Department of Cellular and Genetic Medicine, School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, China.
School of Nursing, Binzhou Medical University, Yantai 264003, China.
Aging (Albany NY). 2021 Apr 30;13(10):13807-13821. doi: 10.18632/aging.202975.
Pulmonary fibrosis is a common pulmonary interstitial disease of pathogenesis without effective drugs for treatment. Therefore, discovering new and effective drugs is urgently needed. In the present study, we prepared a novel compound named acetyl oxygen benzoate engeletin ester (AOBEE), investigated its effect on experimental pulmonary fibrosis, and proposed a long non-coding RNA (lncRNA)-mediated mechanism of its action. Bleomycin-induced pulmonary fibrosis in mice exhibited that AOBEE improved forced vital capacity (FVC) and alveolar structure and inhibited α-SMA, vimentin, and collagen expression. TGFβ1-stimulated fibroblast L929 cells showed that AOBEE reduced these fibrotic proteins expression and inhibited the activated-fibroblast proliferation and migration. Whole transcriptome sequencing was performed to screen out lncRNA-lnc865 and lnc556 with high expression under bleomycin treatment, but AOBEE caused a considerable decrease in lnc865 and lnc556. Mechanistic study elucidated that AOBEE alleviated pulmonary fibrosis through lnc865- and lnc556-mediated mechanism, in which both lnc865 and lnc556 sponged miR-29b-2-5p to target signal transducer and activator of transcription 3 (STAT3). Further signal pathway inhibitors and the Cignal Finder 45-pathway reporter array illustrated that the up- and downstream pathways were TGFβ1-smad2/3 and p38MAPK, and Krüppel-like factor 4 (KLF4), respectively. In conclusion, AOBEE promoted KLF4 degradation leading to the attenuation of pulmonary fibrosis by inhibiting TGFβ1-smad/p38MAPK-lnc865/lnc556-miR-29b-2-5p-STAT3 signal pathway. We hope this work will provide valuable information to design new drugs and therapeutic targets of lncRNAs for pulmonary fibrosis treatment.
肺纤维化是一种常见的肺间质疾病，发病机制尚不清楚，目前尚无有效的治疗药物。因此，迫切需要发现新的有效药物。本研究制备了一种新型化合物乙酰氧苯甲酸莪术二酮酯（AOBEE），研究其对实验性肺纤维化的作用，并提出了长链非编码 RNA（lncRNA）介导的作用机制。博来霉素诱导的小鼠肺纤维化表明，AOBEE 可改善用力肺活量（FVC）和肺泡结构，抑制α-SMA、波形蛋白和胶原蛋白的表达。TGFβ1 刺激的成纤维细胞 L929 细胞表明，AOBEE 降低了这些纤维化蛋白的表达，抑制了活化成纤维细胞的增殖和迁移。全转录组测序筛选出博来霉素处理后高表达的 lncRNA-lnc865 和 lnc556，但 AOBEE 使 lnc865 和 lnc556 显著下调。机制研究表明，AOBEE 通过 lnc865 和 lnc556 介导的机制减轻肺纤维化，lnc865 和 lnc556 均可海绵吸附 miR-29b-2-5p 靶向信号转导和转录激活因子 3（STAT3）。进一步的信号通路抑制剂和 Cignal Finder 45 通路报告基因阵列表明，上下游通路分别为 TGFβ1-smad2/3 和 p38MAPK，以及 Krüppel 样因子 4（KLF4）。综上所述，AOBEE 通过抑制 TGFβ1-smad/p38MAPK-lnc865/lnc556-miR-29b-2-5p-STAT3 信号通路，促进 KLF4 降解，从而减轻肺纤维化。我们希望这项工作将为设计新的药物和 lncRNA 治疗肺纤维化的治疗靶点提供有价值的信息。
