College of Pharmaceutical Sciences, Soochow University, 199 Renai Road, Suzhou 215123, China.
College of Pharmaceutical Sciences, Soochow University, 199 Renai Road, Suzhou 215123, China.
Toxicol Appl Pharmacol. 2020 Mar 15;391:114916. doi: 10.1016/j.taap.2020.114916. Epub 2020 Feb 7.
Fibroblast-to-myofibroblast differentiation is one of the most important characteristics of pulmonary fibrosis, and screening natural compounds targeting fibroblast differentiation is always a promising approach to discover drug candidates for treatment of pulmonary fibrosis. Trehalose reportedly has many potential medical applications, especially in treating neurodegeneration diseases. However, it remains unclear whether trehalose suppresses lung fibroblast differentiation. In this work, we found that trehalose decreased the expression levels of α-smooth muscle actin (α-SMA) following the induction of transforming growth factor β1 (TGF-β1) in pretreatment, co-treatment, and post-treatment groups. Trehalose also reduced the production of type I collagen, lung fibroblast-containing gel contractility and cell filament formation in TGF-β1-stimulated MRC-5 cells. Although trehalose is a known autophagy inducer, our results showed that its suppressive effect on fibroblast differentiation was not via trehalose-induced autophagy. And it did not affect canonical TGFβ/Smad2/3 pathway. By applying proteomic profiling technology, we demonstrated that the downregulation of β-catenin was involved in the trehalose-repressive action on fibroblast differentiation. The β-catenin agonist, SKL2001, reversed the suppressive effect of trehalose on fibroblast differentiation. Overall, these experiments demonstrated that trehalose suppressed fibroblast differentiation via the downregulation of β-catenin, but not through canonical autophagy and TGFβ/Smad2/3 pathway, which is not only a novel understanding of trehalose, but also quite helpful for in vivo research of trehalose on pulmonary fibrosis in future.
成纤维细胞向肌成纤维细胞分化是肺纤维化的最重要特征之一，筛选针对成纤维细胞分化的天然化合物一直是发现治疗肺纤维化药物候选物的有前途的方法。海藻糖据称具有许多潜在的医学应用，尤其是在治疗神经退行性疾病方面。然而，海藻糖是否抑制肺成纤维细胞分化仍不清楚。在这项工作中，我们发现海藻糖在预处理、共处理和后处理组中，在转化生长因子β1（TGF-β1）诱导后降低了α-平滑肌肌动蛋白（α-SMA）的表达水平。海藻糖还降低了 TGF-β1 刺激的 MRC-5 细胞中 I 型胶原、含肺成纤维细胞的凝胶收缩性和细胞丝形成的产生。尽管海藻糖是一种已知的自噬诱导剂，但我们的结果表明，其对成纤维细胞分化的抑制作用不是通过海藻糖诱导的自噬。并且它不影响经典的 TGFβ/Smad2/3 途径。通过应用蛋白质组学分析技术，我们证明了β-连环蛋白的下调参与了海藻糖对成纤维细胞分化的抑制作用。β-连环蛋白激动剂 SKL2001 逆转了海藻糖对成纤维细胞分化的抑制作用。总体而言，这些实验表明，海藻糖通过下调β-连环蛋白抑制成纤维细胞分化，而不是通过经典的自噬和 TGFβ/Smad2/3 途径，这不仅是对海藻糖的新认识，而且对未来海藻糖在肺纤维化的体内研究也很有帮助。
