Pathogenesis of Pulmonary Fibrosis in Systemic Sclerosis: Lessons from Interstitial Lung Disease

Veraldi, Kristen L.; Hsu, Eileen; Feghali‐Bostwick, Carol

doi:10.1007/s11926-009-0071-8

Cited by 16 publications

(11 citation statements)

References 48 publications

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“…The opposite from what is reported in other studies is also observed for several of these genes in this study. For example, hypermethylation of both FLI1 in SSc and SOCS1 in SLE was not observed in our study even though hypermethylation of promoter regions of both genes has been previously implicated in the pathophysiology of SSc and SLE, respectively [ 40 - 42 ]. However, FLI-1 overexpression, probably as a result of promoter hypomethylation, has been detected in various types of cancer and other diseases [ 43 ].…”

Section: Discussioncontrasting

confidence: 71%

DNA methylation similarities in genes of black South Africans with systemic lupus erythematosus and systemic sclerosis

et al. 2015

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BackgroundSystemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are systemic autoimmune connective tissue diseases that share overlapping clinico-pathological features. It is highly probable that there is an overlap in epigenetic landscapes of both diseases. This study aimed to identify similarities in DNA methylation changes in genes involved in SLE and SSc. Global DNA methylation and twelve genes selected on the basis of their involvement in inflammation, autoimmunity and/or fibrosis were analyzed using PCR arrays in three groups, each of 30 Black South Africans with SLE and SSc, plus 40 healthy control subjects.ResultsGlobal methylation in both diseases was significantly lower (<25 %) than in healthy subjects (>30 %, p = 0.0000001). In comparison to healthy controls, a similar gene-specific methylation pattern was observed in both SLE and SSc. Three genes, namely; PRF1, ITGAL and FOXP3 were consistently hypermethylated while CDKN2A and CD70 were hypomethylated in both diseases. The other genes (SOCS1, CTGF, THY1, CXCR4, MT1-G, FLI1, and DNMT1) were generally hypomethylated in SLE whereas they were neither hyper- nor hypo-methylated in SSc.ConclusionsSSc and SLE patients have a higher global hypomethylation than healthy subjects with specific genes being hypomethylated and others hypermethylated. The majority of genes studied were hypomethylated in SLE compared to SSc. In addition to the commonly known hypomethylated genes in SLE and SSc, there are other hypomethylated genes (such as MT-1G and THY-1) that have not previously been investigated in SLE and SSc though are known to be hypermethylated in cancer.

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Section: Discussioncontrasting

confidence: 71%

DNA methylation similarities in genes of black South Africans with systemic lupus erythematosus and systemic sclerosis

et al. 2015

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“…However, it has been recognized that the most serious clinical manifestations of the disease and its high mortality are the result of SSc-associated-interstitial lung disease (ILD) or pulmonary arterial hypertension (PAH). SSc-associated ILD results from exaggerated and often progressive accumulation of fibrous collagens and other extracellular matrix molecules in the lung parenchyma, whereas, SSc-associated PAH is caused by functional alterations and structural fibroproliferative vasculopathy affecting the small and medium sized pulmonary arterioles [8–12]. …”

Section: Introductionmentioning

confidence: 99%

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

Jimenez

Piera-Velázquez

2016

Matrix Biology

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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.

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“…Pulmonary fibrosis is characterized by the accumulation of fibroblasts and extracellular matrix (ECM) in the lung (5)(6)(7)(8)(9). The disorder arises from a variety of etiologies that initiate inflammation (9)(10)(11) and excess production of inflammatory cytokines (e.g., IL-1b, IL-6), which promote the progression to lung fibrosis (10,11).…”

mentioning

confidence: 99%

Sirtuin1 Protects against Systemic Sclerosis–related Pulmonary Fibrosis by Decreasing Proinflammatory and Profibrotic Processes

Chu¹,

Jiang

Liu

et al. 2018

Am J Respir Cell Mol Biol

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Pulmonary fibrosis is the leading cause of death in systemic sclerosis (SSc). Sirtuin1 (SIRT1) is a deacetylase with known antiinflammatory and antifibrotic activity in the liver, kidney, and skin. The role of SIRT1 in SSc-related pulmonary fibrosis is unknown. In the present work, we determined that the expression of SIRT1 in peripheral blood mononuclear cells of patients with SSc with pulmonary fibrosis is lower than that in patients with SSc without pulmonary fibrosis. In in vivo studies of bleomycin-induced lung fibrosis in mice, SIRT1 activation with resveratrol reduced collagen production when it was administered either prophylactically during the inflammatory stage or after the development of fibrosis. Furthermore, SIRT1 activation or overexpression inhibited tumor necrosis factor-α-induced inflammatory responses in vitro in human fetal lung fibroblasts, depletion of SIRT1 in fibroblasts enhanced inflammation, and these effects were related to changes in the acetylation of NF-κB. In addition, SIRT1 activation or exogenous overexpression inhibited collagen production in vitro, and these manipulations also inhibited fibrosis via inactivation of transforming growth factor-β/mothers against decapentaplegic homolog and mammalian target of rapamycin signaling. Taken together, our results show that a loss of SIRT1 may participate in the pathogenesis of SSc-related pulmonary fibrosis, and that SIRT1 activation is an effective treatment for both the early (inflammatory) and late (fibrotic) stages of pulmonary fibrosis. Thus, SIRT1 may be a promising therapeutic target in the management of SSc-related pulmonary fibrosis.

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Pathogenesis of Pulmonary Fibrosis in Systemic Sclerosis: Lessons from Interstitial Lung Disease

Cited by 16 publications

References 48 publications

DNA methylation similarities in genes of black South Africans with systemic lupus erythematosus and systemic sclerosis

DNA methylation similarities in genes of black South Africans with systemic lupus erythematosus and systemic sclerosis

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

Sirtuin1 Protects against Systemic Sclerosis–related Pulmonary Fibrosis by Decreasing Proinflammatory and Profibrotic Processes

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