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DZ2002 ameliorates fibrosis, inflammation, and vasculopathy in experimental systemic sclerosis models

BACKGROUND: Systemic sclerosis is a multisystem inflammatory and vascular lesion leading to extensive tissue fibrosis. A reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, DZ2002, modulates the pathologic processes of various inflammatory diseases and autoimmune diseases. This study is...

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Autores principales: Zhang, Zongwang, Wu, Yanwei, Wu, Bing, Qi, Qing, Li, Heng, Lu, Huimin, Fan, Chen, Feng, Chunlan, Zuo, Jianping, Niu, Lili, Tang, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916442/
https://www.ncbi.nlm.nih.gov/pubmed/31842999
http://dx.doi.org/10.1186/s13075-019-2074-9
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author Zhang, Zongwang
Wu, Yanwei
Wu, Bing
Qi, Qing
Li, Heng
Lu, Huimin
Fan, Chen
Feng, Chunlan
Zuo, Jianping
Niu, Lili
Tang, Wei
author_facet Zhang, Zongwang
Wu, Yanwei
Wu, Bing
Qi, Qing
Li, Heng
Lu, Huimin
Fan, Chen
Feng, Chunlan
Zuo, Jianping
Niu, Lili
Tang, Wei
author_sort Zhang, Zongwang
collection PubMed
description BACKGROUND: Systemic sclerosis is a multisystem inflammatory and vascular lesion leading to extensive tissue fibrosis. A reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, DZ2002, modulates the pathologic processes of various inflammatory diseases and autoimmune diseases. This study is designed to investigate the therapeutic potentiality of DZ2002 for experimental systemic sclerosis models. METHODS: The anti-inflammatory and anti-fibrotic features of DZ2002 and its mechanisms were investigated in a bleomycin (BLM)-induced dermal fibrosis mice model. The effects of DZ2002 on expression of extracellular matrix components and TGF-β signaling in human dermal fibroblasts were analyzed. Simultaneously, the effects of DZ2002 on macrophage activation and endothelial cell adhesion molecule expression were also evaluated. RESULTS: DZ2002 significantly attenuated dermal fibrosis in BLM-induced mice. Consistently, DZ2002 inhibited the expression of various molecules associated with dermal fibrosis, including transforming growth factor β1, connective tissue growth factor, tumor necrosis factor-α, interferon-γ, IL-1β, IL-4, IL-6, IL-10, IL-12p40, IL-17A, and monocyte chemotactic protein 1 in the lesional skin of BLM-induced mice. Furthermore, DZ2002 decreased the proportion of macrophages, neutrophils, and T cells (especially T helper cells) in the skin tissue of BLM-induced mice. In addition, DZ2002 attenuated both M1 macrophage and M2 macrophage differentiation in vivo and in vitro. Importantly, DZ2002 directly reversed the profibrotic phenotype of transforming growth factor-β1-treated dermal fibroblasts and suppressed ICAM-1, VCAM-1, VEGF, bFGF, and ET-1 expression in endothelial cells. Finally, our investigations showed that DZ2002 relieved systemic sclerosis by regulating fibrosis TGF-β/Smad signaling pathway. CONCLUSIONS: DZ2002 prevents the development of experimental dermal fibrosis by reversing the profibrotic phenotype of various cell types and would be a potential drug for the treatment of systemic sclerosis.
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spelling pubmed-69164422019-12-20 DZ2002 ameliorates fibrosis, inflammation, and vasculopathy in experimental systemic sclerosis models Zhang, Zongwang Wu, Yanwei Wu, Bing Qi, Qing Li, Heng Lu, Huimin Fan, Chen Feng, Chunlan Zuo, Jianping Niu, Lili Tang, Wei Arthritis Res Ther Research Article BACKGROUND: Systemic sclerosis is a multisystem inflammatory and vascular lesion leading to extensive tissue fibrosis. A reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, DZ2002, modulates the pathologic processes of various inflammatory diseases and autoimmune diseases. This study is designed to investigate the therapeutic potentiality of DZ2002 for experimental systemic sclerosis models. METHODS: The anti-inflammatory and anti-fibrotic features of DZ2002 and its mechanisms were investigated in a bleomycin (BLM)-induced dermal fibrosis mice model. The effects of DZ2002 on expression of extracellular matrix components and TGF-β signaling in human dermal fibroblasts were analyzed. Simultaneously, the effects of DZ2002 on macrophage activation and endothelial cell adhesion molecule expression were also evaluated. RESULTS: DZ2002 significantly attenuated dermal fibrosis in BLM-induced mice. Consistently, DZ2002 inhibited the expression of various molecules associated with dermal fibrosis, including transforming growth factor β1, connective tissue growth factor, tumor necrosis factor-α, interferon-γ, IL-1β, IL-4, IL-6, IL-10, IL-12p40, IL-17A, and monocyte chemotactic protein 1 in the lesional skin of BLM-induced mice. Furthermore, DZ2002 decreased the proportion of macrophages, neutrophils, and T cells (especially T helper cells) in the skin tissue of BLM-induced mice. In addition, DZ2002 attenuated both M1 macrophage and M2 macrophage differentiation in vivo and in vitro. Importantly, DZ2002 directly reversed the profibrotic phenotype of transforming growth factor-β1-treated dermal fibroblasts and suppressed ICAM-1, VCAM-1, VEGF, bFGF, and ET-1 expression in endothelial cells. Finally, our investigations showed that DZ2002 relieved systemic sclerosis by regulating fibrosis TGF-β/Smad signaling pathway. CONCLUSIONS: DZ2002 prevents the development of experimental dermal fibrosis by reversing the profibrotic phenotype of various cell types and would be a potential drug for the treatment of systemic sclerosis. BioMed Central 2019-12-16 2019 /pmc/articles/PMC6916442/ /pubmed/31842999 http://dx.doi.org/10.1186/s13075-019-2074-9 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Zhang, Zongwang
Wu, Yanwei
Wu, Bing
Qi, Qing
Li, Heng
Lu, Huimin
Fan, Chen
Feng, Chunlan
Zuo, Jianping
Niu, Lili
Tang, Wei
DZ2002 ameliorates fibrosis, inflammation, and vasculopathy in experimental systemic sclerosis models
title DZ2002 ameliorates fibrosis, inflammation, and vasculopathy in experimental systemic sclerosis models
title_full DZ2002 ameliorates fibrosis, inflammation, and vasculopathy in experimental systemic sclerosis models
title_fullStr DZ2002 ameliorates fibrosis, inflammation, and vasculopathy in experimental systemic sclerosis models
title_full_unstemmed DZ2002 ameliorates fibrosis, inflammation, and vasculopathy in experimental systemic sclerosis models
title_short DZ2002 ameliorates fibrosis, inflammation, and vasculopathy in experimental systemic sclerosis models
title_sort dz2002 ameliorates fibrosis, inflammation, and vasculopathy in experimental systemic sclerosis models
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916442/
https://www.ncbi.nlm.nih.gov/pubmed/31842999
http://dx.doi.org/10.1186/s13075-019-2074-9
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