrosis. They are regulated by another family of proteins called tissue inhibitors of metalloproteinases. The interplay between these proteins governs tissue fibrosis in a variety of conditions. In addition, certain cytokines are known to promote pro-fibrotic events. We have attempted to elucidate the role of the above-mentioned factors in disease pathogenesis by comparing the plasma levels of the various markers in four groups of individuals: chronic pathology individuals with or without active filarial infection; asymptomatic, filaria-infected individuals; and uninfected, endemic normal individuals. We show that altered ratios of the metalloproteinases and their inhibitors—as well as elevated levels of pro-fibrotic cytokines—characterize filarial infection-induced lymphatic pathology.
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Mentink-Kane MM, Cheever AW, Wilson MS, Madala SK, Beers LM, Ramalingam TR, A.Wynn T. Accelerated and progressive and lethal liver fibrosis in mice that lack interleukin (IL)-10, IL-12p40, and IL-13Rα2. Gastroenterology 2011; 141:2200-9. [PMID: 21864478 PMCID: PMC3221932 DOI: 10.1053/j.gastro.2011.08.008] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2011] [Revised: 07/29/2011] [Accepted: 08/08/2011] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Progressive fibrosis contributes to the morbidity of several chronic diseases; it typically develops slowly, so the mechanisms that control its progression and resolution have been difficult to model. The proteins interleukin (IL)-10, IL-12p40, and IL-13Rα2 regulate hepatic fibrosis following infection with the helminth parasite Schistosoma mansoni. We examined whether these mediators interact to slow the progression of hepatic fibrosis in mice with schistosomiasis. METHODS IL-10(-/-), IL-12/23(p40)(-/-), and IL-13Rα2(-/-) mice were crossed to generate triple knockout (TKO) mice. We studied these mice to determine whether the simultaneous deletion of these 3 negative regulators of the immune response accelerated mortality from liver fibrosis following infection with S mansoni. RESULTS Induction of inflammation by S mansoni, liver fibrosis, and mortality increased greatly in TKO mice compared with wild-type mice; 100% of the TKO mice died by 10 weeks after infection. Morbidity and mortality were associated with the development of portal hypertension, hepatosplenomegaly, gastrointestinal bleeding, ascites, thrombocytopenia, esophageal and gastric varices, anemia, and increased levels of liver enzymes, all features of advanced liver disease. IL-10, IL-12p40, and IL-13Rα2 reduced the production and activity of the profibrotic cytokine IL-13. A neutralizing antibody against IL-13 reduced the morbidity and mortality of the TKO mice following S mansoni infection. CONCLUSIONS IL-10, IL-12p40, and IL-13Rα2 act cooperatively to suppress liver fibrosis in mice following infection with S mansoni. This model rapidly reproduces many of the complications observed in patients with advanced cirrhosis, so it might be used to evaluate the efficacy of antifibrotic reagents being developed for schistosomiasis or other fibrotic diseases associated with a T-helper 2 cell-mediated immune response.
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Affiliation(s)
- Margaret M. Mentink-Kane
- Program in Barrier Immunity and Repair, Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health, Bethesda, Maryland 20892, USA
| | | | - Mark S. Wilson
- Program in Barrier Immunity and Repair, Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Satish K. Madala
- Program in Barrier Immunity and Repair, Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Lara Megan Beers
- Program in Barrier Immunity and Repair, Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Thirumalai R. Ramalingam
- Program in Barrier Immunity and Repair, Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Thomas A.Wynn
- Program in Barrier Immunity and Repair, Laboratory of Parasitic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health, Bethesda, Maryland 20892, USA
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Migrating Schistosoma japonicum schistosomula induce an innate immune response and wound healing in the murine lung. Mol Immunol 2011; 49:191-200. [PMID: 21917316 DOI: 10.1016/j.molimm.2011.08.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2011] [Revised: 08/10/2011] [Accepted: 08/18/2011] [Indexed: 01/13/2023]
Abstract
The migrating schistosomulum is an important stage of the schistosome lifecycle and represents a key target for elimination of infection by natural and vaccine-induced host immune responses. To gain a better understanding of how schistosomes initiate a primary host immune response we have characterised the host lung response to migrating Schistosoma japonicum schistosomula using a combination of histopathology, microarray analysis and real-time PCR. Our findings indicate that the early pulmonary response to these migrating larvae is characteristic of innate inflammation and wound healing. This response is associated with significant up-regulation of several genes with immunoregulatory function including Ch25h, Hmox1 and Retnla which may act to control the nature or magnitude of the inflammatory response to the migrating schistosomula, promoting both parasite and host survival. These findings contribute to our understanding of host-parasite interactions associated with schistosome and, especially, S. japonicum infection, and may aid the future design of novel vaccines that target the lung stage schistosomulum.
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Endo H, Niioka M, Sugioka Y, Itoh J, Kameyama K, Okazaki I, Ala-Aho R, Kähäri VM, Watanabe T. Matrix metalloproteinase-13 promotes recovery from experimental liver cirrhosis in rats. Pathobiology 2011; 78:239-52. [PMID: 21849805 DOI: 10.1159/000328841] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2011] [Accepted: 04/19/2011] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE To evaluate the role of matrix metalloproteinase (MMP)-13 gene expression in the early phase of recovery from liver fibrosis/cirrhosis. METHODS Liver fibrosis was induced in male Wistar rats by administration of carbon tetrachloride (CCl(4)) for 10 weeks. Recombinant adenovirus-mediated human MMP-13 gene transfer (RAdMMP-13) was performed via the femoral vein on day 3 after the last CCl(4) injection. The role of MMP-13 in stably expressing cell lines was also analyzed. RESULTS Fibrous deposition in the liver was decreased in RAdMMP-13-injected rats by day 3 after gene transfer compared with empty vector RAd66-injected rats. Furthermore, MMP-2 and MMP-9 enzymatic activity was markedly enhanced in the liver of RAdMMP-13 injected rats. Hepatocyte growth factor (HGF) induction was also increased in RAdMMP-13 injected rats. In established stable HT-1080 cells transfected with MMP-13, HGF-α expression and MMP-2 and MMP-9 enzymatic activity were increased. The conversion of precursor HGF into mature HGF was also increased in the MMP-13 expressing cell lines. CONCLUSION Forced MMP-13 expression effectively accelerated recovery from liver cirrhosis via the effects of MMP-13-mediated HGF, MMP-2, and MMP-9 expression, which induced the degradation of collagen fibers and promoted hepatic regeneration.
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Affiliation(s)
- Hitoshi Endo
- Center for Molecular Prevention and Environmental Medicine, Department of Community Health, Tokai University School of Medicine, Isehara, Japan
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Hayashi H, Sakai T. Animal models for the study of liver fibrosis: new insights from knockout mouse models. Am J Physiol Gastrointest Liver Physiol 2011; 300:G729-38. [PMID: 21350186 PMCID: PMC3094136 DOI: 10.1152/ajpgi.00013.2011] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Fibrosis arises as part of a would-healing response that maintains organ structure and integrity following tissue damage but also contributes to a variety of human pathologies such as liver fibrosis. Liver fibrosis is an abnormal response of the liver to persistent injury with the excessive accumulation of collagenous extracellular matrices. Currently there is no effective treatment, and many patients end up with a progressive form of the disease, eventually requiring a liver transplant. The clarification of mechanisms underlying pathogenesis of liver fibrosis and the development of effective therapy are of clinical importance. Experimental animal models, in particular targeted gene knockouts (loss of function) in mice, have become a powerful resource to address the molecular mechanisms or significance of the targeted gene in hepatic functions and diseases. This review will focus on the recent advances in knowledge obtained from genetically engineered mice that provide novel insights into the pathophysiology of liver fibrosis.
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Affiliation(s)
- Hiromitsu Hayashi
- 1Department of Biomedical Engineering, Lerner Research Institute and
| | - Takao Sakai
- 1Department of Biomedical Engineering, Lerner Research Institute and ,2Orthopedic and Rheumatologic Research Center, Cleveland Clinic, Cleveland, Ohio
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Onozuka I, Kakinuma S, Kamiya A, Miyoshi M, Sakamoto N, Kiyohashi K, Watanabe T, Funaoka Y, Ueyama M, Nakagawa M, Koshikawa N, Seiki M, Nakauchi H, Watanabe M. Cholestatic liver fibrosis and toxin-induced fibrosis are exacerbated in matrix metalloproteinase-2 deficient mice. Biochem Biophys Res Commun 2011; 406:134-40. [PMID: 21300023 DOI: 10.1016/j.bbrc.2011.02.012] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Accepted: 02/02/2011] [Indexed: 01/28/2023]
Abstract
Matrix metalloproteinase (MMP) plays an important role in homeostatic regulation of the extracellular environment and degradation of matrix. During liver fibrosis, several MMPs, including MMP-2, are up-regulated in activated hepatic stellate cells, which are responsible for exacerbation of liver cirrhosis. However, it remains unclear how loss of MMP-2 influences molecular dynamics associated with fibrogenesis in the liver. To explore the role of MMP-2 in hepatic fibrogenesis, we employed two fibrosis models in mice; toxin (carbon tetrachloride, CCl4)-induced and cholestasis-induced fibrosis. In the chronic CCl4 administration model, MMP-2 deficient mice exhibited extensive liver fibrosis as compared with wild-type mice. Several molecules related to activation of hepatic stellate cells were up-regulated in MMP-2 deficient liver, suggesting that myofibroblastic change of hepatic stellate cells was promoted in MMP-2 deficient liver. In the cholestasis model, fibrosis in MMP-2 deficient liver was also accelerated as compared with wild type liver. Production of tissue inhibitor of metalloproteinase 1 increased in MMP-2 deficient liver in both models, while transforming growth factor β, platelet-derived growth factor receptor and MMP-14 were up-regulated only in the CCl4 model. Our study demonstrated, using 2 experimental murine models, that loss of MMP-2 exacerbates liver fibrosis, and suggested that MMP-2 suppresses tissue inhibitor of metalloproteinase 1 up-regulation during liver fibrosis.
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Affiliation(s)
- Izumi Onozuka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan
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Abstract
SUMMARYSuccessful metazoan parasitism, among many other factors, requires a supply of nutrients and the removal of waste products. There is a prerequisite for a parasite-defined vasculature. The angiogenic mechanism(s) involved presumably depend on the characteristics of the tissue- and vascular system-dwelling, parasitic helminths. Simplistically, 2 possibilities or a combination of both have been considered in this review. The multifactorial induction of parasitic helminth-associated neovascularization could arise through, either a host-, a parasite- or a host-/parasite-dependent, angiogenic switch. Most studies appear to support the first and third hypotheses, but evidence exists for the intrahepatic cestodeEchinococcus multilocularis, the free-living nematodeCaenorhabditis elegansand the intravascular trematodeSchistosoma mansonifor the second inference. In contrast, the nematode anti-coagulant protein NAPc2 from adultAncylostoma caninumis also an anti-angiogenic factor.
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Fabre V, Wu H, PondTor S, Coutinho H, Acosta L, Jiz M, Olveda R, Cheng L, White ES, Jarilla B, McGarvey ST, Friedman JF, Kurtis JD. Tissue inhibitor of matrix-metalloprotease-1 predicts risk of hepatic fibrosis in human Schistosoma japonicum infection. J Infect Dis 2011; 203:707-14. [PMID: 21199883 DOI: 10.1093/infdis/jiq099] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Schistosomes infect 200 million individuals annually and cause significant hepatic fibrosis in up to 20%. Little is known regarding the mechanisms of schistosome-associated hepatic fibrosis in humans, and few biomarkers for risk of fibrosis have been identified. METHODS We treated 611 Schistosoma japonicum-infected Filipinos with praziquantel (PZQ) and performed ultrasound to quantify hepatic fibrosis at baseline and 12 months after PZQ treatment. We developed a multiplexed assay (FibroPlex) that quantifies predictors and effect modifiers of fibrosis. We measured FibroPlex analytes produced by peripheral blood mononuclear cells stimulated with schistosome egg antigen 4 weeks after PZQ treatment and related these levels to risk of fibrosis 1 year after PZQ treatment. RESULTS After adjusting for potential confounders, including baseline grade of fibrosis, individuals with detectable tissue inhibitor of matrix-metalloprotease-1 (TIMP-1) had a 3.5-fold greater risk of fibrosis 1 year after PZQ treatment, compared with individuals with undetectable levels (odds ratio, 3.48; 95% confidence interval, 1.41-8.43; P = .007). DISCUSSION Because TIMP-1 inhibits most matrix metalloproteases, which are responsible for collagen degradation, these data suggest that schistosome-associated hepatic fibrosis results, in part, from excessive inhibition of collagen remodeling. These data further suggest that TIMP-1 is a promising biomarker for assessing risk of hepatic fibrosis in schistosomiasis and, potentially, other infectious and noninfectious causes of liver disease.
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Affiliation(s)
- Valeria Fabre
- Department of Medicine, Memorial Hospital of Rhode Island, Brown University Medical School, Providence, RI, USA.
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Wei L. Immunological aspect of cardiac remodeling: T lymphocyte subsets in inflammation-mediated cardiac fibrosis. Exp Mol Pathol 2010; 90:74-8. [PMID: 20965166 DOI: 10.1016/j.yexmp.2010.10.004] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2010] [Accepted: 10/13/2010] [Indexed: 01/08/2023]
Abstract
Cardiac fibrosis is defined as a progressive accumulation of fibrillar extracellular matrix (ECM) in the myocardium. The regulation of extracellular matrix remodeling is primarily mediated by cardiac fibroblasts (CF). Evidences suggest that various T lymphocyte phenotypes differentially affect organ fibrosis through modulating CF collagen and MMP/TIMP gene expression, MMP activity and cardiac collagen cross-linking, leading to altered ECM composition. In regard to the importance of cytokines in cardiac fibrosis and heart failure, in this review, we will address the role of different T cell subsets in inflammation-mediated cardiac fibrosis, from a distinct perspective of T cell and fibroblast interaction. We conclude that in addition to preventive strategies, therapies based on deviation of Th1/Th2 paradigm, and manipulation of Tregs and Th17 would show promising results in future studies.
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Affiliation(s)
- Liu Wei
- Department of Cardiology, First Affiliated Hospital of Harbin Medical University, 150001, China.
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Zhang Y, Liu P, Gao X, Qian W, Xu K. rAAV2-TGF-β(3) decreases collagen synthesis and deposition in the liver of experimental hepatic fibrosis rat. Dig Dis Sci 2010; 55:2821-30. [PMID: 20108118 DOI: 10.1007/s10620-009-1119-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2009] [Accepted: 12/28/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Hepatic fibrosis is one kind of common wound-healing response to chronic liver injury. Transforming growth factor (TGF)-β(3) performs an anti-fibrosis function under certain conditions such as pancreatic fibrosis and wound healing. This study aimed at investigating the effect of TGF-β(3) on the histology in the liver of rat with liver fibrosis. METHODS Recombinantadeno-associated virus (rAAV) 2-TGF-β(3) and rAAV2-EGFP were constructed. Rats were randomly divided into normal control group, model group, negative control group and TGF-β(3) treated group. The hepatic fibrosis model was induced by CCl(4) administration. We injected a single dose of either rAAV2-TGF-β(3) or rAAV2-EGFP into the TGF-β(3) group and the negative control group. The histopathologic changes of liver were determined by hematoxylin and eosin (HE) staining and Masson staining. The expressions of type I collagen, MMP-9, MMP-2, and TIMP-1 in liver were detected by Immunohistochemical staining. RESULTS With the treatment of TGF-β(3), the degree of fibrosis and the deposition of collagen fiber in liver were markedly reduced, and the expression of MMP-9 was obviously increased (P < 0.001), while type I collagen and TIMP-1 were decreased (P = 0.004, P = 0.001) compared with the model group, but the expressed difference of MMP-2 had no statistical significance (P = 0.180). CONCLUSION rAAV2-TGF-β(3) reduces the histopathologic damage of liver fibrosis on rats, and it may suppress the synthesis and deposition of type I collagen by regulating the expressions of matrix metalloproteinases and their inhibitors. Potentially, our findings might help with the design of a new TGF-β(3)-based therapy for hepatic fibrosis.
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Affiliation(s)
- Yi Zhang
- Department of Gastroenterology, Union Hospital, Tongji Medical Collage, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Fukui T, Suga T, Iida RH, Morito M, Luan X, Diekwisch TG, Nakamura Y, Yamane A. BMP-2 Regulates the Formation of Oral Sulcus in Mouse Tongue by Altering the Balance Between TIMP-1 and MMP-13. Anat Rec (Hoboken) 2010; 293:1408-15. [DOI: 10.1002/ar.21164] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Changes in TIMP-1 and -2 expression in the early stage of porcine serum-induced liver fibrosis in rats. ACTA ACUST UNITED AC 2010; 63:357-61. [PMID: 20226641 DOI: 10.1016/j.etp.2010.02.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2009] [Revised: 02/19/2010] [Accepted: 02/21/2010] [Indexed: 12/29/2022]
Abstract
It is widely recognized that tissue inhibitors of metalloproteinases (TIMPs), especially TIMP-1 and -2, play a key role in the progression of hepatic fibrosis. In the present study, we examined the changes in TIMP-1 and -2 expressions in the early stage of porcine serum (PS)-induced liver fibrosis in Brown Norway (BN) and Wistar rats. The rats were injected intraperitoneally with 0.5 ml/head of PS twice a week for up to 8 weeks and examined at 2, 4 and 8 weeks. Hepatic fibrosis and inflammatory cell infiltration developed at 4 and 8 weeks in BN and Wistar rats, respectively, and formation of pseudolobules was detected at 8 weeks in rats of both strains. The expression of liver TIMP-1 and -2 mRNAs significantly increased at 8 weeks in rats of both strains. At the same time, TIMP-1 and -2 activities were also detected in the liver of both strains. On the other hand, the expression of serum TIMP-1 and -2 proteins increased earlier (at 4 weeks for TIMP-1 and at 2 or 4 weeks for TIMP-2) than that of liver TIMP-1 and -2 mRNAs did. Although there are some reports suggestive of why the elevation of serum TIMP-1 and -2 proteins preceded that of liver TIMP-1 and -2 mRNAs, the exact reason is still obscure. In conclusion, the present study showed for the first time the mode of TIMP-1 and -2 expression and activity in the early stage of PS-induced rat liver fibrosis model.
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Madala SK, Pesce JT, Ramalingam TR, Wilson MS, Minnicozzi S, Cheever AW, Thompson RW, Mentink-Kane MM, Wynn TA. Matrix metalloproteinase 12-deficiency augments extracellular matrix degrading metalloproteinases and attenuates IL-13-dependent fibrosis. THE JOURNAL OF IMMUNOLOGY 2010; 184:3955-63. [PMID: 20181883 DOI: 10.4049/jimmunol.0903008] [Citation(s) in RCA: 123] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Infection with the parasitic helminth Schistosoma mansoni causes significant liver fibrosis and extracellular matrix (ECM) remodeling. Matrix metalloproteinases (MMP) are important regulators of the ECM by regulating cellular inflammation, extracellular matrix deposition, and tissue reorganization. MMP12 is a macrophage-secreted elastase that is highly induced in the liver and lung in response to S. mansoni eggs, confirmed by both DNA microarray and real-time PCR analysis. However, the function of MMP12 in chronic helminth-induced inflammation and fibrosis is unclear. In this study, we reveal that MMP12 acts as a potent inducer of inflammation and fibrosis after infection with the helminth parasite S. mansoni. Surprisingly, the reduction in liver and lung fibrosis in MMP12-deficient mice was not associated with significant changes in cytokine, chemokine, TGF-beta1, or tissue inhibitors of matrix metalloproteinase expression. Instead, we observed marked increases in MMP2 and MMP13 expression, suggesting that Mmp12 was promoting fibrosis by limiting the expression of specific ECM-degrading MMPs. Interestingly, like MMP12, MMP13 expression was highly dependent on IL-13 and type II-IL-4 receptor signaling. However, in contrast to MMP12, expression of MMP13 was significantly suppressed by the endogenous IL-13 decoy receptor, IL-13Ralpha2. In the absence of MMP12, expression of IL-13Ralpha2 was significantly reduced, providing a possible explanation for the increased IL-13-driven MMP13 activity and reduced fibrosis. As such, these data suggest important counter-regulatory roles between MMP12 and ECM-degrading enzymes like MMP2, MMP9, and MMP13 in Th2 cytokine-driven fibrosis.
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Affiliation(s)
- Satish K Madala
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Min AK, Kim MK, Seo HY, Kim HS, Jang BK, Hwang JS, Choi HS, Lee KU, Park KG, Lee IK. Alpha-lipoic acid inhibits hepatic PAI-1 expression and fibrosis by inhibiting the TGF-beta signaling pathway. Biochem Biophys Res Commun 2010; 393:536-41. [PMID: 20153726 DOI: 10.1016/j.bbrc.2010.02.050] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2010] [Accepted: 02/09/2010] [Indexed: 02/09/2023]
Abstract
Accumulating evidence suggests that plasminogen activator inhibitor (PAI)-1 plays an important role in the development of hepatic fibrosis via its involvement in extracellular matrix remodeling. We previously reported that alpha-lipoic acid (ALA), a naturally occurring thiol antioxidant, prevents hepatic steatosis by inhibiting the expression of sterol regulatory element binding protein-1c. The aim of the present study was to determine whether ALA prevents hepatic PAI-1 expression and fibrosis through the inhibition of multiple TGF-beta-mediated molecular mediators. We investigated whether ALA inhibited the development of hepatic fibrosis in mice following bile duct ligation (BDL), an established animal model of liver fibrosis. We found that ALA markedly inhibited BDL-induced hepatic fibrosis and PAI-1 expression. We also found that ALA attenuated TGF-beta-stimulated PAI-1 mRNA expression, and inhibited PAI-1 promoter activity in liver cells; this effect was mediated by Smads and the JNK and ERK pathways. The results of the present study indicate that ALA inhibits hepatic PAI-1 expression through inhibition of TGF-beta-mediated molecular mediators, including Smad3, AP1, and Sp1, and prevents the development of BDL-induced hepatic fibrosis. These findings suggest that ALA may have a clinical application in preventing the development and progression of hepatic fibrosis.
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Affiliation(s)
- Ae-Kyung Min
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu 700-712, South Korea
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Syn WK, Yang L, Chiang DJ, Qian Y, Jung Y, Karaca G, Choi SS, Witek RP, Omenetti A, Pereira TA, Diehl AM. Genetic differences in oxidative stress and inflammatory responses to diet-induced obesity do not alter liver fibrosis in mice. Liver Int 2009; 29:1262-72. [PMID: 19490416 PMCID: PMC3610179 DOI: 10.1111/j.1478-3231.2009.02036.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVE To determine how genetic factors might influence the progression of nonalcoholic fatty liver disease (NAFLD). DESIGN/INTERVENTION Beginning in adolescence, male C57BL6 (BL6) and 129/SVJ mice were fed control (n=15/group) or high-fat (HF) diets (n=30/group) for 6 months. MAIN OUTCOME MEASURES Assessed were body weight, insulin resistance, hepatic production of free radicals, expression of cytokines and fibrosis-related genes and severity of hepatic steatosis, injury and fibrosis. RESULTS High-fat diets induced comparable obesity, hepatic steatosis and insulin resistance in the two strains. Compared with BL6 mice, 129/SVJ mice had impaired induction of antioxidant genes, generated three- to four-fold more free radicals and exhibited two-fold greater induction of profibrogenic cytokines (interleukin-4 and transforming growth factor-beta1) and fibrosis-related genes (fibronectin and tissue inhibitor of metalloproteinase-1) (all P<0.05 for 129 vs BL6). Surprisingly, however, induction of collagen I alpha1 mRNA and accumulation of Sirius red-stained fibrils and hepatic hydroxyproline were similar in BL6 and 129/SVJ mice, and although patchy sinusoidal fibrosis emerged in both strains, neither developed bridging fibrosis. CONCLUSIONS Although BL6 and 129/SVJ mice with diet-induced obesity, insulin resistance and steatosis differed with respect to several factors that are thought to influence human NAFLD progression, they developed comparable liver fibrosis. Moreover, none of the risk factors for NAFLD-related cirrhosis in humans, including obesity, insulin resistance, chronic inflammatory and oxidant stress, steatohepatitis or activation of fibrogenic genes, proved to be sufficient to cause cirrhosis in these mice, even when exposure to one or more of these insults was very prolonged.
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Affiliation(s)
- Wing-Kin Syn
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Liu Yang
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Dian Jung Chiang
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Yue Qian
- Division of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA
| | - Youngmi Jung
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Gamze Karaca
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Steve S. Choi
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Rafal P. Witek
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Alessia Omenetti
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Thiago A. Pereira
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | - Anna Mae Diehl
- Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
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Mononuclear cells in liver fibrosis. Semin Immunopathol 2009; 31:345-58. [PMID: 19533130 DOI: 10.1007/s00281-009-0169-0] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2009] [Accepted: 05/28/2009] [Indexed: 02/07/2023]
Abstract
Fibrosis is a multicellular wound healing process, where myofibroblasts that express extracellular matrix components extensively cross-talk with other cells resident in the liver or recruited from the bloodstream. Macrophages and infiltrating monocytes participate in the development of fibrosis via several mechanisms, including secretion of cytokines and generation of oxidative stress-related products. However, macrophages are also pivotal in the process of fibrosis resolution, where they contribute to matrix degradation. T lymphocytes modulate the fibrogenic process by direct interaction with myofibroblasts and secreting cytokines. In general, Th2 polarized responses promote fibrosis, while Th1 cytokines may be antifibrogenic. NK cells limit the development of fibrosis and favor its resolution, at least in part via killing of fibrogenic cells. The possible role of NKT cells and B cells is emerging in recent studies. Thus, mononuclear cells represent a critical regulatory system during fibrogenesis and may become an appealing target for therapy.
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Immunomodulatory effects of curcumin treatment on murine schistosomiasis mansoni. Immunobiology 2009; 214:712-27. [PMID: 19249123 DOI: 10.1016/j.imbio.2008.11.017] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2008] [Revised: 11/28/2008] [Accepted: 11/29/2008] [Indexed: 11/23/2022]
Abstract
Curcumin is a polyphenol derived from the dietary spice turmeric. It has been shown to regulate numerous transcription factors, cytokines, adhesion molecules, and enzymes that have been linked to inflammation. In addition to inhibiting the growth of a variety of pathogens, curcumin has been shown to have nematocidal activity. The present study was designed to evaluate the schistosomicidal activity of curcumin in vivo as well as immunomodulation of granulomatous inflammation and liver pathology in acute schistosomiasis mansoni. Mice were infected each with 80 Schistosoma (S.) mansoni cercariae and injected intraperitoneally with curcumin at a total dose of 400mg/kg body weight. Curcumin was effective in reducing worm and tissue-egg burdens, hepatic granuloma volume and liver collagen content by 44.4%, 30.9%, 79%, and 38.6%, respectively. Curcumin treatment restored hepatic enzymes activities to the normal levels and enhanced catalase activity in the liver tissue of infected mice. Moreover, hepato-spleenomegaly and eosinophilia induced by S. mansoni infection were largely improved with curcumin treatment. Infected mice treated with curcumin showed low serum level of both interleukin (IL)-12 and tumor necrosis factor alpha (TNF-alpha), but IL-10 level was not significantly altered. Specific IgG and IgG1 responses against both soluble worm antigen (SWAP) and soluble egg antigen (SEA) were augmented with curcumin treatment, but IgM and IgG2a responses were not significantly changed. In conclusion, curcumin treatment modulates cellular and humoral immune responses of infected mice and lead to a significant reduction of parasite burden and liver pathology in acute murine schistosomiasis mansoni.
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Immunological investigation of the hepatic tissue from infants with biliary atresia. Pediatr Surg Int 2009; 25:157-62. [PMID: 19089432 DOI: 10.1007/s00383-008-2311-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/13/2008] [Indexed: 10/21/2022]
Abstract
PURPOSE Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] have been implicated in tissue injury and remodeling in many organs. The objective of this study was to evaluate the expression of MMP-3 and -9, and TIMP-1, -2, and -3 and their relationship to liver fibrosis in infants with biliary atresia. METHODS The expression of MMP-3 and-9 and TIMP-1, -2 and -3 was investigated in liver tissue samples of nine patients with biliary atresia. In addition, the expression of CCR-4 and CCR-5 was analyzed to investigate the activation of Th1 and Th2 cells. The mRNA levels were measured by semiquantitative reverse transcriptase polymerase chain reaction. RESULTS The expression of MMP-3 was higher than that of MMP-9 in all samples (P < 0.01). The expression of TIMP-1 was higher than that of TIMP-2 and -3 in all samples (P < 0.01). The expression of CCR-5 was higher than that of CCR-4 (P < 0.05), which implied higher activation of Th1 cells relative to Th2 cells. CONCLUSION Our findings suggest that MMP-3, possibly induced by Th1 cytokines, and its balance with TIMP-1, may be one of the factors involved in the pathogenesis of biliary atresia.
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Lee H, Lim C, Lee J, Kim N, Bang S, Lee H, Min B, Park G, Noda M, Stetler-Stevenson WG, Oh J. TGF-beta signaling preserves RECK expression in activated pancreatic stellate cells. J Cell Biochem 2008; 104:1065-74. [PMID: 18300271 DOI: 10.1002/jcb.21692] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Activated pancreatic stellate cells (PSCs) play a pivotal role in the pathogenesis of pancreatic fibrosis, but the detailed mechanism for dysregulated accumulation of extracellular matrix (ECM) remains unclear. Cultured rat PSCs become activated by profibrogenic mediators, but these mediators failed to alter the expression levels of matrix metalloproteinases (MMPs) to the endogenous tissue inhibitors of metalloproteinases (TIMPs). Here, we examined the expression of RECK, a novel membrane-anchored MMP inhibitor, in PSCs. Although RECK mRNA levels were largely unchanged, RECK protein expression was barely detected at 2, 5 days after plating PSCs, but appeared following continued in vitro culture and cell passage which result in PSC activation. When PSCs at 5 days after plating (PSCs-5d) were treated with pepstatin A, an aspartic protease inhibitor, or TGF-beta1, a profibrogenic mediator, RECK protein was detected in whole cell lysates. Conversely, Smad7 overexpression or suppression of Smad3 expression in PSCs after passage 2 (PSCs-P2) led to the loss of RECK protein expression. These findings suggest that RECK is post-translationally processed in pre-activated PSCs but protected from proteolytic degradation by TGF-beta signaling. Furthermore, collagenolytic activity of PSCs-5d was greatly reduced by TGF-beta1, whereas that of PSCs-P2 was increased by anti-RECK antibody. Increased RECK levels were also observed in cerulein-induced acute pancreatitis. Therefore, our results suggest for the first time proteolytic processing of RECK as a mechanism regulating RECK activity, and demonstrate that TGF-beta signaling in activated PSCs may promote ECM accumulation via a mechanism that preserves the protease inhibitory activity of RECK.
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Affiliation(s)
- Hongsik Lee
- Department of Internal Medicine, Ansan Korea University Hospital, Ansan, Gyeonggi do, Korea
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Xenophontos S, Hadjivassiliou M, Karagrigoriou A, Demetriou N, Miltiadous G, Marcou I, Elisaf M, Mikhailidis DP, Cariolou MA. Low HDL cholesterol, smoking and IL-13 R130Q polymorphism are associated with myocardial infarction in Greek Cypriot males. A pilot study. Open Cardiovasc Med J 2008; 2:52-9. [PMID: 18949100 PMCID: PMC2570578 DOI: 10.2174/1874192400802010052] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2008] [Revised: 07/02/2008] [Accepted: 07/04/2008] [Indexed: 11/22/2022] Open
Abstract
This study was carried out in Greek Cypriot males to identify risk factors that predispose to myocardial infarction (MI). Genetic and lipid risk factors were investigated for the first time in a Greek Cypriot male case-control study.Contrary to other studies, mean low density lipoprotein cholesterol did not differ between cases and controls. High density lipoprotein cholesterol on the other hand, although within normal range in cases and controls, was significantly higher in the control population. In agreement with many other studies, smoking was significantly more prevalent in cases compared with controls. In pooled cases and controls, smokers had a significantly lower HDL-C level compared with non-smokers. The frequency of the IL-13 R130Q homozygotes for the mutation (QQ), as well as the mutant allele were significantly higher in cases compared with controls. The IL-13 R130Q variant, or another locus, linked to it, may increase the risk of MI.
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Affiliation(s)
- Stavroulla Xenophontos
- Department of Cardiovascular Genetics & The Laboratory of Forensic Genetics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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Inhibition of matrix metalloproteinases suppresses the migration of skeletal muscle cells. J Muscle Res Cell Motil 2008; 29:37-44. [DOI: 10.1007/s10974-008-9140-2] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2008] [Accepted: 05/28/2008] [Indexed: 10/21/2022]
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Abe K, Ikeda T, Wake K, Sato T, Sato T, Inoue H. Glycyrrhizin prevents of lipopolysaccharide/D-galactosamine-induced liver injury through down-regulation of matrix metalloproteinase-9 in mice. J Pharm Pharmacol 2008; 60:91-7. [PMID: 18251086 PMCID: PMC7166488 DOI: 10.1211/jpp.60.1.0012] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Glycyrrhizin, a biological active compound isolated from the liquorice root, has been used as a treatment for chronic hepatitis. We have examined the involvement of matrix metalloproteinase (MMP)‐9 in the development of lipopolysaccharide (LPS) and D‐galactosamine (GalN)‐induced liver injury in mice. We also investigated the effect of glycyrrhizin on expression of MMP‐9 in this model. Levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased after LPS/GalN treatment. Expression of MMP‐9 mRNA and protein was markedly up‐regulated in liver tissues 6–8 h after LPS/GalN treatment. Pretreatment with glycyrrhizin (50 mg kg−1) and the MMP inhibitor (5 mg kg−1) suppressed increases in serum levels of ALT and AST in mice treated with LPS/GalN. Furthermore, glycyrrhizin inhibited levels of both mRNA and protein for MMP‐9. Immunohistochemical reaction for MMP‐9 was observed in macrophages/monocytes infiltrated in the inflammatory area of liver injury. Glycyrrhizin reduced the infiltration of inflammatory cells and immunoreactive MMP‐9 in liver injury. The results indicated that MMP‐9 played a role in the development of LPS/GalN‐induced mouse liver injury, and suggested that an inhibition by glycyrrhizin of the acute liver injury may have been due to a down‐regulation of MMP‐9.
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Affiliation(s)
- Kazuki Abe
- Pharmacological Research Department, Minophagen Pharmaceutical Co., Kanagawa, Japan
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