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Pezeshkian F, Shahriarirad R, Mahram H. An overview of the role of chemokine CX3CL1 (Fractalkine) and CX3C chemokine receptor 1 in systemic sclerosis. Immun Inflamm Dis 2024; 12:e70034. [PMID: 39392260 PMCID: PMC11467895 DOI: 10.1002/iid3.70034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 09/13/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024] Open
Abstract
INTRODUCTION Systemic sclerosis (SSc) is a complex autoimmune disease characterized by fibrosis, vascular damage, and immune dysregulation. Fractalkine or chemokine (C-X3-C motif) ligand 1 (CX3CL1), a chemokine and adhesion molecule, along with its receptor CX3CR1, have been implicated in the inflammatory processes of SSc. CX3CL1 functions as both a chemoattractant and an adhesion molecule, guiding immune cell trafficking. This systematic review examines the role of CX3CL1 and its receptor CX3CR1 in the pathogenesis of SSc, with a focus on pulmonary and vascular complications. METHODS A systematic literature search was conducted across databases including PubMed, Scopus, and Web of Science from inception to November 2020. The search focused on studies investigating the CX3CL1/CX3CR1 axis in the context of SSc. RESULTS The review identified elevated CX3CL1 expression in SSc patients, particularly in the skin and lungs, where CX3CR1 is expressed on infiltrating immune cells. Higher levels of CX3CL1 were correlated with the severity of interstitial lung disease in SSc patients, indicating a potential predictive marker for disease progression. CX3CR1-positive monocytes and NK cells were recruited to inflamed tissues, contributing to fibrosis and tissue damage. Animal studies showed that inhibition of the CX3CL1/CX3CR1 axis reduced fibrosis and improved vascular function. CONCLUSION The CX3CL1/CX3CR1 axis plays a key role in immune cell recruitment and fibrosis in SSc. Elevated CX3CL1 levels are associated with lung and vascular complications, making it a potential biomarker for disease progression and a promising therapeutic target.
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Affiliation(s)
| | - Reza Shahriarirad
- Thoracic and Vascular Surgery Research CenterShiraz University of Medical SciencesShirazIran
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Almadori A, Griffin M, Ryan CM, Hunt DF, Hansen E, Kumar R, Abraham DJ, Denton CP, Butler PEM. Stem cell enriched lipotransfer reverses the effects of fibrosis in systemic sclerosis. PLoS One 2019; 14:e0218068. [PMID: 31314805 PMCID: PMC6636710 DOI: 10.1371/journal.pone.0218068] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 05/17/2019] [Indexed: 12/15/2022] Open
Abstract
Oro-facial fibrosis in systemic sclerosis (Scleroderma;SSc) has a major impact on mouth function, facial appearance, and patient quality of life. Lipotransfer is a method of reconstruction that can be used in the treatment of oro-facial fibrosis. The effect of this treatment not only restores oro-facial volume but has also been found to reverse the effects of oro-facial fibrosis. Adipose derived stem cells (ADSCs) within the engrafted adipose tissue have been shown to be anti-fibrotic in SSc and are proposed as the mechanism of the anti-fibrotic effect of lipotransfer. A cohort of 62 SSc patients with oro-facial fibrosis were assessed before and after stem cell enriched lipotransfer treatment. Clinical evaluation included assessment of mouth function using a validated assessment tool (Mouth Handicap in Systemic Sclerosis Scale-MHISS), validated psychological measurements and pre and post-operative volumetric assessment. In addition, to understand the mechanism by which the anti-fibrotic effect of ADSCs occur, SSc derived fibroblasts and ADSCs from this cohort of patients were co-cultured in direct and indirect culture systems and compared to monoculture controls. Cell viability, DNA content, protein secretion of known fibrotic mediators including growth factor- β1 (TGF β-1) and connective tissue growth factor (CTGF) using ELISA analysis and fibrosis gene expression using a fibrosis pathway specific qPCR array were evaluated. Mouth function (MHISS) was significantly improved (6.85±5.07) (p<0.0001) after treatment. All psychological measures were significantly improved: DAS 24 (12.1±9.5) (p<0.0001); HADS-anxiety (2.8±3.2) (p<0.0001), HADS-depression (2.0±3.1) (p<0.0001); BFNE (2.9 ± 4.3) (p<0.0001); VAS (3.56±4.1) (p<0.0001). Multiple treatments further improved mouth function (p<0.05), DAS (p<0.0001) and VAS (p = 0.01) scores. SSc fibroblast viability and proliferation was significantly reduced in co-culture compared to monoculture via a paracrine effect over 14 days (p < 0.0001). Protein secretion of transforming growth factor (TGF-β1) and connective tissue growth factor (CTGF) was significantly reduced in co-culture compared to monoculture (p < 0.0001). Multiple fibrosis associated genes were down regulated in SSc co-culture compared to monoculture after 14 days including Matrix metalloproteinase-8 (MMMP-8), Platelet derived growth factor-β (PDGF-β) and Integrin Subunit Beta 6 (ITG-β6). Autologous stem cell enriched lipotransfer significantly improved the effects of oro-facial fibrosis in SSc in this open cohort study. Lipotransfer may reduce dermal fibrosis through the suppression of fibroblast proliferation and key regulators of fibrogenesis including TG-β1 and CTGF. Our findings warrant further investigation in a randomised controlled trial.
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Affiliation(s)
- Aurora Almadori
- UCL Division of Surgery & Interventional Science, University College London, London, United Kingdom
- Department of Plastic Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
- The Charles Wolfson Center for Reconstructive Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
| | - Michelle Griffin
- UCL Division of Surgery & Interventional Science, University College London, London, United Kingdom
- Department of Plastic Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
- The Charles Wolfson Center for Reconstructive Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
- * E-mail: (MG); (PEMB)
| | - Caroline M. Ryan
- UCL Division of Surgery & Interventional Science, University College London, London, United Kingdom
- Department of Plastic Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
| | - Debbie F. Hunt
- UCL Division of Surgery & Interventional Science, University College London, London, United Kingdom
- Department of Plastic Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
| | - Esther Hansen
- Department of Plastic Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
| | - Ravi Kumar
- UCL Division of Surgery & Interventional Science, University College London, London, United Kingdom
- Department of Plastic Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
- The Charles Wolfson Center for Reconstructive Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
| | - David J. Abraham
- Centre for Rheumatology, UCL Division of Medicine and Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
| | - Christopher P. Denton
- Centre for Rheumatology, UCL Division of Medicine and Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
| | - Peter E. M. Butler
- UCL Division of Surgery & Interventional Science, University College London, London, United Kingdom
- Department of Plastic Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
- The Charles Wolfson Center for Reconstructive Surgery, Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
- Centre for Rheumatology, UCL Division of Medicine and Royal Free London NHS Foundation Trust Hospital, London, United Kingdom
- * E-mail: (MG); (PEMB)
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Cohen SR, Hewett S, Ross L, Delaunay F, Goodacre A, Ramos C, Leong T, Saad A. Regenerative Cells For Facial Surgery: Biofilling and Biocontouring. Aesthet Surg J 2017; 37:S16-S32. [PMID: 29025218 DOI: 10.1093/asj/sjx078] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Zuk et al in 2001 identified stem and regenerative cells within the stromal vascular fraction of fat. In preclinical studies, these cells appeared to stimulate angiogenesis and reduce inflammation, and soon thereafter, clinical use of stromal vascular fraction (SVF) evolved as researchers such as Rigotti, Coleman, Mojallal, our group, and others demonstrated that fat can be used for both therapeutic and aesthetic indications. The regenerative effects of fat and its contents on facial aesthetics have been shown at the histologic and cellular level. Regeneration of elastin and collagen fibers as well as improvement in capillary density and reduction of inflammation have been reported. We review our current approach to the use of regenerative cells and different types of fat grafts in facial surgery. The fat graft is classified, both from a regenerative point of view as well as a tissue product that can be modified into different tissue characteristics, depending on the area and condition treated. Clinical use of SVF enriched fat, millifat, microfat, and nanofat grafts as well as composite fat grafts are reviewed. Based on clinical experience and evidence to date, it appears that the regenerative effects seen with the use of SVF in aesthetic surgery are modest, but there appear to be definite histologic findings of regeneration. These improvements may not be clinically apparent to a patient when cell enriched fat grafts are compared to fat grafts alone. However, the subtle changes seen in histology may be cumulative over time. Three types of fat grafts are defined: millifat (parcel size 2.4<), microfat (1.2<), and nanofat (400-600 μm). Each are characterized by their injectability ratings and emulsification parcel size as well as amount of sSVF cells. Newer concepts of periosteal fat grafting, buccal fat pad grafting, pyriform aperture fat grafting, intraorbital fat grafting, and nanofat grafting are discussed. Composite fat grafts are presented as a new concept as is biofilling and biocontouring. The use of regenerative cells in facial surgery is evolving rapidly. Our understanding of the anatomic changes that occur with aging has become more precise and our ability to target histologic changes seen with aging has become more effective. Deep fat compartment grafting, superficial fat grafting, nanofat, and SVF are becoming important components of contemporary facial rejuvenation. The use of regenerative approaches in facial rejuvenation is a logical step in changing the paradigm from surgical treatment of aging to a more proactive prevention and maintenance approach that keeps up with changes in the tissues as they age.
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Affiliation(s)
- Steven R Cohen
- Division of Plastic Surgery, University of California at San Diego, San Diego, CA
| | - Sierra Hewett
- University of California at San Diego, San Diego, CA
| | | | - Flore Delaunay
- Division of Plastic Surgery, Hospital Le Belvedere, Mont Saint Aignan, France
| | | | - Char Ramos
- Private plastic surgical practice, San Diego, CA
| | | | - Ahmad Saad
- Division of Plastic Surgery, University of California at San Diego, San Diego, CA
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Shell extracts of the edible mussel and oyster induce an enhancement of the catabolic pathway of human skin fibroblasts, in vitro. Cytotechnology 2017; 69:815-829. [PMID: 28474214 DOI: 10.1007/s10616-017-0096-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 04/09/2017] [Indexed: 01/08/2023] Open
Abstract
Mollusc shells are composed of more than 95% calcium carbonate and less than 5% organic matrix consisting mostly of proteins, glycoproteins and polysaccharides. In this study, we investigated the effects of matrix macromolecular components extracted from the shells of two edible molluscs of economic interest, i.e., the blue mussel Mytilus edulis and the Pacific oyster Crassostrea gigas. The potential biological activities of these organic molecules were analysed on human dermal fibroblasts in primary culture. Our results demonstrate that shell extracts of the two studied molluscs modulate the metabolic activities of the cells. In addition, the extracts caused a decrease of type I collagen and a concomitant increase of active MMP-1, both at the mRNA and the protein levels. Therefore, our results suggest that shell extracts from M. edulis and C. gigas contain molecules that promote the catabolic pathway of human dermal fibroblasts. This work emphasises the potential use of these shell matrices in the context of anti-fibrotic strategies, particularly against scleroderma. More generally, it stresses the usefulness to valorise bivalve shells that are coproducts of shellfish farming activity.
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Horimoto AMC, Matos ENN, Costa MRD, Takahashi F, Rezende MC, Kanomata LB, Locatelli EPP, Finotti LT, Maegawa FKM, Rondon RMR, Machado NP, Couto FMAATD, Figueiredo TPAD, Ovidio RA, Costa IPD. Incidence and prevalence of systemic sclerosis in Campo Grande, State of Mato Grosso do Sul, Brazil. REVISTA BRASILEIRA DE REUMATOLOGIA 2017; 57:107-114. [PMID: 28343614 DOI: 10.1016/j.rbre.2016.09.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 05/02/2016] [Indexed: 10/20/2022] Open
Abstract
INTRODUCTION Systemic sclerosis is an autoimmune disease which shows extreme heterogeneity in its clinical presentation and that follows a variable and unpredictable course. Although some discrepancies in the incidence and prevalence rates between geographical regions may reflect methodological differences in the definition and verification of cases, they may also reflect true local differences. OBJECTIVES To determine the prevalence and incidence of systemic sclerosis in the city of Campo Grande, state capital of Mato Grosso do Sul (MS), Brazil, during the period from January to December 2014. METHODS All health care services of the city of Campo Grande - MS with attending in the specialty of Rheumatology were invited to participate in the study through a standardized form of clinical and socio-demographic assessment. Physicians of any specialty could report a suspected case of systemic sclerosis, but necessarily the definitive diagnosis should be established by a rheumatologist, in order to warrant the standardization of diagnostic criteria and exclusion of other diseases resembling systemic sclerosis. At the end of the study, 15 rheumatologists reported that they attended patients with systemic sclerosis and sent the completed forms containing epidemiological data of patients. RESULTS The incidence rate of systemic sclerosis in Campo Grande for the year 2014 was 11.9 per million inhabitants and the prevalence rate was 105.6 per million inhabitants. Systemic sclerosis patients were mostly women, white, with a mean age of 50.58 years, showing the limited form of the disease with a mean duration of the disease of 8.19 years. Regarding laboratory tests, 94.4% were positive for antinuclear antibody, 41.6% for anti-centromere antibody and 19.1% for anti-Scl70; anti-RNA Polymerase III was performed in 37 patients, with 16.2% positive. CONCLUSIONS The city of Campo Grande, the state capital of MS, presented a lower incidence/prevalence of systemic sclerosis in comparison with those numbers found in US studies and close to European studies' data.
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Affiliation(s)
- Alex Magno Coelho Horimoto
- Universidade Federal de Mato Grosso do Sul (UFMS), Campo Grande, MS, Brazil; Hospital Regional de Mato Grosso do Sul, Serviço de Reumatologia, Campo Grande, MS, Brazil; Universidade Federal de Mato Grosso do Sul (UFMS), Hospital Universitário, Serviço de Reumatologia, Campo Grande, MS, Brazil.
| | - Erica Naomi Naka Matos
- Universidade Federal de Mato Grosso do Sul (UFMS), Hospital Universitário, Serviço de Reumatologia, Campo Grande, MS, Brazil; Universidade de Brasília (UnB), Brasília, DF, Brazil; Prefeitura Municipal de Campo Grande, Ambulatório de Especialidades Médicas, Campo Grande, MS, Brazil
| | - Márcio Reis da Costa
- Universidade Federal de Mato Grosso do Sul (UFMS), Hospital Universitário, Serviço de Reumatologia, Campo Grande, MS, Brazil
| | - Fernanda Takahashi
- Prefeitura Municipal de Campo Grande, Ambulatório de Especialidades Médicas, Campo Grande, MS, Brazil; Universidade Anhanguera (Uniderp), Faculdade de Medicina, Ambulatório de Especialidades Médicas, Campo Grande, MS, Brazil
| | | | - Letícia Barrios Kanomata
- Caixa de Assistência aos Servidores do Mato Grosso do Sul (CASSEMS), Ambulatório de Especialidades Médicas, Coxim, MS, Brazil
| | | | - Leandro Tavares Finotti
- Universidade Federal de Mato Grosso do Sul (UFMS), Hospital Universitário, Serviço de Reumatologia, Campo Grande, MS, Brazil; Prefeitura Municipal de Campo Grande, Ambulatório de Especialidades Médicas, Campo Grande, MS, Brazil
| | | | | | - Natália Pereira Machado
- Universidade Federal de Mato Grosso do Sul (UFMS), Hospital Universitário, Serviço de Reumatologia, Campo Grande, MS, Brazil; Universidade Anhanguera (Uniderp), Faculdade de Medicina, Ambulatório de Especialidades Médicas, Campo Grande, MS, Brazil; Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil
| | | | | | - Raphael Antonio Ovidio
- Universidade Federal da Grande Dourados (UFGD), Hospital Universitário, Serviço de Reumatologia, Dourados, MS, Brazil
| | - Izaias Pereira da Costa
- Universidade Federal de Mato Grosso do Sul (UFMS), Hospital Universitário, Serviço de Reumatologia, Campo Grande, MS, Brazil; Universidade de São Paulo (USP), São Paulo, SP, Brazil
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Horimoto AMC, Matos ENN, Costa MRD, Takahashi F, Rezende MC, Kanomata LB, Locatelli EPP, Finotti LT, Maegawa FKM, Rondon RMR, Machado NP, Couto FMAATD, Figueiredo TPAD, Ovidio RA, Costa IPD. Incidência e prevalência de esclerose sistêmica em Campo Grande, Estado de Mato Grosso do Sul, Brasil. REVISTA BRASILEIRA DE REUMATOLOGIA 2017. [DOI: 10.1016/j.rbr.2016.05.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
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Saito S, Ishii T, Kamogawa Y, Watanabe R, Shirai T, Fujita Y, Shirota Y, Fujii H, Ito K, Shimokawa H, Yamaguchi T, Kawaguchi Y, Harigae H. Extracorporeal Shock Wave Therapy for Digital Ulcers of Systemic Sclerosis: A Phase 2 Pilot Study. TOHOKU J EXP MED 2016; 238:39-47. [PMID: 26686380 DOI: 10.1620/tjem.238.39] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Patients with systemic sclerosis (SSc) often display Raynaud's phenomenon and digital skin ulcers. As these ulcers are not associated with autoimmune factors or abnormal coagulation, conventional immunosuppressive therapies, vasodilators, and anticoagulants are often ineffective. Here, we used extracorporeal shock wave therapy (ESWT) to treat these ulcers. Nine SSc patients with new digital ulcers, previously treated with at least one currently available vasodilator or anticoagulant were enrolled. One ESWT session consisted of 100 pulses at 0.08-0.25 mJ/mm(2) in 20 areas on both hands and 15 areas on both feet, totaling 7,000 pulses. Treatment was performed once per week for 9 weeks with observations over 20 weeks. Outcomes were evaluated according to the number and diameter of ulcers, Rodnan skin score, Health Assessment Questionnaire (HAQ), EuroQol 5 dimensions (EQ-5D), visual analog scale for pain, and the PainVision system. The surface skin temperature of all the fingers was measured using thermography. Ulcers showed signs of healing after one session, and their mean number decreased from 5.4 to 1.1 at 9 weeks. In particular, of the 18 large ulcers (> 5 mm) observed in 7 patients before the treatment, 10 disappeared and the rest became smaller; namely, the mean size decreased from 10.9 mm to 2.5 mm at 20 weeks. The average scores on the HAQ, EQ-5D, and PainVision system also improved. Treatment was minimally invasive and could be repeated without any adverse effects. ESWT may be added to standard treatments for indolent digital ulcers of SSc, as an effective and safe method.
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Affiliation(s)
- Shinichiro Saito
- Department of Rheumatology and Hematology, Tohoku University Graduate School of Medicine
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Verrecchia F, Wang Y, Vija L, Farge D. Evidence of an antifibrotic effect of immunosuppressive drugs: applications in the treatment of systemic sclerosis. Expert Rev Clin Immunol 2014; 5:35-43. [DOI: 10.1586/1744666x.5.1.35] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Arai M, Ikawa Y, Chujo S, Hamaguchi Y, Ishida W, Shirasaki F, Hasegawa M, Mukaida N, Fujimoto M, Takehara K. Chemokine receptors CCR2 and CX3CR1 regulate skin fibrosis in the mouse model of cytokine-induced systemic sclerosis. J Dermatol Sci 2012; 69:250-8. [PMID: 23142052 DOI: 10.1016/j.jdermsci.2012.10.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Revised: 10/02/2012] [Accepted: 10/17/2012] [Indexed: 11/29/2022]
Abstract
BACKGROUND Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive accumulation of extracellular matrix (ECM), and develop under the influence of certain cytokines. We previously established a mouse model of skin fibrosis induced by exogenous application of cytokines. We have revealed that both the number of macrophages and the levels of macrophage chemoattractant protein-1 (MCP-1) mRNA positively correlate with the extent of skin fibrosis. Macrophages can be divided into two subsets, the first expressing CCR2, and the second expressing CX3CR1. OBJECTIVE To elucidate the role of skin infiltrating macrophages based on CCR2 and CX3CR1 in this cytokine-induced murine fibrosis model. METHODS We examined the amounts of collagen deposited in granulation tissues, the numbers of macrophages and the levels of several mRNA in wild type (WT) mice, CCR2(-/-) mice, and CX3CR1(-/-) mice during injections of transforming growth factor-β (TGF-β) followed by injections of connective tissue growth factor (CTGF). RESULTS TGF-β injection increased the expressions of MCP-1, fractalkine, CCR2 and CX3CR1 mRNA in WT mice. The overproduction of collagen induced by TGF-β was significantly reduced by CCR2 deficiency, while collagen contents induced by CTGF were restored to wild-type levels. In contrast, overproduction of collagen in CX3CR1-deficient mice decreased nearly 50% by both TGF-β and CTGF stimulations. CONCLUSION The involvement of CCR2/MCP-1 interaction (CCR2-dependent loop) was during the TGF-β phase. In contrast, the fractalkine/CX3CR1 interaction contributes to the initiation of fibrosis by TGF-β and its maintenance by CTGF. Collectively, two subsets of macrophages both cooperatively and independently play important roles in the development of fibrosis.
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Affiliation(s)
- Minako Arai
- Department of Dermatology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan
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Hasegawa M, Takehara K. Potential immunologic targets for treating fibrosis in systemic sclerosis: a review focused on leukocytes and cytokines. Semin Arthritis Rheum 2012; 42:281-96. [PMID: 22542279 DOI: 10.1016/j.semarthrit.2012.03.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Revised: 03/17/2012] [Accepted: 03/21/2012] [Indexed: 02/09/2023]
Abstract
OBJECTIVES Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis. Although the pathogenesis remains unclear, a variety of cells contribute to the fibrotic process via interactions with each other and production of various cytokines. Recent literature related to the immunologic pathogenesis and future strategies for treating the fibrosis of SSc are discussed and, especially, this literature-based review that includes the authors' perspective, focused on leukocytes and cytokines. METHODS A PubMed search for articles published between January 2005 and January 2012 was conducted using the following keywords: systemic sclerosis, leukocyte, cytokine, growth factor, and chemokine. The reference lists of identified articles were searched for further articles. RESULTS Targeting profibrogenic cytokines, including transforming growth factor-β, is still a very active area of research in SSc and most cellular studies have focused on the roles of fibroblasts in SSc. However, a growing number of recent studies indicate a role for B cells in the development of SSc and other autoimmune diseases such as systemic lupus erythematosus. Therefore, B-cell-targeted therapies, including currently available monoclonal antibodies against CD19, CD20, CD22, and B-cell-activating factor, belonging to the tumor necrosis factor family represent possible treatment options. Furthermore, the modulation of T-cell costimulatory molecules such as a recombinant fusion protein of cytotoxic T-lymphocyte antigen-4 may be as effective in SSc as it is in treating other autoimmune diseases. Approaches to antagonize interleukin (IL)-1, IL-6, or IL-17A signaling may also be attractive. CONCLUSIONS This review describes recent advances in the treatment of fibrosis in SSc patients focused on immunologic strategies, such as leukocyte- or cytokine-targeted therapies.
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Affiliation(s)
- Minoru Hasegawa
- Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
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Systemic Sclerosis: Severe Involvement of Internal Organs. Autoimmune Dis 2011. [DOI: 10.1007/978-0-85729-358-9_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Serum chemokine and cytokine levels as indicators of disease activity in patients with systemic sclerosis. Clin Rheumatol 2010; 30:231-7. [PMID: 21049277 DOI: 10.1007/s10067-010-1610-4] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2010] [Revised: 09/20/2010] [Accepted: 10/19/2010] [Indexed: 10/18/2022]
Abstract
To determine the clinical utility of serum levels of chemokines and cytokines for the evaluation of disease activity in patients with systemic sclerosis (SSc), concentrations of four chemokines (interferon γ-inducible protein-10 [IP-10, CXCL10], monokine induced by interferon γ [MIG/CXCL9], monocyte chemoattractant protein-1 [MCP-1/CCL2], interleukin 8 [IL-8/CXCL8]) and six cytokines (IL-2, IL-4, IL-6, IL-10, tumor necrosis factor [TNF]-α, interferon [IFN]- γ) were measured using cytometric beads array kits in serum samples from 31 Japanese patients with SSc and 20 normal controls. Clinical and laboratory data and serum chemokine and cytokine levels were assessed for each patient at their first visit and each subsequent year for 3 years. Among these chemokines and cytokines, serum levels of IP-10, MIG and MCP-1 were significantly elevated in SSc patients compared with normal controls at their first visit. Serum MCP-1 levels declined year and year, along with improvement for skin sclerosis. The variations of MCP-1, but not IP-10 and MIG, were significantly associated with the variations of skin thickness score and vital capacity during 3 years. These results suggest that MCP-1 is a serological indicator of the activity of skin and lung involvement in patients with SSc. However, a longer-term prospective study in a larger population will be needed to confirm its clinical utility as predictors of outcomes.
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Postlethwaite AE, Harris LJ, Raza SH, Kodura S, Akhigbe T. Pharmacotherapy of systemic sclerosis. Expert Opin Pharmacother 2010; 11:789-806. [PMID: 20210685 DOI: 10.1517/14656561003592177] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
IMPORTANCE OF THE FIELD Systemic sclerosis (SSc) is an uncommon autoimmune disease with variable degrees of fibroproliferation in blood vessels and certain organs of the body. There is currently no cure. The purpose of this article is to review the current literature regarding pathogenesis and treatment of complications of SSc. AREAS COVERED IN THIS REVIEW All available articles regarding research related to SSc pathogenesis and treatment listed in the PubMed database were searched; relevant articles were then reviewed and used as sources of information for this review. WHAT THE READER WILL GAIN This review attempts to highlight for the reader some current thought regarding mechanisms of SSc pathogenesis and how autoimmunity relates to vascular changes and fibrogenesis of the disease, as well as providing a review of results of completed clinical trials and current ongoing clinical trials that address organ-specific or global therapies for this disease. This can aid physicians who provide medical care for patients with SSc. TAKE HOME MESSAGE SSc is a complex autoimmune disease, the pathogenesis of which, although not completely understood, is under active study; new insights into pathogenesis are continually being discovered. Although there is no effective disease-modifying treatment for patients with SSc, quality of life, morbidity and mortality can be improved by using targeted therapy directed at affecting the consequences of damage to lungs, blood vessels, kidneys and the gastrointestinal tract. Innovative approaches to treating SSc are under intense investigation.
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Affiliation(s)
- Arnold E Postlethwaite
- Department of Medicine, Division of Connective Tissue Diseases, University of Tennessee Health Science Center, Room G326, Memphis, TN 38163, USA.
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Abstract
PURPOSE OF REVIEW To review evidence and best practice for current disease-modifying therapies for the treatment of systemic sclerosis. RECENT FINDINGS Cyclophosphamide remains the treatment of choice for lung disease and severe skin disease associated with systemic sclerosis. Methotrexate is the treatment of choice for scleroderma overlap syndromes, whereas mycophenolate and azathioprine are also used for both skin and lung disease, alone or for maintenance therapy after cyclophosphamide induction. Haematopoietic stem cell transplantation and imatinib look promising, but trial results are awaited. Relaxin is contraindicated due to inefficacy and severe renal side effects on discontinuation of the drug. Tolerance to type I collagen may be a useful treatment in a carefully selected group of patients. Further trials are needed for biological agents such as infliximab, rituximab and intravenous immunoglobulin. SUMMARY Although there is still no treatment that is well tolerated and unequivocally effective currently for systemic sclerosis, we have come a long way in the past number of years with respect to identifying possible treatments and new therapeutic targets. A number of novel agents including antiinterleukin-6, transforming growth factor-beta-directed therapies and other novel biological agents such as hyperimmune caprine serum are being developed based on new insights into the pathophysiology of disease.
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Abstract
Systemic sclerosis (SSc) is a generalised autoimmune disease, of yet unknown origin, with two major clinical subsets: the limited (lcSSc) and the diffuse cutaneous (dcSSc) forms, which can be distinguished by the extent of skin involvement, the autoantibody profile and the pattern of organ involvement. With an incidence of 1/10(5), SSc affects around 250,000 people in Europe and is responsible for significant morbidity with a 5-year mortality rate of at least 30% of all patients. In patients with rapidly progressive dcSSc, the 5-year mortality is estimated to be 40-50%. Hematopoietic stem cell transplantation (HSCT), mostly autologous but also allogeneic in some specific cases, has been employed worldwide since 1996 as a new therapeutic strategy in patients with a poor prognosis. In 2007, 150 HSCT procedures have been reported in the EBMT data base. We review herein both the short and the long-term reports from the various European and North American phase I-II studies, which have shown that autologous HSCT in selected patients with severe dcSSc results in sustained improvement of skin thickening and stabilisation of organ function up to seven years after transplantation. Based on these promising results, ongoing phase III trials have been designed in parallel, both in Europe (ASTIS) and in North America (SCOTT) aiming to analyse the respective benefits from autologous HSCT respectively without or with high dose irradiation. This review reports the current data concerning the effects of HSCT on survival, skin, and major organ function in patients with severe dcSSc.
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Affiliation(s)
- Dominique Farge
- Service de Médecine Interne, Hopital Saint Louis, Paris, France.
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18
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Tinazzi E, Amelio E, Marangoni E, Guerra C, Puccetti A, Codella OM, Simeoni S, Cavalieri E, Montagnana M, Adani R, Corrocher R, Lunardi C. Effects of shock wave therapy in the skin of patients with progressive systemic sclerosis: a pilot study. Rheumatol Int 2010; 31:651-6. [DOI: 10.1007/s00296-009-1339-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2009] [Accepted: 12/27/2009] [Indexed: 11/30/2022]
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Hasegawa M, Matsushita Y, Horikawa M, Higashi K, Tomigahara Y, Kaneko H, Shirasaki F, Fujimoto M, Takehara K, Sato S. A novel inhibitor of Smad-dependent transcriptional activation suppresses tissue fibrosis in mouse models of systemic sclerosis. ACTA ACUST UNITED AC 2010; 60:3465-75. [PMID: 19877032 DOI: 10.1002/art.24934] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
OBJECTIVE Tissue fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc), and an increasing number of promising molecular targets for antifibrotic therapies have been described recently. Transforming growth factor beta (TGFbeta) is well known to be the principal factor that leads to tissue fibrosis. The present study was undertaken to investigate the ability of HSc025, a novel small compound that antagonizes TGFbeta/Smad signaling through the activation of nuclear translocation of Y-box binding protein 1, to prevent tissue fibrosis in vitro or in mouse models of SSc. METHODS Human dermal fibroblasts were exposed to HSc025 at various concentrations in the presence of TGFbeta, and levels of collagen or fibronectin expression were determined. HSc025 (15 mg/kg/day for 14 days) was administered orally to tight skin mice and to mice with bleomycin-induced pulmonary fibrosis. Improvement of tissue fibrosis was evaluated by histologic or biochemical examination in each model. RESULTS Pretreatment with HSc025 prevented Smad-dependent promoter activation, in a dose-dependent manner; however, HSc025 had no effect on TGFbeta-induced phosphorylation of Smad3. The inhibitory effects of HSc025 on TGFbeta-induced collagen or fibronectin expression were also confirmed in vitro. Orally administered HSc025 significantly reduced hypodermal thickness and hydroxyproline content in tight skin mice, and markedly decreased the histologic score and hydroxyproline content in the lungs of bleomycin-treated mice. CONCLUSION These results demonstrate that HSc025 is a novel inhibitor of TGFbeta/Smad signaling, resulting in the improvement of skin and pulmonary fibrosis. Orally available HSc025 might therefore be useful in the treatment of SSc.
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Affiliation(s)
- Minoru Hasegawa
- Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
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Verrecchia F, Michel L, Keshtmand H, Wang Y, Launay D, Farge D. Existe-t-il une action antifibrosante spécifique des immunosuppresseurs utilisés pour traiter la sclérodermie systémique ? Rev Med Interne 2009; 30:955-62. [DOI: 10.1016/j.revmed.2009.02.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2008] [Revised: 02/16/2009] [Accepted: 02/25/2009] [Indexed: 10/20/2022]
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Denton CP, Engelhart M, Tvede N, Wilson H, Khan K, Shiwen X, Carreira PE, Diaz Gonzalez F, Black CM, van den Hoogen FH. An open-label pilot study of infliximab therapy in diffuse cutaneous systemic sclerosis. Ann Rheum Dis 2009; 68:1433-9. [PMID: 18782794 DOI: 10.1136/ard.2008.096123] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
AIM The safety and potential efficacy of a chimaeric anti-tumour necrosis factor alpha monoclonal antibody (infliximab) were examined in diffuse cutaneous systemic sclerosis (dcSSc). METHODS A 26-week open-label pilot study in which 16 cases of dcSSc received five infusions of infliximab (5 mg/kg). Clinical assessment included skin sclerosis score, scleroderma health assessment questionnaire, self-reported functional score and physician global visual analogue scale. Collagen turnover, skin biopsy analysis and full safety evaluation were performed. RESULTS There was no significant change in skin score at 26 weeks but a trend for lower modified Rodnan skin score at 22 weeks (OR 17, 95% CI 6 to 46) compared with peak value (OR 29, 95% CI 11 to 44; p = 0.10). Serum aminoterminal propeptide of type III collagen level was significantly lower at week 26 compared with baseline (p = 0.03). Secretion of type I collagen by dermal fibroblasts was reduced at 26 weeks compared with baseline (p = 0.02). There were no deaths during the study and no suspected unexpected serious adverse reactions. 21 serious adverse events (AE) occurred in seven subjects, mostly attributable to dcSSc. 127 distinct AE occurred in 16 subjects. Of these, 19 AE (15%) were probably or definitely related to infliximab treatment. Eight (50%) patients prematurely discontinued infliximab. Anti-infliximab antibodies developed during the study in five subjects and were significantly associated with suspected infusion reactions (p = 0.025). CONCLUSION In dcSSc infliximab did not show clear benefit at 26 weeks but was associated with clinical stabilisation and a fall in two laboratory markers of collagen synthesis. The frequency of suspected infusion reactions may warrant additional immunosuppression in any future studies in systemic sclerosis.
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Affiliation(s)
- C P Denton
- Centre for Rheumatology, Royal Free Hospital, Pond Street, London NW3 2QG, UK.
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Mugii N, Hasegawa M, Hamaguchi Y, Tanaka C, Kaji K, Komura K, Ueda-Hayakawa I, Horie S, Ikuta M, Tachino K, Ogawa F, Sato S, Fujimoto M, Takehara K. Reduced red blood cell velocity in nail-fold capillaries as a sensitive and specific indicator of microcirculation injury in systemic sclerosis. Rheumatology (Oxford) 2009; 48:696-703. [PMID: 19439504 DOI: 10.1093/rheumatology/kep066] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE To assess red blood cell velocity in finger nail-fold capillaries using video capillaroscopy in patients with SSc and other collagen diseases. METHODS This study included 127 patients with SSc as well as patients with SLE (n = 33), DM/PM (n = 21), RA (n = 13) and APS (n = 12), and 20 healthy subjects. Red blood cell velocity was evaluated using frame-to-frame determination of the position of capillary plasma gaps. RESULTS The mean red blood cell velocity was significantly decreased in patients with SSc compared to healthy controls (63.0% reduction) and patients with other conditions. Mean blood velocity was similar between patients with dcSSc and lcSSc. Importantly, even SSc patients with normal or non-specific nail-fold video capillaroscopic (NVC) patterns or a scleroderma early NVC pattern exhibited a significantly lower red blood cell velocity compared to healthy controls (51.7 and 61.4% reduction, respectively) or patients with other conditions, despite normal or mild capillary changes. Patients with the scleroderma active and late NVC pattern showed a more decreased blood velocity (65.5 and 66.2% reduction, respectively). This reduced blood velocity was significantly associated with NVC findings, including capillary ramification and capillary loss. Although remarkably reduced velocity was observed in SSc patients with intractable digital ulcers (72.1% reduction), it was significantly improved by lipo-prostaglandin E(1) (lipo-PGE(1)) infusion. CONCLUSION Our results suggest that reduced blood velocity is a hallmark of SSc. Furthermore, measurement of red blood cell velocity may be useful in evaluating therapeutic effects on microcirculation.
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Affiliation(s)
- Naoki Mugii
- Department of Rehabilitation, Kanazawa University Hospital, Kanazawa, Japan
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McLaughlin V, Humbert M, Coghlan G, Nash P, Steen V. Pulmonary arterial hypertension: the most devastating vascular complication of systemic sclerosis. Rheumatology (Oxford) 2009; 48 Suppl 3:iii25-31. [PMID: 19487219 DOI: 10.1093/rheumatology/kep107] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of CTDs. In patients with SSc, PAH has a dramatic impact on prognosis and survival and is the single most common cause of disease-related death.Yearly echocardiographic screening for PAH is recommended in patients with SSc. If suspected, confirmation of PAH diagnosis by right heart catheterization is necessary. Treatment goals for patients with PAH associated with SSc (PAH-SSc) aim to slow disease progression and improve quality of life. Some measures used to gauge the effect of treatment in patients with PAH-SSc remain to be fully validated; the 6-min walk distance, for example, is a simple and reproducible means of assessing exercise capacity, but there exists a need to understand what constitutes a clinically relevant change in this specific patient population. Currently, pharmacological intervention in PAH-SSc may target one or more of three pathophysiological pathways in PAH. The prostacyclin analogue epoprostenol has been shown to improve exercise capacity and haemodynamics in PAH-SSc patients and similar data are available from smaller studies on trepostinil and iloprost. The dual endothelin receptor antagonist bosentan has been shown to improve exercise capacity and haemodynamics in PAH-SSc, and similar data have been obtained in small numbers of patients treated with the endothelin receptor A antagonists sitaxsentan and ambrisentan. Impaired production of nitric oxide may be addressed by inhibiting phosphodiesterase type-5 with sildenafil or possibly tadalafil. Combinations of multiple targeted therapies may be beneficial to this patient population.
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Affiliation(s)
- V McLaughlin
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
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Hofstee HMA, Vonk Noordegraaf A, Voskuyl AE, Dijkmans BAC, Postmus PE, Smulders YM, Serné EH. Nailfold capillary density is associated with the presence and severity of pulmonary arterial hypertension in systemic sclerosis. Ann Rheum Dis 2009; 68:191-5. [PMID: 18375538 DOI: 10.1136/ard.2007.087353] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
OBJECTIVE The aim of this study was to investigate whether there are differences in capillary nailfold changes in patients with systemic sclerosis (SSc) with and without pulmonary arterial hypertension (PAH), and whether these changes are associated with PAH severity and disease specificity. METHODS Capillary density and loop dimensions were studied in 21 healthy controls, 20 patients with idiopathic PAH (IPAH) and 40 patients with SSc. Of the 40 patients with SSc, 19 had no PAH (SSc-nonPAH) and 21 had PAH (SSc-PAH), of whom eight had PAH during exercise. RESULTS Capillary density was lower in SSc-PAH compared with patients who had SSc-nonPAH (4.33/mm vs 6.56/mm respectively, p = 0.001), but loop dimensions were equal. In comparison with IPAH, patients with SSc-PAH had reduced capillary density (4.33/mm vs 7.86/mm, p<0.001) and larger loop dimensions (total width 101.05 microm vs 44.43 microm, p<0.001). Capillary density in healthy controls (9.87/mm) was significantly higher when compared with SSc-nonPAH (6.56/mm), SSc-PAH (4.33/mm) and with IPAH (7.86/mm). No differences in capillary dimensions were present between healthy controls and IPAH. Capillary density correlated with mean pulmonary arterial pressure (PAP) at rest in SSc-PAH at rest (r = -0.58, p = 0.039) and IPAH (r = -0.67, p = 0.001). CONCLUSIONS Reduction of nailfold capillary density, but not capillary loop dimensions is associated with PAH, and correlates with the severity of PAH in both SSc and IPAH. This suggests that either systemic microvascular changes play a part in the development of PAH, or that PAH itself contributes to systemic microvascular changes.
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Affiliation(s)
- H M A Hofstee
- Department of Internal Medicine, VU University Medical Centre, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
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Molecular subtypes of systemic sclerosis in association with anti-centromere antibodies and digital ulcers. Genes Immun 2009; 10:210-8. [DOI: 10.1038/gene.2008.98] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Tuan TL, Hwu P, Ho W, Yiu P, Chang R, Wysocki A, Benya PD. Adenoviral overexpression and small interfering RNA suppression demonstrate that plasminogen activator inhibitor-1 produces elevated collagen accumulation in normal and keloid fibroblasts. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 173:1311-25. [PMID: 18832570 DOI: 10.2353/ajpath.2008.080272] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Keloids are tumor-like skin scars that grow as a result of the aberrant healing of skin injuries, with no effective treatment. We provide new evidence that both overexpression of plasminogen activator inhibitor-1 (PAI-1) and elevated collagen accumulation are intrinsic features of keloid fibroblasts and that these characteristics are causally linked. Using seven strains each of early passage normal and keloid fibroblasts, the keloid strains exhibited inherently elevated collagen accumulation and PAI-1 expression in serum-free, 0.1% ITS+ culture; larger increases in these parameters occurred when cells were cultured in 3% serum. To demonstrate a causal relationship between PAI-1 overexpression and collagen accumulation, normal fibroblasts were infected with PAI-1-expressing adenovirus. Such cells exhibited a two- to fourfold increase in the accumulation of newly synthesized collagen in a viral dose-dependent fashion in both monolayers and fibrin gel, provisional matrix-like cultures. Three different PAI-1-targeted small interfering RNAs, alone or in combination, produced greater than an 80% PAI-1 knockdown and reduced collagen accumulation in PAI-1-overexpressing normal or keloid fibroblasts. A vitronectin-binding mutant of PAI-1 was equipotent with wild-type PAI-1 in inducing collagen accumulation, whereas a complete protease inhibitor mutant retained approximately 50% activity. Thus, PAI-1 may use more than its protease inhibitory activity to control keloid collagen accumulation. PAI-1-targeted interventions, such as small interfering RNA and lentiviral short hairpin RNA-containing microRNA sequence suppression reported here, may have therapeutic utility in the prevention of keloid scarring.
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Affiliation(s)
- Tai-Lan Tuan
- Saban Research Institute of Childrens Hospital, Los Angeles, CA 90027, USA.
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Wang F, Garza LA, Cho S, Kafi R, Hammerberg C, Quan T, Hamilton T, Mayes M, Ratanatharathorn V, Voorhees JJ, Fisher GJ, Kang S. Effect of increased pigmentation on the antifibrotic response of human skin to UV-A1 phototherapy. ACTA ACUST UNITED AC 2008; 144:851-8. [PMID: 18645136 DOI: 10.1001/archderm.144.7.851] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
OBJECTIVE To investigate the efficacy, potential limitations, and biological mechanisms of UV-A1 phototherapy for skin sclerosis due to collagen deposition disorders. DESIGN Before-and-after trial of UV-A1 irradiation of sclerotic skin; in vivo biochemical analyses after UV-A1 irradiation of normal skin. SETTING Academic referral center. PARTICIPANTS Patients with morphea/scleroderma or sclerodermoid graft-vs-host disease and volunteers without skin disease. Intervention Sclerotic skin was treated with high-dose (130 J/cm(2); n = 12) or medium-dose (65 J/cm(2); n = 6) UV-A1 phototherapy 3 times per week for 14 weeks; normal skin was treated with UV-A1 irradiation at various doses and frequencies, with biopsies performed afterwards. MAIN OUTCOME MEASURES In sclerotic skin, induration was clinically assessed using a scoring scale. In normal skin, quantitative polymerase chain reaction was used to assess antifibrotic responses, defined as decreased type I and type III procollagen and increased matrix metalloproteinase levels. RESULTS In patients with sclerotic skin treated with high-dose UV-A1 irradiation, clinical scores for induration modestly decreased. To investigate what factors prevented further improvement (ie, complete clearance), normal skin with light pigmentation was exposed to UV-A1 irradiation (70-150 J/cm(2)) and was assessed for antifibrotic responses. A single high-dose exposure (110-150 J/cm(2)) elicited substantial antifibrotic responses and induced skin darkening. This skin darkening attenuated responses to subsequent UV-A1 exposures and was dose dependent. Thus, to minimize skin darkening, additional patients with sclerotic skin were treated with medium-dose UV-A1 phototherapy, which was no less effective than high-dose therapy. CONCLUSION Clinical responses of sclerotic skin to UV-A1 phototherapy were modest because of UV-A1-induced skin darkening, which is photoprotective and attenuates antifibrotic responses. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00129415.
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Affiliation(s)
- Frank Wang
- Department of Dermatology, University of Michigan Medical School, 1618 A. Alfred Taubman Healthcare Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109, USA.
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Treml LS, Quinn WJ, Treml JF, Scholz JL, Cancro MP. Manipulating B cell homeostasis: a key component in the advancement of targeted strategies. Arch Immunol Ther Exp (Warsz) 2008; 56:153-64. [PMID: 18512030 DOI: 10.1007/s00005-008-0017-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2007] [Accepted: 01/04/2008] [Indexed: 11/28/2022]
Abstract
Understanding the homeostatic mechanisms governing lymphocyte pools achieves critical importance as lymphocyte-targeted therapies expand in use and scope. The primacy of B lymphocyte stimulator (BLyS) family ligands and receptors in governing B lymphocyte homeostasis has become increasingly clear in recent years, affording insight into novel opportunities and potential pitfalls for targeted B cell therapeutics. Interclonal competition for BLyS-BR3 interactions determines the size of naïve B cell pools and can regulate the stringency of selection applied as cells complete maturation. Thus one of the predicted consequences of ablative therapies targeting primary pools is relaxed negative selection. This suggests that BLyS levels and B cell reconstitution rates may serve useful prognostic roles and that BLyS itself might be targeted to circumvent relapse. Alternatively, manipulations that allow rare, minimally autoreactive specificities to survive and mature may lead to opportunities in cases where antibody-based vaccine development has heretofore been unsuccessful. BLyS family ligands and receptors also play a role in activated and memory B cell pools, suggesting they might likewise be targeted to promote or delete particular antigen-experienced subpopulations in a similar way.
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Affiliation(s)
- Laura S Treml
- Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6082, USA
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Abstract
Scleroderma, the general name of a group of progressive diseases affecting the connective tissues is the most deadly of the varying connective tissue disorders. Characterized by abnormal thickening of the skin, this collagen-vascular disease is associated with immune dysfunction. Hallmark signs of scleroderma include fibrosis, vascular instability and initial inflammation resulting from excessive collagen deposition. Oral facial involvement is considerable, necessitating adaptations in patient oral self-care and influencing oral hygiene. Appropriate dental hygiene management of patients with this autoimmune disorder requires an understanding of clinical characteristics, the recognition of oral facial involvement, treatment considerations and pharmacological interventions. With this information, dental hygienists will be better prepared to provide compassionate, safe and effective dental hygiene management and care to patients with scleroderma.
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Affiliation(s)
- S L Tolle
- School of Dental Hygiene, Old Dominion University, Norfolk, VA 23529-0499, USA.
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Systemic sclerosis. Clin Immunol 2008. [DOI: 10.1016/b978-0-323-04404-2.10055-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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HASEGAWA M. The roles of chemokines in the development of systemic sclerosis. ACTA ACUST UNITED AC 2008; 31:23-36. [DOI: 10.2177/jsci.31.23] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Minoru HASEGAWA
- Department of Dermatology, Kanazawa University Graduate School of Medical Science
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Grassegger A, Pohla-Gubo G, Frauscher M, Hintner H. Autoantibodies in systemic sclerosis (scleroderma): clues for clinical evaluation, prognosis and pathogenesis. Wien Med Wochenschr 2008; 158:19-28. [DOI: 10.1007/s10354-007-0451-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2007] [Accepted: 06/21/2007] [Indexed: 12/28/2022]
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Abstract
The precise aetiology of systemic sclerosis (SSc) remains elusive, but significant advances over the past few years have improved our understanding of the underlying pathogenic processes and identified key pathways and mediators that are potential therapeutic targets. The situation is complicated by the clinical heterogeneity of SSc and the differential pathogenesis that underlies the two commonest subsets, namely diffuse and limited cutaneous disease. However, there are common mediators that could be targeted to provide clinical benefit in both types of disease. To date, clinical success with therapies directed against logical profibrotic mediators, such as connective tissue growth factor and transforming growth factor-β, is yet to be reported, although studies are ongoing. More promising clinical results have been obtained with the dual endothelin receptor antagonist bosentan, which has been shown to manage two vascular complications of SSc effectively: pulmonary arterial hypertension and digital ulceration. It remains to be determined whether the identification of additional mediators merely furthers our knowledge of the natural history of SSc or presents targets that can be manipulated to manage SSc patients effectively.
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Affiliation(s)
- Christopher P Denton
- Centre for Rheumatology, Royal Free and University College Medical School, Rowland Hill Street, London, NW3 2PF, UK.
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Venkatesan N, Punithavathi D, Babu M. Protection from acute and chronic lung diseases by curcumin. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2007; 595:379-405. [PMID: 17569221 DOI: 10.1007/978-0-387-46401-5_17] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The aim of this review has been to describe the current state of the therapeutic potential of curcumin in acute and chronic lung injuries. Occupational and environmental exposures to mineral dusts, airborne pollutants, cigarette smoke, chemotherapy, and radiotherapy injure the lungs, resulting in acute and chronic inflammatory lung diseases. Despite major advances in treating lung diseases, until now disease-modifying efficacy has not been demonstrated for any of the existing drugs. Current medical therapy offers only marginal benefit; therefore, there is an essential need to develop new drugs that might be of effective benefit in clinical settings. Over the years, there has been increasing evidence that curcumin, a phytochemical present in turmeric (Curcuma longa), has a wide spectrum of therapeutic properties and a remarkable range of protective effects in various diseases. Several experimental animal models have tested curcumin on lung fibrosis and these studies demonstrate that curcumin attenuates lung injury and fibrosis caused by radiation, chemotherapeutic drugs, and toxicants. The growing amount of data from pharmacological and animal studies also supports the notion that curcumin plays a protective role in chronic obstructive pulmonary disease, acute lung injury, acute respiratory distress syndrome, and allergic asthma, its therapeutic action being on the prevention or modulation of inflammation and oxidative stress. These findings give substance to the possibility of testing curcumin in patients with lung diseases.
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Abstract
Transforming growth factor-β (TGF-β), a prototype of multifunctional cytokine, is a key regulator of extracellular matrix (ECM) assembly and remodeling. Specifically, TGF-β isoforms have the ability to induce the expression of ECM proteins in mesenchymal cells, and to stimulate the production of protease inhibitors that prevent enzymatic breakdown of the ECM. Elevated TGF-β expression in affected organs, and subsequent deregulation of TGF-β functions, correlates with the abnormal connective tissue deposition observed during the onset of fibrotic diseases. During the last few years, tremendous progress has been made in the understanding of the molecular aspects of intracellular signaling downstream of the TGF-β receptors. In particular, Smad proteins, TGF-β receptor kinase substrates that translocate into the cell nucleus to act as transcription factors, have been studied extensively. The role of Smad3 in the transcriptional regulation of typeIcollagen gene expression and in the development of fibrosis, demonstrated both in vitro and in animal models with a targeted deletion of Smad3, is of critical importance because it may lead to novel therapeutic strategies against these diseases. This review focuses on the mechanisms underlying Smad modulation of fibrillar collagen expression and how it relates to fibrotic processes.
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Affiliation(s)
- Franck Verrecchia
- INSERM U697, Hopital Saint-Louis, Pavillon Bazin, 1 avenue Claude Vellefaux, Paris 75010, France.
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Hinchcliff M, Varga J. Novel paradigm for treating vasculopathy in systemic sclerosis: vascular progenitor cells and statins. Curr Rheumatol Rep 2007; 9:1-3. [PMID: 17437659 DOI: 10.1007/s11926-007-0014-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Monique Hinchcliff
- Division of Rheumatology, Northwestern University Feinberg School of Medicine, McGaw Pavilion, 240 East Huron Street, Chicago, IL 60611-2909, USA
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Tamási L, Szekanecz Z. Biological therapy of arthritis and systemic autoimmune diseases. Orv Hetil 2007; 148 Suppl 1:63-70. [PMID: 17430797 DOI: 10.1556/oh.2007.28038] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
A biológiai terápia lényege, hogy a gyulladás egyetlen, jól meghatározott pontján (pl. egy adott citokin szintjén) hat. Ezáltal a sokszor igen bonyolult mechanizmusokból álló patogenetikai hálózatot egy adott ponton szakítja meg. Ma a rheumatoid arthritis a biológiai terápia szempontjából modellbetegség, mivel a legtöbb szerrel ebben a kórképben próbálkoztak. Ezt követően egyéb arthritisekben (pl. spondylitis ankylopoetica, psoriasisos arthropathia), majd egyes szisztémás autoimmun kórképekben (pl. szisztémás lupus erythematosus, scleroderma, myositisek, vasculitisek, Sjögren-szindróma stb.) kezdték el alkalmazni. A legtöbb kórkép esetében egy központi szereppel bíró citokin, a tumornekrózis faktor-α (TNF-α) gátlószerei állnak a terápia középpontjában. Azonban a biológiai terápia megtervezésekor az adott kórkép patogenezisét (pl. döntően Th1 vagy Th2 jellegét) figyelembe kell venni. Nem véletlen, hogy amíg egyes kórképekben (pl. rheumatoid arthritis, spondylitis ankylopoetica, psoriasis, polymyositis, polyarticularis juvenilis arthritis) döntően a TNF-blokkolók és a T-sejtek elleni gátlás vált be, addig másoknál (pl. lupus, Sjögren-szindróma, dermatomyositis) a B-sejt elleni terápia kecsegtet sikerrel. Ezen összefoglalóban a szerzők áttekintik az arthritisek és szisztémás autoimmun kórképek biológiai terápiájára vonatkozó legfontosabb adatokat. Kitérnek az alkalmazott szerek tulajdonságaira, a hatékonyság és biztonságosság kérdéseire egyaránt.
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Abstract
Scleroderma or systemic sclerosis (SSc) is a complex disease in which the vasculopathy and the activation of the immune system with production of inflammatory mediators lead to dysregulated fibroblast activation. The resulting excessive deposition of collagens and other extracellular matrix proteins ends in fibrosis and organ dysfunction. The cause is unknown, but environmental factors are thought to play a role by triggering abnormal responses in genetically susceptible hosts. The recent past has witnessed important advances in the definition of mechanisms that underlie the persistent activation in fibroblasts of genes involved in uncontrolled fibrosis, a hallmark of SSc. These include the preferential production of type 2 T cell cytokines in target organs, the presence of autoantibodies with fibroblast-activating capacities, the production of vasoconstrictive mediators that impact on fibroblast biosynthetic properties, the transforming growth factor-beta-related metabolic signature, and the presence of altered signaling pathways in fibroblasts. Furthermore, while no animal models recapitulate all the features of SSc, they have been instrumental for assessing the relevance of specific processes to the development of fibrosis. More importantly, some of the research findings are leading to therapies that target altered processes with the potential of changing the prognosis of some dismal aspects of the disease.
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Affiliation(s)
- Carlo Chizzolini
- Immunology and Allergy, University Hospital, School of Medicine, Geneva, Switzerland.
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Navarro C, Bustos ML. [Etiopathogenesis. New concepts]. ACTA ACUST UNITED AC 2006; 2 Suppl 3:S6-9. [PMID: 21794388 DOI: 10.1016/s1699-258x(06)73100-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Systemic sclerosis is a complex, progressive autoimmune disease. The origin is, so far, unknown and it is characterized by immunological and endothelial damage followed by fibrosis. Interaction between the host genetic backgrounds with environmental factors is thought to turn out an abnormal immune response characterized by clonal expansion of Th2 repertoire, upregulation of pro-fibrotic cytokines and dysregulated B cells. Specific autoantibodies profiles are associated with clinical subtypes of the diseases. Endothelial activation is an early feature with damage of the vasocontrictive and vasodilation response. Finally, persistent tissue ischemia and abnormal immune response produce myofibroblast proliferation andoverproduction of extracellular matrix proteins and fibrosis.
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Affiliation(s)
- Carmen Navarro
- Subdirección de Investigación Clínica. Instituto Nacional de Enfermedades Respiratorias. Tlalpan. México DF. México
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Navarro C. [Pulmonary involvement in systemic sclerosis. Alveolitis, fibrosis and pulmonar arterial hypertension]. REUMATOLOGIA CLINICA 2006; 2 Suppl 3:S16-S19. [PMID: 21794381 DOI: 10.1016/s1699-258x(06)73102-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Pulmonary involvement in systemic sclerosis. Alveolitis, fibrosis and pulmonar arterial hypertension Lung disease is present in most of the patients with systemic sclerosis and is now the most important cause of mortality. Interstitial lung disease and pulmonary hypertension are, so far, the main disorders found and both are difficult to detect at the earliest stages. However, diagnostic tools such as immunological test, lung function test, high resolution CT, bronchoalveolar lavage, echocardiography, right-side cardiac catheterization, or lung biopsy are necessary to accurately evaluate the clinical status and allow to improve the management organ-specific ad hoc. Progress in immunological and vascular therapies as well as other emergence drugs offer new expectations to scleroderma patients.
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Affiliation(s)
- Carmen Navarro
- Subdirección de Investigación Clínica. Instituto Nacional de Enfermedades Respiratorias. Tlalpan. México DF. México
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Abstract
Progress in the understanding of the aetiopathogenesis of scleroderma (systemic sclerosis) has been painfully slow and this has greatly impeded the application of specific disease modifying treatments. This article provides a brief historical overview of scleroderma (including the important Australian contribution of Dr Alfred Barnett and colleagues--see accompanying article in this issue on pages 513-18), highlights some recent pathogenic developments and summarises some exciting new therapies. Cautious optimism can now be offered to scleroderma sufferers.
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Affiliation(s)
- P J Roberts-Thomson
- Department of Immunology, Allergy and Arthritis, Flinders Medical Centre, Adelaide, South Australia, Australia.
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Abstract
Scleroderma is an umbrella term for a spectrum of rare and complex autoimmune connective tissue diseases, the cause and pathogenesis of which is only partially defined. Scleroderma can be divided into two main subgroups--systemic and localized--but the hallmark of both is skin fibrosis. As yet no drug has been found to be effective in reversing the disease process, however early intervention has been shown to give maximum benefit. Due to the chronic nature of the condition a multidisciplinary approach is essential and the nurse's input from an early stage is vital in supporting the patient to manage both their medical treatment and their activities of daily living.
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Affiliation(s)
- Helen Wilson
- Centre for Rheumatology, Royal Free Hospital, London
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Verrecchia F, Mauviel A, Farge D. Transforming growth factor-beta signaling through the Smad proteins: role in systemic sclerosis. Autoimmun Rev 2006; 5:563-9. [PMID: 17027893 DOI: 10.1016/j.autrev.2006.06.001] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2006] [Accepted: 06/08/2006] [Indexed: 12/12/2022]
Abstract
Transforming growth factor-beta (TGF-beta) plays a critical role in the development of tissue fibrosis. Its expression is consistently elevated in affected organs and correlates with increased extracellular matrix deposition. During the last few years, tremendous progress has been made in understanding the molecular aspects of intracellular signaling downstream of the TGF-beta receptors. In particular, Smad proteins, TGF-beta receptor kinase substrates that translocate into the cell nucleus to act as transcription factors, have been studied extensively. Their role in the transcriptional regulation of type I collagen and other extracellular matrix (ECM) genes expression, and in the development of fibrosis is of critical importance because it may lead to novel therapeutic strategies for the treatment of these multi-organ tissue reactions to injury. Systemic sclerosis (SSc) is a complex autoimmune disease characterized by pathological remodelling of connective tissues correlated to the activation of TGF-beta/Smad signaling pathway. This review focuses on the mechanisms underlying Smad modulation of gene expression and how they relate to fibrotic process. Potential implications for the development of therapeutic approaches against tissue fibrosis during SSc are discussed.
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Affiliation(s)
- Franck Verrecchia
- INSERM U697, Hôpital Saint-Louis, Pavillon Bazin, 1 Avenue Claude Vellefaux, Paris, France.
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