Oxidative stress in the pathogenesis of systemic scleroderma: An overview

Vona, Rosa; Giovannetti, Antonello; Gambardella, Lucrezia; Malorni, Walter; Pietraforte, Donatella; Straface, Elisabetta

doi:10.1111/jcmm.13630

Cited by 58 publications

(46 citation statements)

References 58 publications

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“…We find that SSc patients exhibit increased oxidative stress and AP sites, which is in line with previous studies showing that oxidative stress is implicated in the development and perpetuation of SSc ( 7 , 40 ). Indeed, several oxidative stress biomarkers, such as malondialdehyde (a marker of lipid peroxidation), nitric oxide, and endogenous nitric oxide inhibitor asymmetric dimethylarginine are increased in the blood of SSc patients ( 41 ). In contrast, antioxidative biomarkers, such as superoxide dismutase and vitamin C, are lower in SSc patients’ blood ( 7 ).…”

Section: Discussionmentioning

confidence: 99%

Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis

et al. 2020

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Increased endogenous DNA damage and type I interferon pathway activation have been implicated in systemic sclerosis (SSc) pathogenesis. Because experimental evidence suggests an interplay between DNA damage response/repair (DDR/R) and immune response, we hypothesized that deregulated DDR/R is associated with a type I interferon signature and/or fibrosis extent in SSc. DNA damage levels, oxidative stress, induction of abasic sites and the efficiency of DNA double-strand break repair (DSB/R) and nucleotide excision repair (NER) were assessed in peripheral blood mononuclear cells (PBMCs) derived from 37 SSc patients and 55 healthy controls; expression of DDR/R-associated genes and type I interferon–induced genes was also quantified. Endogenous DNA damage was significantly higher in untreated diffuse or limited SSc (Olive tail moment; 14.7 ± 7.0 and 9.5 ± 4.1, respectively) as well as in patients under cytotoxic treatment (15.0 ± 5.4) but not in very early onset SSc (5.6 ± 1.2) compared with controls (4.9 ± 2.6). Moreover, patients with pulmonary fibrosis had significantly higher DNA damage levels than those without (12.6 ± 5.8 vs. 8.8 ± 4.8, respectively). SSc patients displayed increased oxidative stress and abasic sites, defective DSB/R but not NER capacity, downregulation of genes involved in DSB/R (MRE11A, PRKDC) and base excision repair (PARP1, XRCC1), and upregulation of apoptosis-related genes (BAX, BBC3). Individual levels of DNA damage in SSc PBMCs correlated significantly with the corresponding mRNA expression of type I interferon–induced genes (IFIT1, IFI44 and MX1, r =0.419-0.490) as well as with corresponding skin involvement extent by modified Rodnan skin score ( r =0.481). In conclusion, defective DDR/R may exert a fuel-on-fire effect on type I interferon pathway activation and contribute to tissue fibrosis in SSc.

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Section: Discussionmentioning

confidence: 99%

Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis

et al. 2020

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“…In addition, oxidative stress is involved in the pathogenesis of SSc [87]. That is, SSc patients are characterized by increased production of ROS in the skin, visceral fibroblasts, and endothelial cells, as well as by reduced concentrations of various antioxidants, including antioxidant vitamins (ascorbic acid, α-tocopherol, β-carotene) and minerals (zinc, selenium) [88]. Also, oxidative stress has been observed in patients with RA.…”

Section: Oxidative Stress Causes Dna Damage That Activates the Immunementioning

confidence: 99%

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

Souliotis

Vlachogiannis

Παππά

et al. 2019

IJMS

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The DNA damage response and repair (DDR/R) network, a sum of hierarchically structured signaling pathways that recognize and repair DNA damage, and the immune response to endogenous and/or exogenous threats, act synergistically to enhance cellular defense. On the other hand, a deregulated interplay between these systems underlines inflammatory diseases including malignancies and chronic systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Patients with these diseases are characterized by aberrant immune response to self-antigens with widespread production of autoantibodies and multiple-tissue injury, as well as by the presence of increased oxidative stress. Recent data demonstrate accumulation of endogenous DNA damage in peripheral blood mononuclear cells from these patients, which is related to (a) augmented DNA damage formation, at least partly due to the induction of oxidative stress, and (b) epigenetically regulated functional abnormalities of fundamental DNA repair mechanisms. Because endogenous DNA damage accumulation has serious consequences for cellular health, including genomic instability and enhancement of an aberrant immune response, these results can be exploited for understanding pathogenesis and progression of systemic autoimmune diseases, as well as for the development of new treatments.

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“…So far, there are no data regarding the role of CTSS in the development of SSc-ILD, but previous studies revealed the contribution of ROS to this complication. For instance, there are several reports demonstrating the increased concentration of ROS in SSc patients, [26][27][28][29] especially in patients with SSc-ILD. 30,31 In addition, a perturbation of mitochondria homeostasis in alveolar macrophages has been reported in idiopathic pulmonary fibrosis (IPF) that shares a part of the pathological process with SSc-ILD, especially its fibrotic phase.…”

Section: Discussionmentioning

confidence: 99%

Decreased serum cathepsin S levels in patients with systemic sclerosis‐associated interstitial lung disease

Toyama

Yamashita

Saigusa

et al. 2020

The Journal of Dermatology

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Cathepsin S (CTSS) is a lysosomal proteolytic enzyme regulating intracellular and extracellular biological activities, including immunity/inflammation and remodeling of vasculature and extracellular matrix, which are the three cardinal pathological events associated with systemic sclerosis (SSc). To elucidate the potential role of CTSS in the development of SSc, we investigated the clinical correlation of serum CTSS levels. Because serum CTSS levels were inversely correlated with estimated glomerular filtration rate (eGFR) in SSc patients with renal dysfunction (eGFR, <60 min/mL per 1.73 m2), SSc patients with normal renal function (eGFR, ≥60 min/mL per 1.73 m2) were analyzed. Serum CTSS levels were significantly decreased in diffuse cutaneous SSc patients compared with limited cutaneous SSc patients and healthy controls. Among vascular and fibrotic clinical manifestations, Raynaud’s phenomenon and interstitial lung disease (ILD) were relevant to a significant decrease in serum CTSS levels. Importantly, serum CTSS levels negatively correlated with serum levels of Krebs von den Lungen‐6 and surfactant protein D in total SSc patients, while not correlating with modified Rodnan total skin thickness score and the percentage of predicted diffusion lung capacity for carbon monoxide and showing a positive trend with the percentage of predicted vital capacity. These results suggest a potential contribution of decreased CTSS expression to the development of ILD in patients with SSc.

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Oxidative stress in the pathogenesis of systemic scleroderma: An overview

Cited by 58 publications

References 58 publications

Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis

Association Between DNA Damage Response, Fibrosis and Type I Interferon Signature in Systemic Sclerosis

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

Decreased serum cathepsin S levels in patients with systemic sclerosis‐associated interstitial lung disease

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