2. Academic Validation
  3. DZ2002 ameliorates fibrosis, inflammation, and vasculopathy in experimental systemic sclerosis models

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

  • Arthritis Res Ther. 2019 Dec 16;21(1):290. doi: 10.1186/s13075-019-2074-9.
Zongwang Zhang 1 2,  Yanwei Wu 2,  Bing Wu 2 3,  Qing Qi 2,  Heng Li 2 3,  Huimin Lu 2 3,  Chen Fan 2,  Chunlan Feng 2,  Jianping Zuo 4 5,  Lili Niu 6,  Wei Tang 7 8
Affiliations

Affiliations

  • 1 School of Life Sciences, Shanghai University, 333 Nanchen Road, Baoshan District, Shanghai, 200444, China.
  • 2 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 School of Pharmacy, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. jpzuo@simm.ac.cn.
  • 5 School of Pharmacy, University of Chinese Academy of Sciences, Beijing, 100049, China. jpzuo@simm.ac.cn.
  • 6 School of Life Sciences, Shanghai University, 333 Nanchen Road, Baoshan District, Shanghai, 200444, China. lilyniu@126.com.
  • 7 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. tangwei@simm.ac.cn.
  • 8 School of Pharmacy, University of Chinese Academy of Sciences, Beijing, 100049, China. tangwei@simm.ac.cn.
PMID: 31842999 DOI: 10.1186/s13075-019-2074-9
Abstract

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.

Keywords

Fibrosis; Inflammation; SAHH inhibitor; Systemic sclerosis; TGF-β; Vasculopathy.

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