Oxidative stress in the pathogenesis of systemic scleroderma: An overview

Systemic sclerosis (SSc) is a rare disorder of the connective tissue characterized by fibrosis of the skin, skeletal muscles and visceral organs. Additional manifestations include activation of the immune system and vascular injury. SSc causes disability and death as the result of end-stage organ failure. Two clinical subsets of the SSc are accepted: limited cutaneous SSc (lc-SSc) and diffuse cutaneous SSc (dc-SSc). At present, the aetiology and pathogenesis of SSc remain obscure, and consequently, disease outcome is unpredictable. Numerous studies suggest that reactive oxidizing species (ROS) play an important role in the pathogenesis of scleroderma. Over the years, several reports have supported this hypothesis for both lc-SSc and dc-SSc, although the specific role of oxidative stress in the pathogenesis of vascular injury and fibrosis remains to be clarified. The aim of the present review was to report and comment the recent findings regarding the involvement and role of oxidative stress in SSc pathogenesis. Biomarkers proving the link between ROS and the main pathological features of SSc have been summarized

Endothelial to mesenchymal transition (EndoMT) in the pathogenesis of Systemic Sclerosis-associated pulmonary fibrosis and pulmonary arterial hypertension. Myth or reality?

Systemic Sclerosis (SSc) is a systemic autoimmune disease characterized by progressive fibrosis of skin and multiple internal organs and severe functional and structural microvascular alterations. SSc is considered to be the prototypic systemic fibrotic disorder. Despite currently available therapeutic approaches SSc has a high mortality rate owing to the development of SSc-associated interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH), complications that have emerged as the most frequent causes of disability and mortality in SSc. The pathogenesis of the fibrotic process in SSc is complex and despite extensive investigation the exact mechanisms have remained elusive. Myofibroblasts are the cells ultimately responsible for tissue fibrosis and fibroproliferative vasculopathy in SSc. Tissue myofibroblasts in SSc originate from several sources including expansion of quiescent tissue fibroblasts and tissue accumulation of CD34+ fibrocytes. Besides these sources, myofibroblasts in SSc may result from the phenotypic conversion of endothelial cells into activated myofibroblasts, a process known as endothelial to mesenchymal transition (EndoMT). Recently, it has been postulated that EndoMT may play a role in the development of SSc-associated ILD and PAH. However, although several studies have described the occurrence of EndoMT in experimentally induced cardiac, renal, and pulmonary fibrosis and in several human disorders, the contribution of EndoMT to SSc-associated ILD and PAH has not been generally accepted. Here, the experimental evidence supporting the concept that EndoMT plays a role in the pathogenesis of SSc-associated ILD and PAH will be reviewed

Fresh Insights into Disease Etiology and the Role of Microbial Pathogens.

Pathogens have been implicated in the initiation and/or promotion of systemic sclerosis (scleroderma, SSc); however, no evidence was found to substantiate the direct contribution to this disease in past years. Recently, significant advances have been made in understanding the role of the innate immune system in SSc pathogenesis, supporting the idea that pathogens might interact with host innate immune-regulatory responses in SSc. In light of these findings, we review the studies that identified the presence of pathogens in SSc, along with studies on pathogens implicated in driving the innate immune dysregulation in SSc. The goal of this review is to illustrate how these pathogens, specifically viruses, may play important role both as triggers of the innate immune system, and critical players in the development of SSc disease

Epstein-Barr virus lytic infection promotes activation of Toll-like receptor 8 innate immune response in systemic sclerosis monocytes

BACKGROUND: Monocytes/macrophages are activated in several autoimmune diseases, including systemic sclerosis (scleroderma; SSc), with increased expression of interferon (IFN)-regulatory genes and inflammatory cytokines, suggesting dysregulation of the innate immune response in autoimmunity. In this study, we investigated whether the lytic form of Epstein-Barr virus (EBV) infection (infectious EBV) is present in scleroderma monocytes and contributes to their activation in SSc. METHODS: Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) depleted of the CD19+ cell fraction, using CD14/CD16 negative-depletion. Circulating monocytes from SSc and healthy donors (HDs) were infected with EBV. Gene expression of innate immune mediators were evaluated in EBV-infected monocytes from SSc and HDs. Involvement of Toll-like receptor (TLR)8 in viral-mediated TLR8 response was investigated by comparing the TLR8 expression induced by infectious EBV to the expression stimulated by CL075/TLR8/agonist-ligand in the presence of TLR8 inhibitor in THP-1 cells. RESULTS: Infectious EBV strongly induced TLR8 expression in infected SSc and HD monocytes in vitro. Markers of activated monocytes, such as IFN-regulated genes and chemokines, were upregulated in SSc- and HD-EBV-infected monocytes. Inhibiting TLR8 expression reduced virally induced TLR8 in THP-1 infected cells, demonstrating that innate immune activation by infectious EBV is partially dependent on TLR8. Viral mRNA and proteins were detected in freshly isolated SSc monocytes. Microarray analysis substantiated the evidence of an increased IFN signature and altered level of TLR8 expression in SSc monocytes carrying infectious EBV compared to HD monocytes. CONCLUSION: This study provides the first evidence of infectious EBV in monocytes from patients with SSc and links EBV to the activation of TLR8 and IFN innate immune response in freshly isolated SSc monocytes. This study provides the first evidence of EBV replication activating the TLR8 molecular pathway in primary monocytes. Immunogenicity of infectious EBV suggests a novel mechanism mediating monocyte inflammation in SSc, by which EBV triggers the innate immune response in infected cells

Angiogenic and angiostatic factors in renal scleroderma-associated vasculopathy

BACKGROUND: The angiogenesis in systemic sclerosis (SSc) is impaired. An imbalance of pro-angiogenic factors and angiogenesis inhibitors has been implicated in the progression of peripheral microvascular damage, defective vascular repair and fibrosis. Intrarenal resistance index are considered markers of renal vasculopathy. The aim of the study is to evaluate angiogenic and angiostatic factors (VEGF and endostatin) in SSc patients and to correlate with intrarenal hemodynamic parameters. METHODS: 91 SSc patients were enrolled in this study. Serum VEGF and endostatin levels were determined. All patients underwent a renal Doppler ultrasound RESULTS: A significant positive correlation was observed between endostatin and renal Doppler parameters (p<0.0001). A negative correlation was observed between serum levels of endostatin and eGFR (p<0.01). In SSc patients with high resistive index, serum levels of endostatin were significantly (p<0.01) higher than in SSc patients with normal resistive index. The serum levels of endostatin significantly increased with progression of nailfold videocapillaroscopy damage (p<0.01) and were significantly (p<0.05) higher in SSc patients with digital ulcers than in SSc patients without digital ulcers. CONCLUSION: This is the first study that assess in SSc patients intrarenal hemodynamic parameters and endostatin. In SSc patients, endostatin represents a marker of renal scleroderma-associated vasculopathy

Blocking CD248 molecules in perivascular stromal cells of patients with systemic sclerosis strongly inhibits their differentiation toward myofibroblasts and proliferation: A new potential target for antifibrotic therapy

Background: Fibrosis may be considered the hallmark of systemic sclerosis (SSc), the end stage triggered by different pathological events. Transforming growth factor-β (TGF-β) and platelet-derived growth factor BB (PDGF-BB) are profibrotic molecules modulating myofibroblast differentiation and proliferation, respectively. There is evidence linking CD248 with these two molecules, both highly expressed in patients with SSc, and suggesting that CD248 may be a therapeutic target for several diseases. The aim of this work was to evaluate the expression of CD248 in SSc skin and its ability to modulate SSc fibrotic process. Methods: After ethical approval was obtained, skin biopsies were collected from 20 patients with SSc and 10 healthy control subjects (HC). CD248 expression was investigated in the skin, as well as in bone marrow mesenchymal stem cells (MSCs) treated with TGF-β or PDGF-BB, by immunofluorescence, qRT-PCR, and Western blotting. Finally, in SSc-MSCs, the CD248 gene was silenced by siRNA. Results: Increased expression of CD248 was found in endothelial cells and perivascular stromal cells of SSc skin. In SSc-MSCs, the levels of CD248 and α-smooth muscle actin expression were significantly higher than in HC-MSCs. In both SSc- and HC-MSCs, PDGF-BB induced increased expression of Ki-67 when compared with untreated cells but was unable to modulate CD248 levels. After CD248 silencing, both TGF-β and PDGF-BB signaling were inhibited in SSc-MSCs. Conclusions: CD248 overexpression may play an important role in the fibrotic process by modulating the molecular target, leading to perivascular cells differentiation toward myofibroblasts and interfering with its expression, and thus might open a new therapeutic strategy to inhibit myofibroblast generation during SSc

Suppressed radio emission in supercluster galaxies: enhanced ram pressure in merging clusters?

The environmental influence on the 1.4 GHz continuum radio emission of galaxies is analyzed in a 600 deg2 region of the local Universe containing the Shapley Supercluster (SSC). Galaxies in the FLASH and 6dFGS redshift surveys are cross-identified with NVSS radio sources, selected in a subsample doubly complete in volume and luminosity. Environmental effects are studied through a smoothed density field (normalized with random catalogs with the same survey edges and redshift selection function) and the distance to the nearest cluster (R/r200, where r200 is the virial radius, whose relation to the aperture velocity dispersion is quantified). The fraction of high radio loudness (R_K=L_radio/L_K) galaxies in the 10 Mpc Abell 3558 cluster complex at the core of the SSC (SSC-CR) is half as large than elsewhere. In the SSC-CR, R_K is anti-correlated with the density of the large-scale environment and correlated with R/r200: central brightest cluster galaxies (BCGs) in the SSC-CR are 10x less radio-loud than BCGs elsewhere, with signs of suppressed radio loudness in the SSC-CR also present beyond the BCGs, out to at least 0.3 r200. This correlation is nearly as strong as the tight correlation of L_K with R/r200 (K-luminosity segregation), inside the SSC-CR. The suppression of radio loudness in SSC-CR BCGs can be attributed to cluster-cluster mergers that destroy the cool core and thus the supply of gas to the central AGN. We analytically demonstrate that the low radio loudness of non-BCG galaxies within SSC-CR clusters cannot be explained by direct major galaxy mergers or rapid galaxy flyby collisions, but by the loss of gas supply through the enhanced ram pressure felt when these galaxies cross the shock front between the 2 merging clusters and are later subjected to the stronger wind from the 2nd cluster.Comment: Version consolidated with Erratum A&A 499, 4

Satellite estimates of wide-range suspended sediment concentrations in Changjiang (Yangtze) estuary using MERIS data

The Changjiang (Yangtze) estuarine and coastal waters are characterized by suspended sediments over a wide range of concentrations from 20 to 2,500 mg l-1. Suspended sediment plays important roles in the estuarine and coastal system and environment. Previous algorithms for satellite estimates of suspended sediment concentration (SSC) showed a great limitation in that only low to moderate concentrations (up to 50 mg l-1) could be reliably estimated. In this study, we developed a semi-empirical radiative transfer (SERT) model with physically based empirical coefficients to estimate SSC from MERIS data over turbid waters with a much wider range of SSC. The model was based on the Kubelka–Munk two-stream approximation of radiative transfer theory and calibrated using datasets from in situ measurements and outdoor controlled tank experiments. The results show that the sensitivity and saturation level of remote-sensing reflectance to SSC are dependent on wavelengths and SSC levels. Therefore, the SERT model, coupled with a multi-conditional algorithm scheme adapted to satellite retrieval of wide-range SSC, was proposed. Results suggest that this method is more effective and accurate in the estimation of SSC over turbid water

Obstetric Nurses’ Perceived Barriers to Immediate Skin to Skin Contact after Cesarean Birth

Despite the strong evidence supporting immediate skin to skin contact (SSC) after birth, research suggests that patients who undergo cesarean births do not have the same opportunities for SSC as patients who undergo vaginal births. There are limited studies regarding provider attitudes surrounding the practice of immediate SSC after cesarean birth. The aim of this research was to understand obstetric nurses’ perceived barriers to immediate SSC after cesarean section. An exploratory qualitative design was used for the project. The semi-structured, open-ended interviews were conducted via video conferencing. Conventional content analysis methods were used to analyze the data, which yielded the primary overarching theme of “performing safe and effective skin to skin contact after cesarean birth”. The participants identified both barriers and facilitators to SSC after cesarean. It was evident from the interviews that nurses strongly believe in the benefits of SSC after cesarean and try to implement it as often as possible, but various factors prevented SSC in the OR from occurring on a regular basis. This research can be used as a starting point for refining the practice of SSC after cesarean births