Department of Dermatology, Division of Medicine, Faculty of Medical Sciences, University of Fukui, 23-3, Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.
Department of Dermatology, Hanoi Medical University, Hanoi, Vietnam.
Arthritis Res Ther. 2022 Apr 29;24(1):94. doi: 10.1186/s13075-022-02773-2.
Systemic sclerosis (SSc) is a collagen disease that exhibits intractable fibrosis and vascular injury of the skin and internal organs. Transforming growth factor-β (TGF-β)/Smad signaling plays a central role in extracellular matrix (ECM) production by α-SMA-positive myofibroblasts. Myofibroblasts may be partially derived from various precursor cells in addition to resident fibroblasts. Recently, our high-throughput in vitro screening discovered a small compound, LG283, that may disrupt the differentiation of epithelial cells into myofibroblasts. This compound was originally generated as a curcumin derivative.
In this study, we investigated the effect of LG283 on inhibiting fibrosis and its mechanism. The action of LG283 on TGF-β-dependent fibrogenic activity and epithelial-mesenchymal transition (EMT) was analyzed in vitro. The effects of LG283 were also examined in a bleomycin-induced skin fibrosis mouse model.
LG283 suppressed TGF-β-induced expression of ECM, α-SMA, and transcription factors Snail 1 and 2, and Smad3 phosphorylation in cultured human dermal fibroblasts. LG283 was also found to block EMT induction in cultured human epithelial cells. During these processes, Smad3 phosphorylation and/or expression of Snail 1 and 2 were inhibited by LG283 treatment. In the bleomycin-induced skin fibrosis model, oral administration of LG283 efficiently protected against the development of fibrosis and decrease of capillary vessels without significantly affecting cell infiltration or cytokine concentrations in the skin. No apparent adverse effects of LG283 were found. LG283 treatment remarkably inhibited the enhanced expression of α-SMA and phosphorylated Smad3, as well as those of Snail 1 and 2, in the bleomycin-injected skin.
The LG283 compound exhibits antagonistic activity on fibrosis and vascular injury through inhibition of TGF-β/Smad/Snail mesenchymal transition pathways and thus, may be a candidate therapeutic for the treatment of SSc. Although the involvement of EMT in the pathogenesis of SSc remains unclear, the screening of EMT regulatory compounds may be an attractive approach for SSc therapy.
系统性硬化症（SSc）是一种胶原疾病，表现为皮肤和内脏器官的难治性纤维化和血管损伤。转化生长因子-β（TGF-β）/Smad 信号通路在α-SMA 阳性肌成纤维细胞产生细胞外基质（ECM）中起核心作用。肌成纤维细胞可能部分来源于除成纤维细胞以外的各种前体细胞。最近，我们的高通量体外筛选发现了一种小分子化合物 LG283，它可能破坏上皮细胞向肌成纤维细胞的分化。这种化合物最初是作为姜黄素衍生物产生的。
在这项研究中，我们研究了 LG283 抑制纤维化的作用及其机制。在体外分析了 LG283 对 TGF-β依赖性纤维生成活性和上皮-间充质转化（EMT）的作用。还在博来霉素诱导的皮肤纤维化小鼠模型中检查了 LG283 的作用。
LG283 抑制 TGF-β诱导的培养人真皮成纤维细胞 ECM、α-SMA 和转录因子 Snail 1 和 2 的表达，以及 Smad3 磷酸化。LG283 还被发现阻断培养的人上皮细胞 EMT 的诱导。在这些过程中，LG283 处理抑制了 Smad3 磷酸化和/或 Snail 1 和 2 的表达。在博来霉素诱导的皮肤纤维化模型中，口服 LG283 能有效防止纤维化的发展和毛细血管的减少，而对皮肤中的细胞浸润或细胞因子浓度没有明显影响。未发现 LG283 的明显不良反应。LG283 处理显著抑制了博来霉素注射皮肤中α-SMA 和磷酸化 Smad3 的增强表达，以及 Snail 1 和 2 的表达。
LG283 化合物通过抑制 TGF-β/Smad/Snail 间充质转化途径，表现出对纤维化和血管损伤的拮抗活性，因此可能是治疗 SSc 的候选治疗药物。虽然 EMT 在 SSc 的发病机制中的参与仍不清楚，但 EMT 调节化合物的筛选可能是 SSc 治疗的一种有吸引力的方法。
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