Pathogenesis of systemic sclerosis: recent insights of molecular and cellular mechanisms and therapeutic opportunities

2017 ◽  
Vol 2 (3) ◽  
pp. 137-152 ◽  
Author(s):  
John Varga ◽  
Maria Trojanowska ◽  
Masataka Kuwana
Keyword(s):  
Systemic Sclerosis ◽  
Complex Disease ◽  
Repair Process ◽  
Immune Dysregulation ◽  
Lipid Mediators ◽  
Oxygen Species ◽  
Cellular Mechanisms ◽  
Internal Organs ◽  
Matrix Deposition ◽  
Pathogenic Process

Systemic sclerosis (SSc) is a complex disease characterized by early microvascular abnormalities, immune dysregulation and chronic inflammation, and subsequent fibrosis of the skin and internal organs. Excessive fibrosis, distinguishing hallmark of SSc, is the end result of a complex series of interlinked vascular injury and immune activation, and represents a maladaptive repair process. Activated vascular, epithelial, and immune cells generate pro-fibrotic cytokines, chemokines, growth factors, lipid mediators, autoantibodies, and reactive oxygen species. These paracrine and autocrine cues in turn induce activation, differentiation, and survival of mesenchymal cells, ensuing tissue fibrosis through increased collagen synthesis, matrix deposition, tissue rigidity and remodeling, and vascular rarefaction. This review features recent insights of the pathogenic process of SSc, highlighting three major characteristics of SSc, microvasculopathy, excessive fibrosis, and immune dysregulation, and sheds new light on the understanding of molecular and cellular mechanisms contributing to the pathogenesis of SSc and providing novel avenues for targeted therapies.

scholarly journals The Role of PPAR Gamma in Systemic Sclerosis

PPAR Research ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Andréa Tavares Dantas ◽  
Michelly Cristiny Pereira ◽  
Moacyr Jesus Barreto de Melo Rego ◽  
Laurindo Ferreira da Rocha ◽  
Ivan da Rocha Pitta ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Lung Fibrosis ◽  
Ppar Gamma ◽  
Immune Dysregulation ◽  
Unknown Etiology ◽  
Internal Organs ◽  
Medical Need

Fibrosis is recognized as an important feature of many chronic diseases, such as systemic sclerosis (SSc), an autoimmune disease of unknown etiology, characterized by immune dysregulation and vascular injury, followed by progressive fibrosis affecting the skin and multiple internal organs. SSc has a poor prognosis because no therapy has been shown to reverse or arrest the progression of fibrosis, representing a major unmet medical need. Recently, antifibrotic effects of PPARγligands have been studiedin vitroandin vivoand some theories have emerged leading to new insights. Aberrant PPARγfunction seems to be implicated in pathological fibrosis in the skin and lungs. This antifibrotic effect is mainly related to the inhibition of TGF-β/Smad signal transduction but other pathways can be involved. This review focused on recent studies that identified PPARγas an important novel pathway with critical roles in regulating connective tissue homeostasis, with emphasis on skin and lung fibrosis and its role on systemic sclerosis.

scholarly journals Unfolding the pathogenesis of systemic sclerosis through epigenomics

STEMedicine ◽  
2020 ◽  
Vol 1 (1) ◽  
pp. e5
Author(s):  
Xiuzhi Jia ◽  
Hao Cheng ◽  
Ying Xiao
Keyword(s):  
Dna Methylation ◽  
Systemic Sclerosis ◽  
Autoimmune Diseases ◽  
Environmental Stress ◽  
Histone Modification ◽  
Immune Dysregulation ◽  
Epigenetic Mechanisms ◽  
Internal Organs ◽  
Current Information ◽  
Epigenetic Alteration

As a group of autoimmune diseases, systemic sclerosis (scleroderma, SSc) is characterized by immune dysregulation, micro-vessels dominant obliteration, and the final fibrosis of the skin and or internal organs. Although the precise mechanisms are still unknown, increasing data shows that epigenetic mechanisms, such as DNA methylation, histone modification, and microRNA (miRNA), are strictly related to the pathogenesis of scleroderma. Epigenetic mechanisms, which can link genetics and environmental stress, represents a promising field in systemic sclerosis investigation. The objective of this review is, to sum up the current information about epigenetic alteration.

scholarly journals HHV-6A Infection and Systemic Sclerosis: Clues of a Possible Association

2019 ◽  
Vol 8 (1) ◽  
pp. 39
Author(s):  
Elisabetta Caselli ◽  
Irene Soffritti ◽  
Maria D’Accolti ◽  
Daria Bortolotti ◽  
Roberta Rizzo ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Plasma Levels ◽  
Human Herpesvirus ◽  
Infectious Agents ◽  
Internal Organs ◽  
Matrix Deposition ◽  
Skin Biopsies ◽  
Extracellular Matrix Deposition

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, excessive extracellular matrix deposition, and fibrosis of the skin and internal organs. Several infectious agents, including human herpesvirus-6 (HHV-6), have been suggested as possible triggering factors, but a direct association is still missing. We characterized 26 SSc patients for the presence of HHV-6 in tissues and blood, the anti-HHV-6 response, HLA-G plasma levels, and KIR typing. Given the prominent role of endothelial cells (EC) in SSc pathogenesis, along with HHV-6 tropism for EC, we also investigated the expression of pro-fibrosis factors in HHV-6 infected EC. Results showed the presence of HHV-6A in skin biopsies, and an increased virus load was associated with disease severity and poor natural killer (NK) response against the virus, particularly in subjects exhibiting a KIR2 phenotype. HLA-G plasma levels were significantly higher in HHV-6A/B-KIR2 positive SSc patients and in vitro HHV-6A infection-induced pro-fibrosis factors expression in EC, supporting its role in the development of the fibrosing process. Our data suggest an association between virus infection/reactivation and disease, opening the way to future studies to understand the mechanisms by which HHV-6A might contribute to the multifactorial pathogenesis of SSc.

scholarly journals Plant Extracts and Reactive Oxygen Species as Two Counteracting Agents with Anti- and Pro-Obesity Properties

2019 ◽  
Vol 20 (18) ◽  
pp. 4556 ◽  
Author(s):  
Hanna Zielinska-Blizniewska ◽  
Przemyslaw Sitarek ◽  
Anna Merecz-Sadowska ◽  
Katarzyna Malinowska ◽  
Karolina Zajdel ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Plant Extracts ◽  
Complex Disease ◽  
Reactive Oxygen ◽  
Complementary Therapy ◽  
Biologically Active ◽  
Mitochondrial Activity ◽  
Oxygen Species

Obesity is a complex disease of great public health significance worldwide: It entails several complications including diabetes mellitus type 2, cardiovascular dysfunction and hypertension, and its prevalence is increasing around the world. The pathogenesis of obesity is closely related to reactive oxygen species. The role of reactive oxygen species as regulatory factors in mitochondrial activity in obese subjects, molecules taking part in inflammation processes linked to excessive size and number of adipocytes, and as agents governing the energy balance in hypothalamus neurons has been examined. Phytotherapy is the traditional form of treating health problems using plant-derived medications. Some plant extracts are known to act as anti-obesity agents and have been screened in in vitro models based on the inhibition of lipid accumulation in 3T3-L1 cells and activity of pancreatic lipase methods and in in vivo high-fat diet-induced obesity rat/mouse models and human models. Plant products may be a good natural alternative for weight management and a source of numerous biologically-active chemicals, including antioxidant polyphenols that can counteract the oxidative stress associated with obesity. This review presents polyphenols as natural complementary therapy, and a good nutritional strategy, for treating obesity without serious side effects.

An investigation of the inflammatory cytokine and chemokine network in systemic sclerosis

2011 ◽  
Vol 70 (6) ◽  
pp. 1115-1121 ◽  
Author(s):  
Veronica Codullo ◽  
Helen M Baldwin ◽  
Mark D Singh ◽  
Alasdair R Fraser ◽  
Catherine Wilson ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Mononuclear Cells ◽  
Platelet Rich Plasma ◽  
Critical Role ◽  
Serum Levels ◽  
Pcr Analysis ◽  
Peripheral Blood Mononuclear ◽  
Matrix Deposition ◽  
Disease Subtype ◽  
Inflammatory Chemokines

ObjectivesSystemic sclerosis (SSc) is characterised by vasculopathy, an aberrantly activated immune system and excessive extracellular matrix deposition. Inflammatory chemokines control migration of cells to sites of tissue damage; their removal from inflamed sites is essential for resolution of the inflammatory response. The atypical chemokine receptor D6 has a critical role in this physiological balance. To explore potential deregulation of this system in SSc, inflammatory chemokine and D6 expression were compared with that in healthy controls (HC).MethodsSerum levels of inflammatory mediators were assessed by luminex analysis. Peripheral blood mononuclear cells (PBMCs) were used in molecular and immunocytochemical analysis. Platelet-rich plasma was collected and assessed by western blotting for D6 expression levels. Sex-matched HC were used for comparison.Results72 patients with SSc and 30 HC were enrolled in the study. The chemokines MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4 and IL-8/CXCL8 were significantly increased in patients with SSc, regardless of disease subtype and phase. Quantitative PCR analysis revealed a significant 10-fold upregulation of D6 transcripts in patients with SSc compared with controls, and this was paralleled by increased D6 protein expression in the PBMCs of patients with SSc. Platelet lysates also showed strong D6 expression in patients with SSc but not in controls. Importantly, high levels of D6 expression correlated with reduced levels of its ligands in serum.ConclusionsInflammatory chemokines and the regulatory receptor D6 are significantly upregulated in SSc and high D6 levels are associated with lower systemic chemokine levels, indicating that some patients control systemic chemokine levels using D6. These results suggest that chemokines may represent a therapeutic target in SSc.

scholarly journals Correction: Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis

2014 ◽  
Vol 16 (2) ◽  
pp. 406
Author(s):  
Gianluca Bagnato ◽  
Alessandra Bitto ◽  
Natasha Irrera ◽  
Gabriele Pizzino ◽  
Donatella Sangari ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Systemic Sclerosis ◽  
Pulmonary Fibrosis ◽  
Murine Model ◽  
Reactive Oxygen ◽  
Oxygen Species

scholarly journals Hyaluronan in intestinal homeostasis and inflammation: implications for fibrosis

2011 ◽  
Vol 301 (6) ◽  
pp. G945-G949 ◽  
Author(s):  
Carol A. de la Motte
Keyword(s):  
Extracellular Matrix ◽  
Wound Healing ◽  
Intestinal Inflammation ◽  
Cellular Mechanisms ◽  
Matrix Component ◽  
Matrix Deposition ◽  
Fibrotic Tissue ◽  
Myofibroblast Phenotype ◽  
Extracellular Matrix Deposition ◽  
Chronic Intestinal Inflammation

The causes of fibrosis, or the inappropriate wound healing, that follows chronic intestinal inflammation are not well defined and likely involve the contributions of multiple cellular mechanisms. As other articles in this series confirm, inflammatory cytokines clearly play a role in driving cell differentiation to the myofibroblast phenotype, promoting proliferation and extracellular matrix deposition that are characteristic of fibrotic tissue. However, controlling the balance of cytokines produced and process of myofibroblast differentiation appears to be more complex. This review considers ways in which hyaluronan, an extracellular matrix component that is remodeled during the progression of colitis, may provide indirect as well as direct cues that influence the balancing act of intestinal wound healing.

Regulation of matrix turnover: fibroblasts, forces, factors and fibrosis

2007 ◽  
Vol 35 (4) ◽  
pp. 647-651 ◽  
Author(s):  
G.J. Laurent ◽  
R.C. Chambers ◽  
M.R. Hill ◽  
R.J. McAnulty
Keyword(s):  
Cell Phenotype ◽  
Gene Interactions ◽  
Internal Organs ◽  
Matrix Deposition ◽  
Molecular Events ◽  
The Common ◽  
Extracellular Molecules ◽  
Altered Cell ◽  
Key Pathways ◽  
Circulating Fibrocytes

Fibroblasts are multifunctional cells that are responsible for matrix homoeostasis, continuously synthesizing and degrading a diverse group of extracellular molecules and their receptors. Rates of turnover of matrix molecules and the proteases that degrade them are normally under the control of diverse chemical and mechanical cues, with cytokines, growth factors, proteases, lipid mediators and mechanical forces playing roles. The maintenance of this homoeostasis is vital to the preservation of normal tissue function and is clearly lost in chronic diseases of the joints, skin and internal organs where destruction and excessive deposition is seen. Current research is focusing on defining the key pathways of activation either in resident fibroblasts, matrix-producing cells derived from circulating fibrocytes, or from transdifferentiation of resident cells. The common downstream signalling pathways are also being defined, as well as the gene interactions leading to altered cell phenotype. The present article reviews these findings and our current concepts of the key molecular events leading to tissue damage and excessive matrix deposition in tissue fibrosis. These studies are leading to an appreciation of the complexity of events with multiple pathways involved, but, as the facts emerge, we are finding promising new ways to treat fibrosis and halt the inexorable progression that is a feature of so many fibrotic and remodelling disorders.

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