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. 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. 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. 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.

中文翻译：

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DZ2002改善了实验性系统性硬化症模型中的纤维化，炎症和血管病变

系统性硬化症是导致广泛组织纤维化的多系统炎症和血管病变。DZ2002是一种可逆的S-腺苷-1-高半胱氨酸水解酶（SAHH）抑制剂，可调节各种炎症性疾病和自身免疫性疾病的病理过程。这项研究旨在调查DZ2002在实验性系统性硬化症模型中的治疗潜力。在博来霉素（BLM）诱导的皮肤纤维化小鼠模型中研究了DZ2002的抗炎和抗纤维化特性及其机制。分析了DZ2002对人皮肤成纤维细胞中细胞外基质成分表达和TGF-β信号转导的影响。同时，还评估了DZ2002对巨噬细胞活化和内皮细胞粘附分子表达的影响。DZ2002显着减轻了BLM诱导的小鼠的真皮纤维化。一致地，DZ2002抑制与皮肤纤维化相关的各种分子的表达，包括转化生长因子β1，结缔组织生长因子，肿瘤坏死因子-α，干扰素-γ，IL-1β，IL-4，IL-6，IL-10 ，IL-12p40，IL-17A和BLM诱导的小鼠病变皮肤中的单核细胞趋化蛋白1。此外，DZ2002降低了BLM诱导的小鼠皮肤组织中巨噬细胞，嗜中性粒细胞和T细胞（尤其是T辅助细胞）的比例。此外，DZ2002在体内和体外均减弱了M1巨噬细胞和M2巨噬细胞的分化。重要的是，DZ2002直接逆转了转化生长因子-β1处理的真皮成纤维细胞的纤维化表型，并抑制了ICAM-1，VCAM-1，VEGF，bFGF，和ET-1在内皮细胞中的表达。最后，我们的研究表明DZ2002通过调节纤维化TGF-β/ Smad信号传导途径缓解了系统性硬化症。DZ2002通过逆转各种细胞类型的纤维化表型来防止实验性皮肤纤维化的发展，它将成为治疗全身性硬化症的潜在药物。