Vasculopathy in scleroderma

Asano, Yoshihide; Sato, Shinichi

doi:10.1007/s00281-015-0505-5

Cited by 168 publications

(176 citation statements)

References 118 publications

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“…Considering the critical role of pericyte loss for the development of the histological and functional vascular changes characteristic of SSc vasculopathy, such as arteriolar stenosis, capillary dilation, and vascular permeability (Asano and Sato, 2015), glycyrrhizin may exert a disease-modifying effect on SSc vasculopathy by restoring pericyte coverage. To address this issue, we looked at the effect of glycyrrhizin on the vascular phenotype of Fli1 ECKO mice, which recapitulate SSc vasculopathy because of the loss of pericyte coverage (Asano et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis

Yamashita

Asano

Taniguchi

et al. 2017

Journal of Investigative Dermatology

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Systemic sclerosis (SSc) is a multisystem inflammatory and vascular disease resulting in extensive tissue fibrosis. Glycyrrhizin, clinically used for chronic hepatic diseases and itching dermatitis, modulates the pathological processes of inflammation, vasculopathy, and fibrosis in human diseases and their animal models. Therefore, we investigated a potential impact of glycyrrhizin on the key pathological manifestations of SSc, including inflammation, vasculopathy, and tissue fibrosis, with bleomycin-treated mice mimicking the fibrotic and inflammatory components of SSc and endothelial cell-specific Fli1-knockout mice recapitulating SSc vasculopathy. Glycyrrhizin significantly ameliorated dermal fibrosis in bleomycin-treated mice, which was partly attributable to blockade of transforming growth factor-β signaling in dermal fibroblasts through the downregulation of thrombospondin 1, a latent transforming growth factor-β receptor, and transcription factors Smad3 and Ets1. Furthermore, bleomycin-dependent induction of T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition were greatly suppressed in mice administered glycyrrhizin. Glycyrrhizin also improved vascular permeability of endothelial cell-specific Fli1-knockout mice by increasing the expression of molecules regulating vascular integrity. These results indicate that glycyrrhizin ameliorates bleomycin-induced dermal fibrosis through the inhibition of fibroblast activation, T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition and improves endothelial Fli1 deficiency-dependent vascular disintegrity, implying its potential as a disease-modifying drug for SSc.

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Section: Resultsmentioning

confidence: 99%

Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis

Yamashita

Asano

Taniguchi

et al. 2017

Journal of Investigative Dermatology

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“…SSc vasculopathy is marked by specific structural and functional abnormalities (1). The structural changes of SSc vasculature are largely attributable to vascular instability closely related to the altered phenotype of mural cells.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we also demonstrated that Th1-skewed immune polarization in BLM-treated Irf5 −/− mice is linked to IRF5 binding to the Tbet promoter, suggesting that IRF5 directly suppresses Th1 cell differentiation. Given that IRF5's occupancy of the Tbet promoter was decreased in Tlr4 −/− CD4 + T cells, the activation of TLR4-IRF5 axis promotes a Th2/Th17-predominant inflammatory condition through the direct suppression of Th1 cell differentiation, which may be characteristic of SSc (1).…”

Section: Discussionmentioning

confidence: 99%

“…Our study sheds light on the TLR4-IRF5 pathway in the pathology of SSc with clinical implications of targeting the IRF5 pathways in the suppression of disease development. S ystemic sclerosis (SSc) is a multisystem connective tissue disease characterized by immune abnormalities, vasculopathy, and extensive tissue fibrosis (1). Based on the results of etiological and genetic studies, the conventional wisdom is that SSc is caused by a complex interplay between genetic factors and environmental influences.…”

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confidence: 99%

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Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

Saigusa

Asano

Taniguchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Systemic sclerosis (SSc) is a multisystem autoimmune disorder with clinical manifestations resulting from tissue fibrosis and extensive vasculopathy. A potential disease susceptibility gene for SSc is IFN regulatory factor 5 (IRF5), whose SNP is associated with milder clinical manifestations; however, the underlying mechanisms of this association remain elusive. In this study we examined IRF5-deficient (Irf5−/−) mice in the bleomycin-treated SSc murine model. We show that dermal and pulmonary fibrosis induced by bleomycin is attenuated in Irf5−/− mice. Interestingly, we find that multiple SSc-associated events, such as fibroblast activation, inflammatory cell infiltration, endothelial-to-mesenchymal transition, vascular destabilization, Th2/Th17 skewed immune polarization, and B-cell activation, are suppressed in these mice. We further provide evidence that IRF5, activated by Toll-like receptor 4 (TLR4), binds to the promoters of various key genes involved in SSc disease pathology. These observations are congruent with the high level of expression of IRF5, TLR4, and potential endogenous TLR4 ligands in SSc skin lesions. Our study sheds light on the TLR4-IRF5 pathway in the pathology of SSc with clinical implications of targeting the IRF5 pathways in the suppression of disease development.

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“…A current hypothesis for SSc pathogenesis posits that unknown etiologic factors in a genetically receptive host [40–48] trigger microvascular injury characterized by structural and functional endothelial cell abnormalities [49–51]. These abnormalities result in the increased production and release of numerous and potent signaling molecules including cytokines, chemokines, polypeptide growth factors, and reactive oxygen species.…”

Section: Pathophysiologymentioning

confidence: 99%

Treatment of rapidly progressive systemic sclerosis: current and futures perspectives

Mendoza

Mansoor

Jimenez

2015

Expert Opinion on Orphan Drugs

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Introduction Systemic Sclerosis (SSc) is a systemic autoimmune disease characterized by severe and often progressive cutaneous, pulmonary, cardiac and gastrointestinal tract fibrosis, cellular and humoral immunologic alterations, and pronounced fibroproliferative vasculopathy. There is no effective SSc disease modifying therapy. Patients with rapidly progressive SSc have poor prognosis with frequent disability and very high mortality. Areas Covered This paper reviews currently available therapeutic approaches for rapidly progressive SSc and discuss novel drugs under study for SSc disease modification. Expert Opinion The extent, severity, and rate of progression of SSc skin and internal organ involvement determines the optimal therapeutic interventions for SSc. Cyclophosphamide for progressive SSc-associated interstitial lung disease and mycophenolate for rapidly progressive cutaneous involvement have shown effectiveness. Methotrexate has been used for less severe skin progression and for patients unable to tolerate mycophenolate. Rituximab was shown to induce improvement in SSc-cutaneous and lung involvement. Autologous bone marrow transplantation is reserved for selected cases in whom poor survival risk outweighs the high mortality rate of the procedure. Novel agents capable of modulating fibrotic and inflammatory pathways involved in SSc pathogenesis, including tocilizumab, pirfenidone, tyrosine kinase inhibitors, lipid lysophosphatidic acid 1, and NOX4 inhibitors are currently under development for the treatment of rapidly progressive SSc.

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Vasculopathy in scleroderma

Cited by 168 publications

References 118 publications

Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis

Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

Treatment of rapidly progressive systemic sclerosis: current and futures perspectives

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