Li Kaili, Huang Zuotian, Liu Chang, Xu Yuanyuan, Chen Wei, Shi Lu, Li Can, Zhou Fawei, Zhou Fachun
Department of Emergency, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China.
Department of Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, 400030 Chongqing Municipality, China.
Cell Signal. 2023 Nov;111:110870. doi: 10.1016/j.cellsig.2023.110870. Epub 2023 Aug 25.
Acute respiratory distress syndrome (ARDS) has a rapid onset and progression, which lead to the severity and complexity of the primary disease and significantly increase the fatality rate of patients. Transcriptomics provides some ideas for clarifying the mechanism of ARDS, exploring prevention and treatment targets, and searching for related specific markers. In this study, RNA-Seq technology was used to observe the gene expression of human pulmonary microvascular endothelial cells (PMVECs) induced by LPS, and to excavate the key genes and signaling pathways in ARDS process. A total of 2300 up-regulated genes were detected, and a corresponding 1696 down-regulated genes were screened. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and protein-protein interaction (PPI) were also used for functional annotation of key genes. TFDP1 was identified as a cell cycle-dependent differentially expressed gene, and its reduced expression was verified in LPS-treated PMVECs and lung tissues of CLP-induced mice. In addition, the inhibition of TFDP1 on inflammation and apoptosis, and the promotion of proliferation were confirmed. The decreased expression of E2F1, Rb, CDK1 and the activation of MAPK signaling pathway were substantiated in the in vivo and in vitro models of ARDS. Moreover, SREBF1 has been demonstrated to be involved in cell cycle arrest in PMVECs by inhibiting CDK1. Our study shows that transcriptomics combined with basic research can broaden the investigation of ARDS mechanisms and may provide a basis for future mechanistic innovations.
急性呼吸窘迫综合征（ARDS）起病急且进展迅速，这导致了原发疾病的严重性和复杂性，并显著增加了患者的死亡率。转录组学为阐明ARDS的发病机制、探索防治靶点以及寻找相关特异性标志物提供了一些思路。在本研究中，运用RNA测序技术观察脂多糖诱导的人肺微血管内皮细胞（PMVECs）的基因表达情况，并挖掘ARDS过程中的关键基因和信号通路。共检测到2300个上调基因，并筛选出相应的1696个下调基因。还利用基因本体论（GO）、京都基因与基因组百科全书（KEGG）分析以及蛋白质-蛋白质相互作用（PPI）对关键基因进行功能注释。TFDP1被鉴定为细胞周期依赖性差异表达基因，其表达下调在脂多糖处理的PMVECs以及盲肠结扎穿孔（CLP）诱导的小鼠肺组织中得到验证。此外，证实了TFDP1对炎症和凋亡的抑制作用以及对增殖的促进作用。在ARDS的体内和体外模型中证实了E2F1、Rb、CDK1的表达降低以及丝裂原活化蛋白激酶（MAPK）信号通路的激活。此外，已证明固醇调节元件结合转录因子1（SREBF1）通过抑制CDK1参与PMVECs的细胞周期阻滞。我们的研究表明，转录组学与基础研究相结合可以拓宽对ARDS机制的研究范围，并可能为未来的机制创新提供依据。
