Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an 710061, China.
Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, Binzhou Medical University, Binzhou 256603, China.
Molecules. 2022 Aug 22;27(16):5336. doi: 10.3390/molecules27165336.
Pulmonary fibrosis is characterized by the destruction of alveolar architecture and the irreversible scarring of lung parenchyma, with few therapeutic options and effective therapeutic drugs. Here, we demonstrate the anti-pulmonary fibrosis of 3-(4-methoxyphenyl)-4-oxo-4-1-benzopyran-7-yl(αS)-α,3,4-trihydroxybenzenepropanoate (MOBT) in mice and a cell model induced by bleomycin and transforming growth factor-β1. The anti-pulmonary fibrosis of MOBT was evaluated using a MicroCT imaging system for small animals, lung function analysis and H&E and Masson staining. The results of RNA fluorescence in situ hybridization, chromatin immunoprecipitation (ChIP)-PCR, RNA immunoprecipitation, ChIP-seq, RNA-seq, and half-life experiments demonstrated the anti-pulmonary fibrotic mechanism. Mechanistic dissection showed that MOBT inhibited lncITPF transcription by preventing p-Smad2/3 translocation from the cytoplasm to the nucleus, resulting in a reduction in the amount of the lncITPF-hnRNP L complex. The decreased lncITPF-hnRNP L complex reduced MEF2c expression by blocking its alternative splicing, which in turn inhibited the expression of MEF2c target genes, such as TAGLN2 and FMN1. Briefly, MOBT alleviated pulmonary fibrosis through the lncITPF-hnRNP-l-complex-targeted MEF2c signaling pathway. We hope that this study will provide not only a new drug candidate but also a novel therapeutic drug target, which will bring new treatment strategies for pulmonary fibrosis.
肺纤维化的特征是肺泡结构破坏和肺实质的不可逆转瘢痕形成，治疗选择和有效治疗药物很少。在这里，我们在博莱霉素和转化生长因子-β1诱导的小鼠和细胞模型中证明了 3-(4-甲氧基苯基)-4-氧代-4-1-苯并吡喃-7-基（αS）-α，3，4-三羟基苯丙酸酯（MOBT）的抗肺纤维化作用。使用小动物 MicroCT 成像系统、肺功能分析以及 H&E 和 Masson 染色评估 MOBT 的抗肺纤维化作用。RNA 荧光原位杂交、染色质免疫沉淀（ChIP）-PCR、RNA 免疫沉淀、ChIP-seq、RNA-seq 和半衰期实验的结果表明了其抗肺纤维化机制。机制分析表明，MOBT 通过阻止 p-Smad2/3 从细胞质易位到细胞核，从而抑制 lncITPF-hnRNP L 复合物的形成，从而抑制 lncITPF 的转录。减少的 lncITPF-hnRNP L 复合物通过阻断其选择性剪接减少 MEF2c 的表达，从而抑制 MEF2c 靶基因如 TAGLN2 和 FMN1 的表达。简而言之，MOBT 通过 lncITPF-hnRNP-l 复合物靶向 MEF2c 信号通路缓解肺纤维化。我们希望这项研究不仅提供一种新的药物候选物，而且提供一种新的治疗药物靶点，为肺纤维化带来新的治疗策略。
