Department of Respiratory and Critical Care Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, China.
Gene. 2023 Aug 20;878:147582. doi: 10.1016/j.gene.2023.147582. Epub 2023 Jun 21.
Acute respiratory distress syndrome (ARDS) is a life-threatening condition with an unfavorable prognosis. As the pathogenesis of ARDS remains unclear, we aimed to identify the core genes associated with ARDS and the mechanisms by which competing endogenous RNAs (ceRNAs) regulate the disease's progression.
Three mRNA microarray datasets (GSE17355, GSE48787, and GSE130936), derived from the Gene Expression Omnibus (GEO) database, were selected. Common differentially expressed genes (DEGs) related to acute lung injury (ALI) were identified and subjected to enrichment analysis. Then, hub genes were figured out through the protein-protein interaction (PPI) network and functional analysis, and targeted miRNAs and lncRNAs were predicted. Finally, the ceRNA networks associated with ALI were constructed and validated experimentally.
A total of 155 upregulated and 93 downregulated DEGs were identified in the three datasets. The TNF signaling pathway and IL-17 signaling pathway were the most enriched pathways. Then, eleven DEGs enriched in the IL-17 signaling pathway were selected as the hub genes. Three miRNAs (mmu-mir-155-5p, mmu-mir-21a-5p, and mmu-mir-122-5p), which were located in the lung tissue and predicted to bind the hub genes at the same time, and two lncRNAs (Neat1 and Tug1), which have binding sites for the aforementioned miRNAs, were filtered. With qPCR verification, we identified a ceRNA network composed of NEAT1, miR-21-5p, MMP9, and CXCL5. NEAT1 knockdown promoted the migration and reduced the expression of pro-inflammatory factor and reactive oxygen species (ROS) in lung epithelial cells. We eventually confirmed that NEAT1/miR-21-5p/CXCL5/MMP9 played a pivotal role in regulating the inflammatory response in ALI.
The IL-17 signaling pathway is of great importance in the pathogenesis of ARDS. NEAT1/miR-21-5p is involved in the inflammation of ALI by regulating CXCL5 and MMP9.
急性呼吸窘迫综合征（ARDS）是一种危及生命的疾病，预后不佳。由于 ARDS 的发病机制尚不清楚，我们旨在确定与 ARDS 相关的核心基因，并研究竞争内源性 RNA（ceRNA）调节疾病进展的机制。
从基因表达综合数据库（GEO）中选择了三个 mRNA 微阵列数据集（GSE17355、GSE48787 和 GSE130936）。鉴定出与急性肺损伤（ALI）相关的常见差异表达基因（DEG），并进行富集分析。然后，通过蛋白质-蛋白质相互作用（PPI）网络和功能分析找出枢纽基因，并预测靶向 miRNAs 和 lncRNAs。最后，构建并实验验证与 ALI 相关的 ceRNA 网络。
在三个数据集中共鉴定出 155 个上调和 93 个下调的 DEG。TNF 信号通路和 IL-17 信号通路是最富集的通路。然后，选择 11 个在 IL-17 信号通路中富集的 DEG 作为枢纽基因。三个位于肺组织中且同时预测与枢纽基因结合的 miRNAs（mmu-mir-155-5p、mmu-mir-21a-5p 和 mmu-mir-122-5p），以及两个具有上述 miRNAs 结合位点的 lncRNAs（Neat1 和 Tug1）被筛选出来。通过 qPCR 验证，我们鉴定出一个由 NEAT1、miR-21-5p、MMP9 和 CXCL5 组成的 ceRNA 网络。NEAT1 敲低促进了肺上皮细胞的迁移，并降低了促炎因子和活性氧（ROS）的表达。我们最终证实，NEAT1/miR-21-5p/CXCL5/MMP9 在调节 ALI 的炎症反应中起着关键作用。
IL-17 信号通路在 ARDS 的发病机制中非常重要。NEAT1/miR-21-5p 通过调节 CXCL5 和 MMP9 参与 ALI 的炎症反应。
