琥珀酸盐受体介导Foxm1表达促进肺纤维化

Succinate receptor mediates Foxm1 expression to promote pulmonary fibrosis

摘要:

目的：探讨琥珀酸盐受体（succinate receptor，SUCNR1）在肺纤维化发生发展中的作用和机制。方法：用SUCNR1敲除（SUCNR1-/-）小鼠构建博来霉素诱导的肺纤维化模型，观察对肺纤维化的影响。组织生长因子β1（tissue growth factor β1，TGF-β1）刺激SUCNR1-/-原代肺成纤维细胞，MTT检测细胞增殖、Western blot检测细胞外基质（Collagen Ⅰ和α-SMA）生成。检测各组肺纤维化小鼠肺组织中叉头框蛋白M1（forkhead box protein M1，Foxm1）表达，使用Foxm1抑制剂处理TGF-β1和琥珀酸盐刺激的原代肺成纤维细胞，观察对细胞增殖和细胞外基质生成的影响。结果：SUCNR1-/-小鼠肺纤维化较SUCNR1wt明显减轻。刺激SUCNR1-/-原代肺成纤维细胞增殖能力、Collagen Ⅰ和α-SMA生成明显降低。Foxm1在博来霉素诱导的肺纤维化模型中明显升高，但在SUCNR1-/-模型中明显减少；抑制Foxm1可减少TGF-β1和琥珀酸盐诱导的肺成纤维细胞增殖、Collagen Ⅰ和α-SMA生成。结论：SUCNR1参与了肺纤维化的发生发展，其可能机制是通过促进Foxm1表达而启动肺成纤维细胞。

Abstract:

Objective：To investigate the role and mechanism of succinate receptor（SUCNR1） in the occurrence and development of pulmonary fibrogenesis. Methods：A bleomycin-induced lung fiber model was constructed using SUCNR1 knockout（SUCNR1-/-） mice to observe the effects on pulmonary fibrosis. Transforming growth factor β1（TGF-β1） stimulated SUCNR1-/- primary lung fibrob－lasts cell proliferation was detected by MTT，and extracellular matrix（Collagen Ⅰ and α-SMA） was detected by western blot. The expression of forkhead box protein M1（Foxm1） in the lung tissue of each group of pulmonary fibrosis mice was detected. TGF-β1 and succinate stimulated primary lung fibroblasts were treated with Foxm1 inhibitor，and the effects on cell proliferation and extra－cellular matrix formation were observed. Results：The pulmonary fibrosis of SUCNR1-/- mice were significantly less than SUCNR1wt. The cells proliferation，and Collagen Ⅰ and α-SMA production was significantly reduced in SUCNR1-/- primary lung fibroblasts. Foxm1 was significantly elevated in the bleomycin-induced pulmonary fibrosis model，but significantly reduced in the SUCNR1-/- model. Inhibition of Foxm1 reduces TGF-β1 and succinate-induced lung fibroblast proliferation，Collagen Ⅰ and α-SMA generation. Conclusion：SUCNR1 participates in the development of pulmonary fibrosis，and its possible mechanism may be to activate lung fi－broblasts by promoting Foxm1 expression.