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Zhou CJ, Guo Y. Mini review on collagens in normal skin and pathological scars: current understanding and future perspective. Front Med (Lausanne) 2024; 11:1449597. [PMID: 39091289 PMCID: PMC11291465 DOI: 10.3389/fmed.2024.1449597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 07/05/2024] [Indexed: 08/04/2024] Open
Abstract
Pathological scar tissues are characterized by the presence of overabundant collagens whose structure and organization are also different from those in unwounded skin. This causes scar tissues to lose some functions performed by normal skin, and currently, there are no effective measures to prevent scar formation. Inflammation has been shown to modulate fibroblast proliferation, differentiation, and function, hence collagen production and organization. In this minireview, we provide an overview of the current understanding of collagen, specifically collagen type I and III which are main collagens in skin, structure and fibre formation and highlight their differences between normal skin and pathological scars. We discuss the role that cytokines play in modulating fibroblast function. We also identify some potential research directions which could help to further our understanding of the complex and dynamic wound healing and scar formation process.
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Affiliation(s)
| | - Yuan Guo
- School of Food Science and Nutrition, University of Leeds, Leeds, United Kingdom
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2
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Abstract
Chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) or viral hepatitis are characterized by persistent inflammation and subsequent liver fibrosis. Liver fibrosis critically determines long-term morbidity (for example, cirrhosis or liver cancer) and mortality in NAFLD and nonalcoholic steatohepatitis (NASH). Inflammation represents the concerted response of various hepatic cell types to hepatocellular death and inflammatory signals, which are related to intrahepatic injury pathways or extrahepatic mediators from the gut-liver axis and the circulation. Single-cell technologies have revealed the heterogeneity of immune cell activation concerning disease states and the spatial organization within the liver, including resident and recruited macrophages, neutrophils as mediators of tissue repair, auto-aggressive features of T cells as well as various innate lymphoid cell and unconventional T cell populations. Inflammatory responses drive the activation of hepatic stellate cells (HSCs), and HSC subsets, in turn, modulate immune mechanisms via chemokines and cytokines or transdifferentiate into matrix-producing myofibroblasts. Current advances in understanding the pathogenesis of inflammation and fibrosis in the liver, mainly focused on NAFLD or NASH owing to the high unmet medical need, have led to the identification of several therapeutic targets. In this Review, we summarize the inflammatory mediators and cells in the diseased liver, fibrogenic pathways and their therapeutic implications.
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Affiliation(s)
- Linda Hammerich
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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3
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Neves LMG, Wilgus TA, Bayat A. In Vitro, Ex Vivo, and In Vivo Approaches for Investigation of Skin Scarring: Human and Animal Models. Adv Wound Care (New Rochelle) 2023; 12:97-116. [PMID: 34915768 DOI: 10.1089/wound.2021.0139] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Significance: The cutaneous repair process naturally results in different types of scarring that are classified as normal or pathological. Affected individuals are often affected from an esthetic, physical (functional), and psychosocial perspective. The distinct nature of scarring in humans, particularly the formation of pathological scars, makes the study of skin scarring a challenge for researchers in this area. Several established experimental models exist for studying scar formation. However, the increasing development and validation of newly emerging models have made it possible to carry out studies focused on different variables that influence this unique process. Recent Advances: Experimental models such as in vitro, ex vivo, and in vivo models have obtained different degrees of success in the reproduction of the scar formation in its native milieu and true environment. These models also differ in their ability to elucidate the molecular, cellular, and structural mechanisms involved in scarring, as well as for testing new agents and approaches for therapies. The models reviewed here, including cells derived from human skin and in vivo animal models, have contributed to the advancement of skin scarring research. Critical Issues and Future Directions: The absence of experimental models that faithfully reproduce the typical characteristics of the different types of human skin scars makes the improvement of validated models and the establishment of new ones a critical unmet need. The fields of wound healing research combined with tissue engineering have offered newer alternatives for experimental studies with the potential to provide clinically useful knowledge about scar formation.
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Affiliation(s)
- Lia M G Neves
- Plastic & Reconstructive Surgery Research, Centre for Dermatology Research, Wound Healing Theme, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, England, United Kingdom
| | - Traci A Wilgus
- Department of Pathology, Ohio State University, Columbus, Ohio, USA
| | - Ardeshir Bayat
- Plastic & Reconstructive Surgery Research, Centre for Dermatology Research, Wound Healing Theme, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, England, United Kingdom.,Medical Research Council (MRC) Wound Healing Unit, Hair and Skin Research Laboratory, Division of Dermatology, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa
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4
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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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5
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Jhanji V, Billig I, Yam GHF. Cell-Free Biological Approach for Corneal Stromal Wound Healing. Front Pharmacol 2021; 12:671405. [PMID: 34122095 PMCID: PMC8193853 DOI: 10.3389/fphar.2021.671405] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/17/2021] [Indexed: 12/13/2022] Open
Abstract
Corneal opacification is the fourth most common cause of blindness globally behind cataracts, glaucoma, and age-related macular degeneration. The standard treatment of serious corneal scarring is corneal transplantation. Though it is effective for restoring vision, the treatment outcome is not optimal, due to limitations such as long-term graft survival, lifelong use of immunosuppressants, and a loss of corneal strength. Regulation of corneal stromal wound healing, along with inhibition or downregulation of corneal scarring is a promising approach to prevent corneal opacification. Pharmacological approaches have been suggested, however these are fraught with side effects. Tissue healing is an intricate process that involves cell death, proliferation, differentiation, and remodeling of the extracellular matrix. Current research on stromal wound healing is focused on corneal characteristics such as the immune response, angiogenesis, and cell signaling. Indeed, promising new technologies with the potential to modulate wound healing are under development. In this review, we provide an overview of cell-free strategies and some approaches under development that have the potential to control stromal fibrosis and scarring, especially in the context of early intervention.
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Affiliation(s)
- Vishal Jhanji
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Isabelle Billig
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Gary Hin-Fai Yam
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, United States
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6
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van Geffen C, Deißler A, Quante M, Renz H, Hartl D, Kolahian S. Regulatory Immune Cells in Idiopathic Pulmonary Fibrosis: Friends or Foes? Front Immunol 2021; 12:663203. [PMID: 33995390 PMCID: PMC8120991 DOI: 10.3389/fimmu.2021.663203] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/22/2021] [Indexed: 12/20/2022] Open
Abstract
The immune system is receiving increasing attention for interstitial lung diseases, as knowledge on its role in fibrosis development and response to therapies is expanding. Uncontrolled immune responses and unbalanced injury-inflammation-repair processes drive the initiation and progression of idiopathic pulmonary fibrosis. The regulatory immune system plays important roles in controlling pathogenic immune responses, regulating inflammation and modulating the transition of inflammation to fibrosis. This review aims to summarize and critically discuss the current knowledge on the potential role of regulatory immune cells, including mesenchymal stromal/stem cells, regulatory T cells, regulatory B cells, macrophages, dendritic cells and myeloid-derived suppressor cells in idiopathic pulmonary fibrosis. Furthermore, we review the emerging role of regulatory immune cells in anti-fibrotic therapy and lung transplantation. A comprehensive understanding of immune regulation could pave the way towards new therapeutic or preventive approaches in idiopathic pulmonary fibrosis.
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Affiliation(s)
- Chiel van Geffen
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University Hospital Tübingen, Tübingen, Germany
| | - Astrid Deißler
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University Hospital Tübingen, Tübingen, Germany.,Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
| | - Markus Quante
- Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
| | - Harald Renz
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany.,Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany
| | - Dominik Hartl
- Department of Pediatrics I, Eberhard Karls University of Tübingen, Tübingen, Germany.,Dominik Hartl, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Saeed Kolahian
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University Hospital Tübingen, Tübingen, Germany.,Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany.,Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany
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7
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Singampalli KL, Balaji S, Wang X, Parikh UM, Kaul A, Gilley J, Birla RK, Bollyky PL, Keswani SG. The Role of an IL-10/Hyaluronan Axis in Dermal Wound Healing. Front Cell Dev Biol 2020; 8:636. [PMID: 32850791 PMCID: PMC7396613 DOI: 10.3389/fcell.2020.00636] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 06/24/2020] [Indexed: 12/12/2022] Open
Abstract
Scar formation is the typical endpoint of postnatal dermal wound healing, which affects more than 100 million individuals annually. Not only do scars cause a functional burden by reducing the biomechanical strength of skin at the site of injury, but they also significantly increase healthcare costs and impose psychosocial challenges. Though the mechanisms that dictate how dermal wounds heal are still not completely understood, they are regulated by extracellular matrix (ECM) remodeling, neovascularization, and inflammatory responses. The cytokine interleukin (IL)-10 has emerged as a key mediator of the pro- to anti-inflammatory transition that counters collagen deposition in scarring. In parallel, the high molecular weight (HMW) glycosaminoglycan hyaluronan (HA) is present in the ECM and acts in concert with IL-10 to block pro-inflammatory signals and attenuate fibrotic responses. Notably, high concentrations of both IL-10 and HMW HA are produced in early gestational fetal skin, which heals scarlessly. Since fibroblasts are responsible for collagen deposition, it is critical to determine how the concerted actions of IL-10 and HA drive their function to potentially control fibrogenesis. Beyond their independent actions, an auto-regulatory IL-10/HA axis may exist to modulate the magnitude of CD4+ effector T lymphocyte activation and enhance T regulatory cell function in order to reduce scarring. This review underscores the pathophysiological impact of the IL-10/HA axis as a multifaceted molecular mechanism to direct primary cell responders and regulators toward either regenerative dermal tissue repair or scarring.
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Affiliation(s)
- Kavya L Singampalli
- Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Department of Surgery, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, United States.,Department of Bioengineering, Rice University, Houston, TX, United States.,Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, United States
| | - Swathi Balaji
- Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Department of Surgery, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, United States
| | - Xinyi Wang
- Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Department of Surgery, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, United States
| | - Umang M Parikh
- Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Department of Surgery, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, United States
| | - Aditya Kaul
- Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Department of Surgery, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, United States
| | - Jamie Gilley
- Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Department of Surgery, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, United States.,Division of Neonatology, Department of Pediatrics, Texas Children's Hospital, Houston, TX, United States
| | | | - Paul L Bollyky
- Division of Infectious Diseases, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Sundeep G Keswani
- Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Department of Surgery, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, United States
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8
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Wong EA, Evans S, Kraus CR, Engelman KD, Maiello P, Flores WJ, Cadena AM, Klein E, Thomas K, White AG, Causgrove C, Stein B, Tomko J, Mattila JT, Gideon H, Lin PL, Reimann KA, Kirschner DE, Flynn JL. IL-10 Impairs Local Immune Response in Lung Granulomas and Lymph Nodes during Early Mycobacterium tuberculosis Infection. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 204:644-659. [PMID: 31862711 PMCID: PMC6981067 DOI: 10.4049/jimmunol.1901211] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 11/21/2019] [Indexed: 01/04/2023]
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to be a major global health problem. Lung granulomas are organized structures of host immune cells that function to contain the bacteria. Cytokine expression is a critical component of the protective immune response, but inappropriate cytokine expression can exacerbate TB. Although the importance of proinflammatory cytokines in controlling M. tuberculosis infection has been established, the effects of anti-inflammatory cytokines, such as IL-10, in TB are less well understood. To investigate the role of IL-10, we used an Ab to neutralize IL-10 in cynomolgus macaques during M. tuberculosis infection. Anti-IL-10-treated nonhuman primates had similar overall disease outcomes compared with untreated control nonhuman primates, but there were immunological changes in granulomas and lymph nodes from anti-IL-10-treated animals. There was less thoracic inflammation and increased cytokine production in lung granulomas and lymph nodes from IL-10-neutralized animals at 3-4 wk postinfection compared with control animals. At 8 wk postinfection, lung granulomas from IL-10-neutralized animals had reduced cytokine production but increased fibrosis relative to control animals. Although these immunological changes did not affect the overall disease burden during the first 8 wk of infection, we paired computational modeling to explore late infection dynamics. Our findings support that early changes occurring in the absence of IL-10 may lead to better bacterial control later during infection. These unique datasets provide insight into the contribution of IL-10 to the immunological balance necessary for granulomas to control bacterial burden and disease pathology in M. tuberculosis infection.
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Affiliation(s)
- Eileen A Wong
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219
| | - Stephanie Evans
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - Carolyn R Kraus
- Nonhuman Primate Reagent Resource, MassBiologics, University of Massachusetts Medical School, Boston, MA 02126
| | - Kathleen D Engelman
- Nonhuman Primate Reagent Resource, MassBiologics, University of Massachusetts Medical School, Boston, MA 02126
| | - Pauline Maiello
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219
| | - Walter J Flores
- Nonhuman Primate Reagent Resource, MassBiologics, University of Massachusetts Medical School, Boston, MA 02126
| | - Anthony M Cadena
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219
| | - Edwin Klein
- Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA 15261
| | - Kayla Thomas
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219
| | - Alexander G White
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219
| | - Chelsea Causgrove
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219
| | - Brianne Stein
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219
| | - Jaime Tomko
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219
| | - Joshua T Mattila
- Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA 15261; and
| | - Hannah Gideon
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219
| | - P Ling Lin
- Department of Pediatrics, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224
| | - Keith A Reimann
- Nonhuman Primate Reagent Resource, MassBiologics, University of Massachusetts Medical School, Boston, MA 02126
| | - Denise E Kirschner
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109
| | - JoAnne L Flynn
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219;
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9
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Singh R, Alape D, de Lima A, Ascanio J, Majid A, Gangadharan SP. Regulatory T Cells in Respiratory Health and Diseases. Pulm Med 2019; 2019:1907807. [PMID: 31827925 PMCID: PMC6886321 DOI: 10.1155/2019/1907807] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 09/05/2019] [Accepted: 09/10/2019] [Indexed: 02/06/2023] Open
Abstract
Respiratory diseases compromise the health of millions of people all over the world and are strongly linked to the immune dysfunction. CD4+FOXP3+ T regulatory cells, also known as Tregs, have a central role maintaining tissue homeostasis during immune responses. Their activity and clinical impact have been widely studied in different clinical conditions including autoimmune diseases, inflammatory conditions, and cancer, amongst others. Tregs express transcription factor forkhead box P3 (FOXP3), which allows regulation of the immune response through anti-inflammatory cytokines such as IL-10 or transforming growth factor beta (TGF-β) and direct cell-to-cell interaction. Maintenance of immune tolerance is achieved via modulation of effector CD4+ T helper 1, 2 or 17 (Th1, Th2, Th17) cells by Tregs. This review highlights the recent progress in the understanding of Tregs in different disorders of the respiratory system.
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Affiliation(s)
- Rani Singh
- Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Daniel Alape
- Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Andrés de Lima
- Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Juan Ascanio
- Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Adnan Majid
- Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Sidhu P. Gangadharan
- Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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10
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Borthwick LA, Wynn TA, Fisher AJ. Cytokine mediated tissue fibrosis. BIOCHIMICA ET BIOPHYSICA ACTA 2013; 1832:1049-60. [PMID: 23046809 PMCID: PMC3787896 DOI: 10.1016/j.bbadis.2012.09.014] [Citation(s) in RCA: 280] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Revised: 09/28/2012] [Accepted: 09/29/2012] [Indexed: 12/20/2022]
Abstract
Acute inflammation is a recognised part of normal wound healing. However, when inflammation fails to resolve and a chronic inflammatory response is established this process can become dysregulated resulting in pathological wound repair, accumulation of permanent fibrotic scar tissue at the site of injury and the failure to return the tissue to normal function. Fibrosis can affect any organ including the lung, skin, heart, kidney and liver and it is estimated that 45% of deaths in the western world can now be attributed to diseases where fibrosis plays a major aetiological role. In this review we examine the evidence that cytokines play a vital role in the acute and chronic inflammatory responses that drive fibrosis in injured tissues. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
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Affiliation(s)
- Lee A Borthwick
- Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK; Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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11
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John T, Lodka D, Kohl B, Ertel W, Jammrath J, Conrad C, Stoll C, Busch C, Schulze-Tanzil G. Effect of pro-inflammatory and immunoregulatory cytokines on human tenocytes. J Orthop Res 2010; 28:1071-7. [PMID: 20127972 DOI: 10.1002/jor.21079] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Tendon injury induces a local inflammatory response, characterized by the induction of pro-inflammatory cytokines. The aim of the present study was to analyze the effects of TNFalpha, IL-6 and IL-10 on key parameters of tendon homeostasis. Cultured primary human tenocytes were treated with the recombinant cytokines IL-6, IL-10, TNFalpha, or combinations of TNFalpha with IL-6 and IL-10 (10 ng/mL, 6, 24 h). Expression of type I collagen, elastin, MMP-1, TNFalpha, IL-1beta, IL-6, IL-10, and suppressors of cytokine signaling (SOCS1, 3) was analyzed with the use of RTD-PCR, immunocytochemistry, and Western blot analysis. In response to TNFalpha, tenocytes reduced their type I collagen deposition but increased their elastin gene expression and highly upregulated their expression for MMP-1, pro-inflammatory (TNFalpha, IL-1beta) and immunoregulatory (IL-6, IL-10) cytokines. TNFalpha stimulation augmented SOCS1, whereas SOCS3 expression in tenocytes was also induced by IL-6. The treatment of tenocytes with IL-6 and IL-10 had no effect on cytokine expression. Neither IL-6 nor IL-10 modulated the observed effects of TNFalpha significantly. These results indicate that TNFalpha strongly activates the tenocytes to amplify their own TNFalpha expression and, subsequently, that of other regulatory cytokines and matrix degrading enzymes. However, the impact of IL-6 and IL-10 on tenocytes remains unclear.
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Affiliation(s)
- Thilo John
- Department for Trauma and Reconstructive Surgery, Charité-Universitätsmedizin, Campus Benjamin Franklin, FEM, Krahmerstr. 6-10, 12207 Berlin, Germany
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12
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John U, Kemper MJ. Urinary tract infections in children after renal transplantation. Pediatr Nephrol 2009; 24:1129-36. [PMID: 18197424 PMCID: PMC2704952 DOI: 10.1007/s00467-007-0690-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2007] [Revised: 10/02/2007] [Accepted: 10/23/2007] [Indexed: 11/29/2022]
Abstract
Urinary tract infections (UTI) after pediatric kidney transplantation (KTX) are an important clinical problem and occur in 15-33% of patients. Febrile UTI, whether occurring in the transplanted kidney or the native kidney, should be differentiated from afebrile UTI. The latter may cause significant morbidity and is usually associated with acute graft dysfunction. Risk factors for (febrile) UTI include anatomical, functional, and demographic factors as well as baseline immunosuppression and foreign material, such as catheters and stents. Meticulous surveillance, diagnosis, and treatment of UTI is important to minimize acute morbidity and compromise of long-term graft function. In febrile UTI, parenteral antibiotics are usually indicated, although controlled data are not available. As most data concerning UTI have been accumulated retrospectively, future prospective studies have to be performed to clarify pathogenetic mechanisms and risk factors, improve prophylaxis and treatment, and ultimately optimize long-term renal graft survival.
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Affiliation(s)
- Ulrike John
- University Children’s Hospitals, Kochstr. 2, 07745 Jena, Germany
| | - Markus J. Kemper
- Klink für Kinder–und Jugendmedizin, Martinistr. 52, 20246 Hamburg, Germany
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13
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Dai LJ, Li HY, Guan LX, Ritchie G, Zhou JX. The therapeutic potential of bone marrow-derived mesenchymal stem cells on hepatic cirrhosis. Stem Cell Res 2008; 2:16-25. [PMID: 19383405 DOI: 10.1016/j.scr.2008.07.005] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2008] [Revised: 07/11/2008] [Accepted: 07/31/2008] [Indexed: 12/13/2022] Open
Abstract
Hepatic cirrhosis is the end-stage of chronic liver diseases. The majority of patients with hepatic cirrhosis die from life-threatening complications occurring at their earlier ages. Liver transplantation has been the most effective treatment for these patients. Since liver transplantation is critically limited by the shortage of available donor livers, searching for an effective alternative therapy has attracted great interest in preclinical studies. The transplantation of autologous bone marrow-derived mesenchymal stem cells holds great potential for treating hepatic cirrhosis. Mesenchymal stem cells can differentiate to hepatocytes, stimulate the regeneration of endogenous parenchymal cells, and enhance fibrous matrix degradation. Experimental and clinical studies have shown promising beneficial effects. This review is intended to translate the bench study results to the patients' bedside. The potential interventions of mesenchymal stem cells on cirrhosis are illustrated in terms of the cellular and molecular mechanisms of hepatic fibrogenesis.
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Affiliation(s)
- Long-Jun Dai
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
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Skeie JM, Mullins RF. Macrophages in neovascular age-related macular degeneration: friends or foes? Eye (Lond) 2008; 23:747-55. [PMID: 18600240 DOI: 10.1038/eye.2008.206] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
The events that lead to choroidal neovascularization in eyes with age-related macular degeneration are poorly understood. One possibility that has been explored in a number of studies is that macrophages can promote neovascular changes. In this paper, we summarize the evidence for inflammation in general and macrophages in particular in pathologic neovascularization, and discuss how the diverse functions of these cells may promote or inhibit macular disease. We also discuss some of the conflicting findings regarding the role of macrophages in experimental choroidal neovascularization in mouse models, and suggest areas for future research.
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Affiliation(s)
- J M Skeie
- Department of Ophthalmology and Visual Sciences, Carver Family Center for Macular Degeneration, The University of Iowa, Iowa City, IA 52242, USA
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15
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Abstract
Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.
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Affiliation(s)
- T A Wynn
- Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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Abstract
Lightman discusses a new study that found that in a mouse model of choroidal neovascularisation (CNV), IL-10-deficient mice had decreased amounts of CNV.
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Affiliation(s)
- Sue Lightman
- Institute of Ophthalmology, London, United Kingdom.
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17
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Barbarin V, Nihoul A, Misson P, Arras M, Delos M, Leclercq I, Lison D, Huaux F. The role of pro- and anti-inflammatory responses in silica-induced lung fibrosis. Respir Res 2005; 6:112. [PMID: 16212659 PMCID: PMC1274346 DOI: 10.1186/1465-9921-6-112] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2005] [Accepted: 10/07/2005] [Indexed: 01/28/2023] Open
Abstract
Background It has been generally well accepted that chronic inflammation is a necessary component of lung fibrosis but this concept has recently been challenged. Methods Using biochemical, histological, immunohistochemistry, and cellular analyses, we compared the lung responses (inflammation and fibrosis) to fibrogenic silica particles (2.5 and 25 mg/g lung) in Sprague-Dawley rats and NMRI mice. Results Rats treated with silica particles developed chronic and progressive inflammation accompanied by an overproduction of TNF-α as well as an intense lung fibrosis. Dexamethasone or pioglitazone limited the amplitude of the lung fibrotic reaction to silica in rats, supporting the paradigm that inflammation drives lung fibrosis. In striking contrast, in mice, silica induced only a limited and transient inflammation without TNF-α overproduction. However, mice developed lung fibrosis of a similar intensity than rats. The fibrotic response in mice was accompanied by a high expression of the anti-inflammatory and fibrotic cytokine IL-10 by silica-activated lung macrophages. In mice, IL-10 was induced only by fibrotic particles and significantly expressed in the lung of silica-sensitive but not silica-resistant strains of mice. Anti-inflammatory treatments did not control lung fibrosis in mice. Conclusion These results indicate that, beside chronic lung inflammation, a pronounced anti-inflammatory reaction may also contribute to the extension of silica-induced lung fibrosis and represents an alternative pathway leading to lung fibrosis.
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Affiliation(s)
- Virginie Barbarin
- Industrial Toxicology and Occupational Medicine Unit, Faculty of Medicine, Université catholique de Louvain, Clos Chapelle-aux-champs 30.54, 1200 Brussels, Belgium
| | - Aurélie Nihoul
- Industrial Toxicology and Occupational Medicine Unit, Faculty of Medicine, Université catholique de Louvain, Clos Chapelle-aux-champs 30.54, 1200 Brussels, Belgium
| | - Pierre Misson
- Industrial Toxicology and Occupational Medicine Unit, Faculty of Medicine, Université catholique de Louvain, Clos Chapelle-aux-champs 30.54, 1200 Brussels, Belgium
| | - Mohammed Arras
- Industrial Toxicology and Occupational Medicine Unit, Faculty of Medicine, Université catholique de Louvain, Clos Chapelle-aux-champs 30.54, 1200 Brussels, Belgium
| | - Monique Delos
- Laboratory of Pathology, University Hospital of Mont Godinne, Université catholique de Louvain, Avenue Dr. G. Thérasse 1, 5530 Yvoir, Belgium
| | - Isabelle Leclercq
- Unit of Gastro-enterology, Faculty of Medicine, Université catholique de Louvain, 53–79, Avenue E. Mounier 53,1200 Brussels, Belgium
| | - Dominique Lison
- Industrial Toxicology and Occupational Medicine Unit, Faculty of Medicine, Université catholique de Louvain, Clos Chapelle-aux-champs 30.54, 1200 Brussels, Belgium
| | - Francois Huaux
- Industrial Toxicology and Occupational Medicine Unit, Faculty of Medicine, Université catholique de Louvain, Clos Chapelle-aux-champs 30.54, 1200 Brussels, Belgium
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18
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Hofer H, Neufeld JB, Oesterreicher C, Grundtner P, Wrba F, Gangl A, Ferenci P, Gasche C. Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection. Genes Immun 2005; 6:242-7. [PMID: 15729365 DOI: 10.1038/sj.gene.6364168] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Immune response to viral infection is an important determinant of liver injury in chronic hepatitis C (CHC). Experimental and clinical data suggest a protective role of interleukin-10 (IL-10) in hepatic fibrogenesis. The significance of two SNPs of the interleukin-10 receptor 1 (IL-10R1), S138G (SNP3) and G330R (SNP4) was investigated on (i) susceptibility to CHC, (ii) progression of hepatic fibrosis and (iii) response to interferon/ribavirin therapy. DNA and liver biopsies were obtained from 212 patients with HCV (hepatitis C virus)-genotype-1 infection. The allele frequencies were 0.17 for SNP3 and 0.33 for SNP4, both of which were indifferent from healthy controls (0.17 and 0.32, respectively). Stage 1 liver fibrosis was found in 22 cases (10.4%), stage 2 in 108 (50.9%), stage 3 in 27 (12.8%), and stage 4 (cirrhosis) in 55 (25.9%). An association was found between the SNP4 allele and the presence of cirrhosis (P=0.01). Homozygous SNP4 individual variants segregated within the cirrhosis group (P=0.03). We found neither an association with SNP3 nor with the necroinflammatory disease activity (as measured by ALT levels) nor with the response to antiviral therapy. Our work implies that IL-10R1 SNP4 is a recessively inherited risk factor for hepatic cirrhosis in HCV genotype-1 infection.
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Affiliation(s)
- H Hofer
- Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria
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19
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Yates JM, Smith KG, Robinson PP. The effect of triamcinolone hexacetonide on the spontaneous and mechanically-induced ectopic discharge following lingual nerve injury in the ferret. Pain 2004; 111:261-269. [PMID: 15363869 DOI: 10.1016/j.pain.2004.07.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2004] [Revised: 05/21/2004] [Accepted: 07/06/2004] [Indexed: 10/26/2022]
Abstract
Investigations into the aetiology of nerve injury-induced dysaesthesia have revealed the development of spontaneous and mechanically-induced activity from damaged axons. Pharmacological manipulation of this activity could provide a method of treatment for this intractable condition. This study has investigated the effect of a corticosteroid applied to the injury site, as these agents are known to reduce inflammation and scarring. In 24 anaesthetised adult ferrets the left lingual nerve was sectioned and the animals allowed to recover. In eight of these animals the nerve was re-exposed under anaesthesia after 1 month and 100 microl of corticosteroid (triamcinolone hexacetonide, 20 mg/ml) was injected into and around the injury site. In eight others, 100 microl of the steroid carrier was injected, and the eight remaining animals were used as controls. In terminal experiments under general anaesthesia, 3 months after the initial injury, electrophysiological recordings were made from axons in fine filaments dissected from the nerve central to both the injury site and junction with the chorda tympani nerve. Spontaneous activity (SA) was found in approximately 13% of units in control animals, 12% following the application of steroid, and 14% in the carrier group. Mechanically-induced activity at the injury site was found in approximately 13% of units in controls, significantly fewer after the application of steroid 4% (P<0.001) and 12% in the carrier group. These data suggest that local application of the corticosteroid triamcinolone hexacetonide could reduce the level of mechanically-induced, but not spontaneous, dysaesthesia following lingual nerve injury.
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Affiliation(s)
- Julian M Yates
- Department of Oral and Maxillofacial Surgery, School of Clinical Dentistry, University of Sheffield, Claremont Crescent, Sheffield S10 2TA, UK
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20
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Affiliation(s)
- Thomas A Wynn
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 50 South Drive, Room 6154, MSC 8003, Bethesda, Maryland 20892, USA.
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21
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Barbarin V, Arras M, Misson P, Delos M, McGarry B, Phan SH, Lison D, Huaux F. Characterization of the Effect of Interleukin-10 on Silica-Induced Lung Fibrosis in Mice. Am J Respir Cell Mol Biol 2004; 31:78-85. [PMID: 14975940 DOI: 10.1165/rcmb.2003-0299oc] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
We previously described a reduction of silica-induced lung fibrosis in interleukin-10-deficient mice (IL-10-/-) (Huaux and colleagues; Am. J. Respir. Cell Mol. Biol. 1998;18:51-59). In the present study, we further dissect the exact functions of IL-10 in experimental silicosis. The reduced lung fibrotic response to silica in IL-10-/- mice was accompanied by a marked recruitment of TH1 CD4+ lymphocytes. However, treatment with anti-CD4 antibodies reduced silica-induced lung fibrosis in both IL-10-/- and IL-10+/+ mice, suggesting that this T cell population actually contributes to the extension of the fibrotic lesions in a manner that is independent of IL-10. In IL-10-/- mice, silica-induced lung production of the profibrotic mediator transforming growth factor (TGF)-beta1 and the antifibrotic eicosanoid PGE2 were reduced and increased, respectively, relative to that in IL-10+/+ mice. In addition, in vitro experiments indicated that recombinant IL-10 upregulated TGF-beta1 expression in alveolar macrophages while in contrast it downregulated PGE2 production and cyclooxygenase-2 expression in both lung fibroblasts and macrophages. Thus the net profibrotic activity of IL-10 in vivo appears to be mediated by its ability to stimulate the expression of the profibrotic cytokine TGF-beta1 while suppressing the expression of cyclooxygenase-2 and thus production of the antifibrotic eicosanoid PGE2. These effects appear to be independent of the enhanced lung CD4+ T-lymphocytosis observed in IL-10-deficient mice.
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MESH Headings
- Animals
- Antibodies/pharmacology
- CD4-Positive T-Lymphocytes/drug effects
- CD4-Positive T-Lymphocytes/immunology
- Chemotaxis, Leukocyte/drug effects
- Chemotaxis, Leukocyte/immunology
- Cyclooxygenase 2
- Dinoprostone/metabolism
- Disease Models, Animal
- Down-Regulation/drug effects
- Down-Regulation/physiology
- Female
- Fibroblasts/drug effects
- Fibroblasts/metabolism
- Interleukin-10/deficiency
- Interleukin-10/genetics
- Isoenzymes/drug effects
- Isoenzymes/genetics
- Isoenzymes/metabolism
- Lung/drug effects
- Lung/immunology
- Lung/physiopathology
- Macrophages/drug effects
- Macrophages/metabolism
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Prostaglandin-Endoperoxide Synthases/drug effects
- Prostaglandin-Endoperoxide Synthases/genetics
- Prostaglandin-Endoperoxide Synthases/metabolism
- Pulmonary Fibrosis/chemically induced
- Pulmonary Fibrosis/genetics
- Pulmonary Fibrosis/immunology
- RNA, Messenger/drug effects
- RNA, Messenger/metabolism
- Receptors, Interleukin/drug effects
- Receptors, Interleukin/metabolism
- Receptors, Interleukin-10
- Silicon Dioxide
- Th1 Cells/drug effects
- Th1 Cells/immunology
- Transforming Growth Factor beta/drug effects
- Transforming Growth Factor beta/genetics
- Transforming Growth Factor beta/metabolism
- Transforming Growth Factor beta1
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Affiliation(s)
- Virginie Barbarin
- Industrial Toxicology and Occupational Medicine Unit, Faculty of Medicine, University Hospital of Mont Godinne, Yvoir, Université Catholique de Louvain, Brussels, Belgium
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22
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Hill DB, D'Souza NB, Lee EY, Burikhanov R, Deaciuc IV, de Villiers WJS. A role for interleukin-10 in alcohol-induced liver sensitization to bacterial lipopolysaccharide. Alcohol Clin Exp Res 2002. [PMID: 11821657 DOI: 10.1111/j.1530-0277.2002.tb02434.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Proinflammatory cytokines play an important role in alcohol-induced liver injury. The role of anti-inflammatory cytokines in the initiation and progression of alcoholic liver disease has received little attention. This study tested the hypothesis that an imbalance exists between pro- and anti-inflammatory cytokines in the liver during chronic exposure to alcohol. Alcohol exposure results in predominantly proinflammatory cytokine secretion and liver injury. METHODS IL-10 knock-out and their C57BL/6J counterpart wild-type mice were fed alcohol in drinking water for 7 weeks. At the end of alcohol feeding, Gram-negative bacterial lipopolysaccharide (LPS) was administered, and the animals were killed after 3 and 8 hr. Liver histology, plasma alanine aminotransferase and aspartate aminotransferase activity, tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-10 levels, and liver cytokine messenger RNA levels were measured. RESULTS Alcohol feeding and LPS treatment did not change plasma enzyme activity levels in wild-type mice. In the IL-10 knock-out mice, LPS alone increased aspartate aminotransferase and alanine aminotransferase enzyme activity, and this was potentiated by alcohol. Alcohol induced liver steatosis in both wild-type and knock-out mice. LPS markedly enhanced the histological effects further, especially in the knock-out mice, with the emergence of focal necrosis, polymorphonuclear infiltration, and microabscesses in the liver. Plasma tumor necrosis factor-alpha and IL-1beta levels were not affected by alcohol alone. Proinflammatory cytokine levels were increased by LPS and further enhanced by alcohol treatment, particularly in the IL-10 knock-out mice. IL-10 plasma levels in the wild-type animals were down-regulated by alcohol. Changes in liver cytokine messenger RNA paralleled those seen in plasma cytokine levels. CONCLUSIONS Alcohol-induced liver sensitization to LPS in wild-type mice may involve down-regulation of IL-10. This anti-inflammatory cytokine, known for its hepatoprotective effects, is secreted simultaneously with proinflammatory cytokines. IL-10 may also limit alcohol-induced liver damage by counteracting the effects of proinflammatory cytokines.
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Affiliation(s)
- Daniell B Hill
- Department of Internal Medicine, Division of Digestive Diseases, A. B. Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536, USA
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23
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Wangoo A, Sparer T, Brown IN, Snewin VA, Janssen R, Thole J, Cook HT, Shaw RJ, Young DB. Contribution of Th1 and Th2 cells to protection and pathology in experimental models of granulomatous lung disease. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2001; 166:3432-9. [PMID: 11207301 DOI: 10.4049/jimmunol.166.5.3432] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Mice that had received adoptive transfer of DO11.10 TCR transgenic T cells polarized toward a Th1 or a Th2 phenotype were challenged with Ag-coated beads or with recombinant Mycobacterium tuberculosis expressing the OVA determinant. The resulting bead-induced pulmonary granulomas reflected the phenotype of the adoptively transferred T cells, with the Th2 cells promoting a fibrotic reaction. Mice receiving Th1 cells mounted an epitope-specific protective response to challenge with recombinant M. tuberculosis. Th2 recipients were characterized by enhanced weight loss and lung fibrosis during acute high-dose infection. The combination of TCR transgenic T cells and epitope-tagged mycobacteria provides a novel experimental model for investigation of the pathogenesis of tuberculosis.
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Affiliation(s)
- A Wangoo
- Department of Respiratory Medicine, National Heart and Lung Institute, London, United Kingdom
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24
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Yamamoto T, Eckes B, Krieg T. Effect of interleukin-10 on the gene expression of type I collagen, fibronectin, and decorin in human skin fibroblasts: differential regulation by transforming growth factor-beta and monocyte chemoattractant protein-1. Biochem Biophys Res Commun 2001; 281:200-5. [PMID: 11178980 DOI: 10.1006/bbrc.2001.4321] [Citation(s) in RCA: 113] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Interleukin-10 (IL-10) is a cytokine with many regulatory functions. In particular, IL-10 exerts neutralizing effect on other cytokines, and therefore IL-10 is thought to have important therapeutic implications. Recent reports suggest that IL-10 regulates not only immunocytes but also collagen and collagenase gene expression in fibroblasts. In this study, we investigated the effect of IL-10 on gene expression of extracellular matrix (ECM) proteins, such as type I collagen, fibronectin, and decorin, in human skin fibroblasts. Results of Northern blot analysis showed that both collagen I and fibronectin mRNAs were downregulated, while decorin gene expression was enhanced by IL-10 (10 ng/ml) time-dependently (6-24 h). alpha1(I) collagen and fibronectin mRNAs were decreased to one-third and one-fourth, respectively, by 50 ng/ml IL-10, whereas decorin mRNA was increased up to 2.7-fold by 50 ng/ml IL-10. Response to IL-10 by scleroderma fibroblasts was similar to that in normal dermal fibroblasts, with decreased expression levels of collagen and fibronectin and induced decorin mRNA levels. Transforming growth factor-beta (TGF-beta) is a crucial fibrogenic cytokine which upregulates the mRNA expression of collagen and fibronectin, whereas it downregulates decorin mRNA expression in fibroblasts. Monocyte chemoattractant protein-1 (MCP-1) has recently been shown to upregulate the type I collagen mRNA expression in cultured fibroblasts. We therefore examined whether IL-10 alters gene expression of ECM elicited by TGF-beta and MCP-1. Our results demonstrated that IL-10 downregulated the TGF-beta-elicited increase of mRNA expression of type I collagen and fibronectin, while partially recovering TGF-beta-elicited decrease of decorin expression in normal skin fibroblasts. By contrast, IL-10 did not alter the MCP-1-elicited upregulation of mRNA expression of either alpha1(I) collagen and decorin. Our data indicate that IL-10 differentially regulates TGF-beta and MCP-1 in the modulation of ECM proteins and therefore suggest that IL-10 plays a role in the regulation of tissue remodeling.
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Affiliation(s)
- T Yamamoto
- Department of Dermatology, University of Cologne, Joseph-Stelzmann Strasse 9, Cologne, 50924, Germany.
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25
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Dubé J, Chakir J, Dubé C, Grimard Y, Laviolette M, Boulet LP. Synergistic action of endothelin (ET)-1 on the activation of bronchial fibroblast isolated from normal and asthmatic subjects. Int J Exp Pathol 2000; 81:429-37. [PMID: 11298190 PMCID: PMC2517744 DOI: 10.1046/j.1365-2613.2000.00173.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Bronchial subepithelial fibrosis is an histological characteristic of asthma. Cytokines and other mediators, such as PDGF-BB, TGF-beta1 and ET-1 found in the asthmatic submucosa can potentially activate a repair process that leads to fibroblast proliferation and collagen synthesis. The mechanisms of modulation of the repair process leading to extracellular matrix deposition are still to be documented. In this study, we assessed the in vitro proliferation and collagen synthesis of bronchial fibroblasts isolated from normal and asthmatic subjects in response to ET-1, platelet-derived growth factor (PDGF)-BB and transforming growth factor (TGF)-beta1 alone or in combination, in the presence or absence of dexamethasone. The combination of ET-1 with one of the other two growth factors, or the triple combination, significantly increased DNA synthesis and collagen production of bronchial fibroblasts isolated from both normal and asthmatic subjects, but the same growth factors used separately had no significant effect on the same parameters. These results suggest that the simultaneous presence of ET-1, PDGF-BB and TGF-beta1 in both normal and asthmatic subjects is necessary to activate bronchial fibroblast proliferation and collagen synthesis. As these mediators are present in the submucosa of the asthmatic bronchi, they could be responsible, at least in part, for the accumulation of collagen in the mucosa.
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Affiliation(s)
- J Dubé
- Unité de Recherche, Centre de Pneumologie de l'hôpital Laval, Université Laval, Sainte-Foy, Québec, Canada
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26
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Arai T, Abe K, Matsuoka H, Yoshida M, Mori M, Goya S, Kida H, Nishino K, Osaki T, Tachibana I, Kaneda Y, Hayashi S. Introduction of the interleukin-10 gene into mice inhibited bleomycin-induced lung injury in vivo. Am J Physiol Lung Cell Mol Physiol 2000; 278:L914-22. [PMID: 10781421 DOI: 10.1152/ajplung.2000.278.5.l914] [Citation(s) in RCA: 96] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Interleukin (IL)-10 has been shown to reduce many inflammatory reactions. We investigated the in vivo effects of IL-10 on a bleomycin-induced lung injury model. Hemagglutinating virus of Japan (HVJ)-liposomes containing a human IL-10 expression vector (hIL10-HVJ) or a balanced salt solution as a control (Cont-HVJ) was intraperitoneally injected into mice on day -3. This was followed by intratracheal instillation of bleomycin (0.8 mg/kg) on day 0. Myeloperoxidase activity of bronchoalveolar lavage fluid and tumor necrosis factor-alpha mRNA expression in bronchoalveolar lavage fluid cells on day 7 and hydroxyproline content of the whole lung on day 21 were inhibited significantly by hIL10-HVJ treatment. However, Cont-HVJ treatment could not suppress any of these parameters. We also examined the in vitro effects of IL-10 on the human lung fibroblast cell line WI-38. IL-10 significantly reduced constitutive and transforming growth factor-beta-stimulated type I collagen mRNA expression. However, IL-10 did not affect the proliferation of WI-38 cells induced by platelet-derived growth factor. These data suggested that exogenous IL-10 may be useful in the treatment of pulmonary fibrosis.
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Affiliation(s)
- T Arai
- Department of Molecular Medicine, Osaka University Medical School, Suita, Osaka 565-0871, Japan.
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27
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Wangoo A, Brown IN, Marshall BG, Cook HT, Young DB, Shaw RJ. Bacille Calmette-Guérin (BCG)-associated inflammation and fibrosis: modulation by recombinant BCG expressing interferon-gamma (IFN-gamma). Clin Exp Immunol 2000; 119:92-8. [PMID: 10606969 PMCID: PMC1905541 DOI: 10.1046/j.1365-2249.2000.01100.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Immunization with existing BCG vaccines has failed to confer consistent protection against tuberculosis. One of the ways to improve the efficacy of BCG is by enhancing its ability to induce a type-1 T cell response. However, this approach carries the risk that enhanced immunoreactivity may exacerbate tissue pathology associated with vaccination. The aim of the present study was to determine whether use of a recombinant BCG expressing IFN-gamma (BCG-IFN) would result in an alteration in the pattern of inflammation and local tissue fibrosis. A murine intravenous BCG infection model was used in which there was a time- and dose-dependent increase in the weight and number of granulomas in the liver. Infection was associated with increased inflammatory activity in the liver, as shown by the increase in expression of inducible nitric oxide synthase (iNOS) assessed by immunochemistry and by measurement of specific mRNA, and in fibrosis measured by hydroxyproline content of the liver and percentage of granuloma cells staining positively for type 1 procollagen. Infection with BCG-IFN resulted in a reduction in organ weight and bacterial load on day 21 compared with infection with control BCG transformed with vector alone (BCG-plasmid). By day 21, there was also a reduction in iNOS mRNA and iNOS+ cells in granulomas in mice infected with BCG-IFN compared with infection with BCG-plasmid, and a similar reduction in both total number of granulomas and liver hydroxyproline content. These results demonstrate that the granulomas in the areas of mycobacterial infection are active sites of both inflammation and fibrosis, and that the local expression of IFN-gamma by the recombinant BCG results in more efficient bacterial clearance which is accompanied by a reduction in tissue pathology.
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Affiliation(s)
- A Wangoo
- Department of Respiratory Medicine, National Heart and Lung Institute, London, UK.
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28
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29
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Liu B, Connolly MK. The pathogenesis of cutaneous fibrosis. SEMINARS IN CUTANEOUS MEDICINE AND SURGERY 1998; 17:3-11. [PMID: 9512100 DOI: 10.1016/s1085-5629(98)80055-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cutaneous fibrosis is an integral component of a variety of human disorders including keloids, hypertrophic scar, and most notably, scleroderma. Each has its own etiology and unique clinical characteristics, but all involve the dysregulation of connective tissue metabolism, in particular, the activation of dermal fibroblasts. In this review, we examine various molecular events in scleroderma that may lead to fibroblast activation, and propose a new model to explain the persistence of such activation by scleroderma fibroblasts in the apparent absence of exogenous stimuli.
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Affiliation(s)
- B Liu
- Department of Dermatology at UCSF and Scleroderma Research Center at UCSF and Stanford, San Francisco, CA 94143-0517, USA
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