Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis

2004 ◽  
Vol 16 (6) ◽  
pp. 733-738 ◽  
Author(s):  
Arnold E Postlethwaite ◽  
Hidenobu Shigemitsu ◽  
Siva Kanangat
Keyword(s):  
Systemic Sclerosis ◽  
Organ Fibrosis

scholarly journals The JAK/STAT pathway is activated in systemic sclerosis and is effectively targeted by tofacitinib

2019 ◽  
Vol 5 (1) ◽  
pp. 40-50 ◽  
Author(s):  
Wenxia Wang ◽  
Swati Bhattacharyya ◽  
Roberta Goncalves Marangoni ◽  
Mary Carns ◽  
Kathleen Dennis-Aren ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Lung Fibrosis ◽  
Bioinformatic Analysis ◽  
Jak Inhibitor ◽  
Stat3 Phosphorylation ◽  
Fibrotic Diseases ◽  
Lung Biopsies ◽  
Organ Fibrosis ◽  
Substantial Morbidity ◽  
Stat Pathway

Rationale: Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis; accounts for substantial morbidity and mortality; and lacks effective therapy. Myofibroblast activation underlies organ fibrosis, but the key extracellular cues driving persistence of the process remain incompletely characterized. Objectives: The objectives were to evaluate activation of the IL6/JAK/STAT axis associated with fibrosis in skin and lung biopsies from systemic sclerosis patients and effects of the Food and Drug Administration–approved JAK/STAT inhibitor, tofacitinib, on skin and lung fibrosis in animal models. Methods: Bioinformatic analysis showed that IL6/JAK/STAT3 and tofacitinib gene signatures were aberrant in biopsies from systemic sclerosis patients in four independent cohorts. The results were confirmed by JAK and STAT3 phosphorylation in both skin and lung biopsies from patients with systemic sclerosis. Furthermore, treatment of mice with the selective JAK inhibitor tofacitinib not only prevented bleomycin-induced skin and lung fibrosis but also reduced skin fibrosis in TSK1/+ mice. Conclusion: These findings implicate the JAK/STAT pathway in systemic sclerosis skin and lung fibrosis and identify tofacitinib as a potential antifibrotic agent for the treatment of systemic sclerosis and other fibrotic diseases.

scholarly journals SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis

Oncotarget ◽  
2016 ◽  
Vol 7 (43) ◽  
pp. 69321-69336 ◽  
Author(s):  
Kaname Akamata ◽  
Jun Wei ◽  
Mitra Bhattacharyya ◽  
Paul Cheresh ◽  
Michael Y. Bonner ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Organ Fibrosis

Systemic Sclerosis

Chest Imaging ◽  
2019 ◽  
pp. 349-353
Author(s):  
Felipe Martínez
Keyword(s):  
Pulmonary Hypertension ◽  
Systemic Sclerosis ◽  
Pulmonary Disease ◽  
Cause Of Death ◽  
Autoimmune Disorder ◽  
Pulmonary Involvement ◽  
Pulmonary Vascular Disease ◽  
Small Vessels ◽  
Normal Chest Radiograph ◽  
Organ Fibrosis

Systemic sclerosis (SSc), or scleroderma is a chronic autoimmune disorder of small vessels and connective tissue characterized by organ fibrosis, small vessel vasculopathy and disease-specific antibodies. It results in multi system organ fibrosis. The skin, lungs, heart, gastrointestinal tract and kidneys are frequently affected. Skin involvement is typical. Clinically evident pulmonary disease is seen in 25% of affected patients, but autopsy reports demonstrate some degree of pulmonary involvement in all patients with the systemic form of the disease. Pulmonary disease is second only to esophageal fibrosis and has surpassed renal disease as the leading cause of death. Systemic sclerosis associated-interstitial lung disease (SSc-ILD) and pulmonary vascular disease are the two major lung manifestations of SSc. Pulmonary hypertension is the leading cause of death. A normal chest radiograph does not exclude SSc-ILD. High resolution CT (HRCT) should be part of the initial evaluation of patients with SSc, even when pulmonary symptoms are not present. The radiologist should be able to recognize signs of early pulmonary fibrosis and pulmonary hypertension on radiography and HRCT due to the proven benefit of adequate therapy in overall outcome and mortality.

scholarly journals When the Benign Pneumatosis Intestinalis Becomes No Longer Benign: A Rare Case of Bowel Perforation in a Patient with Systemic Sclerosis

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Jian Guan ◽  
Alvina Munaf ◽  
Alric V. Simmonds ◽  
Irteza Inayat
Keyword(s):  
Abdominal Pain ◽  
Systemic Sclerosis ◽  
Bowel Perforation ◽  
Pneumatosis Intestinalis ◽  
Colonic Perforation ◽  
Gi Tract ◽  
Multisystem Disease ◽  
Mild Abdominal Pain ◽  
Tract Involvement ◽  
Organ Fibrosis

Systemic sclerosis is a multisystem disease featured with autoimmunity and organ fibrosis. Although gastrointestinal (GI) tract involvement is common in patients with systemic sclerosis, colonic perforation is extremely rare. Benign pneumatosis intestinalis, a phenomenon more frequently seen in rheumatologic conditions, makes the diagnosis of colonic perforation even more challenging. We report a unique case of colonic perforation in a patient with chronic systemic sclerosis. This patient initially presented with mild abdominal pain and hematemesis. Urgent upper endoscopy was unremarkable and radiology showed stable pneumatosis intestinalis. Due to worsening abdominal pain, laparotomy exploration was performed and colonic perforation with transmural ischemic necrosis was found.

scholarly journals Pan-lysyl oxidase inhibitor PXS-5505 ameliorates multiple-organ fibrosis by inhibiting collagen crosslinks in rodent models of systemic sclerosis

2021 ◽  
Author(s):  
Yimin Yao ◽  
Alison Findlay ◽  
Jessica Stolp ◽  
Benjamin Rayner ◽  
Kjetil Ask ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Lysyl Oxidase ◽  
Multiple Organ ◽  
Oxidase Inhibitor ◽  
Lung Model ◽  
Rodent Models ◽  
Collagen Crosslinks ◽  
Fibrotic Liver ◽  
Lysyl Oxidases ◽  
Organ Fibrosis

Background/Purpose: Systemic sclerosis (SSc) is characterised by progressive multiple-organ fibrosis leading to morbidity and mortality. Lysyl oxidases play a vital role in the cross-linking of collagens and subsequent build-up of fibrosis in the extracellular matrix. As such, their inhibition provides a novel treatment paradigm for SSc. Experimental Approach: Lysyl oxidases are upregulated in preclinical models of fibrosis in skin, lung, heart, kidney and liver. A novel small molecule pan-lysyl oxidase inhibitor, PXS-5505, currently in clinical development for bone fibrosis treatment was evaluated in in vivo rodent models resembling the fibrotic conditions in SSc. Key Results: Both lysyl oxidase and lysyl oxidase-like 2 (LOXL2) expression was elevated in the skin and lung of SSc patients. Once-a-day oral application of PXS-5505 inhibited lysyl oxidase activity in the skin and LOXL2 activity in the lung. PXS-5505 exhibited anti-fibrotic effects in the SSc skin mouse model, reducing dermal thickness and α-smooth muscle actin compared to the disease controls. Similarly, in the bleomycin-induced mouse lung model, PXS-5505 reduced tissue fibrosis toward normal levels. The anti-fibrotic efficacy of PXS-5505 in the bleomycin exposed lungs was mediated by its ability to normalise collagen/elastin crosslink formation, a direct consequence of lysyl oxidase inhibition. PXS-5505 also reduced area of fibrosis in rodent models of the ischaemia-reperfusion heart, the unilateral ureteral obstruction kidney and the CCl4-induced fibrotic liver. Conclusion/Implication: PXS-5505 consistently demonstrates potent anti-fibrotic efficacy in multiple models of organ fibrosis relevant to the pathogenesis of SSc, suggesting that it may be efficacious as a novel approach for treating SSc.

scholarly journals Cytometric Characterization of Main Immunocompetent Cells in Patients with Systemic Sclerosis: Relationship with Disease Activity and Type of Immunosuppressive Treatment

2019 ◽  
Vol 8 (5) ◽  
pp. 625 ◽  
Author(s):  
Olga Gumkowska-Sroka ◽  
Krystyna Jagoda ◽  
Aleksander Owczarek ◽  
Grzegorz Helbig ◽  
Joanna Giemza-Stokłosa ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Disease Activity ◽  
Natural Killer ◽  
Immune Cell ◽  
Immunosuppressive Treatment ◽  
Double Positive ◽  
Nkt Cell ◽  
Organ Fibrosis ◽  
Cell Profile

Systemic sclerosis (SSc) is a connective tissue disease that is characterized by widespread skin and internal organ fibrosis vasculopathy and immune response abnormalities, including T, B, natural killer (NK), and natural killer T (NKT) cell involvement. The aim of the study was to investigate the immune cell profile in patients with systemic sclerosis in relation to the disease activity, severity, and antibody presence and their relation to the type of immunosuppressive treatment. Cytometric examination identified following cell lines: B cells (Breg, B memory, B mature) and plasmablasts, T cell, T double positive—Tdp, T double negative—Tdn, NK, and NKT cell and monocytes. The disease severity and activity were assessed based on the Medsger and the EULAR Scleroderma Trials and Research Group (EUSTAR) 2017 scales respectively. In the study, SSc patients were characterized by higher total lymphocyte count parallel to increased frequency of Ts and Th cells. In SSc patients, increment of Tdp and reduction of Tdn as well as NK and NKT cells were observed. Additionally in SSc patients the reduction of B memory was noted. Head to head comparison between cyclophosphamide (CYC) and mycophenolate mofetil (MMF) treatment showed a reduction of CD19+ cells, but increment of plasmablasts in CYC treated patients.

scholarly journals Role of Alarmins in the Pathogenesis of Systemic Sclerosis

2020 ◽  
Vol 21 (14) ◽  
pp. 4985 ◽  
Author(s):  
Antonello Giovannetti ◽  
Elisabetta Straface ◽  
Edoardo Rosato ◽  
Marco Casciaro ◽  
Giovanni Pioggia ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Immune Functions ◽  
Internal Organs ◽  
Immune System Activation ◽  
System Activation ◽  
Genetic And Environmental Factors ◽  
Chronic Autoimmune Disease ◽  
And Oxidative Stress ◽  
Organ Fibrosis

Systemic sclerosis (SSc) is a rare chronic autoimmune disease associated with significant morbidity and mortality. Two main subsets of SSc are recognized: (i) diffuse cutaneous SSc with rapidly progressive fibrosis of the skin, lungs, and other internal organs; and (ii) limited cutaneous SSc, which is dominated by vascular manifestations, with skin and organ fibrosis generally limited and slowly progressing. In spite of intense investigation, both etiology and pathogenesis of SSc are still unknown. Genetic and environmental factors, as well as abnormalities of immune functions, are strongly suggested for etiology, while microvascular abnormalities, immune system activation, and oxidative stress are suggested for the pathogenesis. Recently, it has been found that a multitude of mediators and cytokines are implicated in the fibrotic processes observed in SSc. Among these, a central role could be exerted by “alarmins”, endogenous and constitutively expressed proteins/peptides that function as an intercellular signal defense. This review describes, in a detailed manner, the role of alarmins in the pathogenesis of scleroderma.

scholarly journals Treatment of Systemic Sclerosis Associated Interstitial Lung Disease

2020 ◽  
Vol 20 (02) ◽  
pp. 56-64
Author(s):  
Iris Yan Ki Tang ◽  
So Ho
Keyword(s):  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Immune Dysregulation ◽  
Connective Tissue Disorder ◽  
Major Contributor ◽  
Biological Therapies ◽  
Visceral Organ ◽  
Common Manifestation ◽  
Organ Fibrosis

Systemic sclerosis (SSc) is a systemic connective tissue disorder characterized by progressive skin and visceral organ fibrosis, vasculopathy, and immune dysregulation. Interstitial lung disease (ILD) is a common manifestation and major contributor to morbidity and mortality. Immunosuppression is usually indicated for extensive or progressive SSc-ILD. Recently, antifibrotic and biological therapies have been shown to be efficacious in treating SSc-ILD in various studies. In this article, we will descriptively review the latest evidence on the treatment of SSc-ILD.

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