Wang Shenglan, Zhong MingFeng, Deng Xiaoli, Liu Chen, Tan Yan, Qian Baojiang, Zhong MingMei
Pulmonary and Critical Care Medicine, The First People'S Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, 157 Jinbi Road, Xishan District, Kunming, 650032, Yunnan, China.
The First People'S Hospital of Zhaotong City, Zhaotong, 657099, Yunnan, China.
Cell Biol Toxicol. 2025 Apr 11;41(1):69. doi: 10.1007/s10565-025-10019-5.
Chronic obstructive pulmonary disease (COPD) ranks as the third most common contributor to global mortality. Oxidative stress has been recognized as a critical driver of multiple interacting mechanisms in COPD development. This research investigated the potential of oxidative stress-related genes (OSRGs) biomarkers and their potential molecular mechanisms for COPD clinical diagnosis and treatment through bioinformatics analyses. As a result, 5 hub genes, CA3, PPP1R15B, MAPT, MMP9, and ECT2, were yielded by LASSO, Boruta, and SVM-RFE, and the performance of the nomogram constructed based on hub genes was favorable. Correlation analyses between hub genes and oxidative stress biomarkers showed that MMP9 and MAPT genes had a high association with oxidative stress biomarkers. Immune cell infiltration identified follicular helper T cells, δ T cells, M0 macrophages, and CD8 T cells as significantly different in COPD. ROC of ECT2 and MMP9 showed a higher capability to discriminate COPD patients from normal samples. In addition, we collected clinical samples and analyzed the core gene expression, which revealed that the hub genes ECT2 and MMP9 had high discriminatory ability in the COPD samples. The epistasis of ECT2 and MMP9 was further verified by constructing animal models, pathological sections, qPCR, immunoblotting, immunohistochemistry, etc. The data indicated the crucial function of MMP9 in CSC-induced oxidative stress injury. Deprivation of MMP9 attenuated CSC-induced injury and promoted macrophage polarisation to M2 macrophages. MMP9 deprivation protected against CSC-induced injury, mainly related to the reduction of cell apoptosis, cell inflammation, and ROS injury in BEAS-2B. It promoted macrophage polarization from M1 to M2. In summary, we found ECT2 and MMP9 are related to oxidative stress in COPD, and MMP9 was related to cell apoptosis, cell inflammation, and ROS injury in BEAS-2B, and the macrophage polarization from M1 to M2.
慢性阻塞性肺疾病（COPD）是全球死亡率的第三大常见病因。氧化应激被认为是COPD发展过程中多种相互作用机制的关键驱动因素。本研究通过生物信息学分析，探讨了氧化应激相关基因（OSRGs）生物标志物在COPD临床诊断和治疗中的潜力及其潜在分子机制。结果，通过LASSO、Boruta和SVM-RFE方法得到了5个枢纽基因，即CA3、PPP1R15B、MAPT、MMP9和ECT2，基于这些枢纽基因构建的列线图表现良好。枢纽基因与氧化应激生物标志物的相关性分析表明，MMP9和MAPT基因与氧化应激生物标志物高度相关。免疫细胞浸润分析发现，滤泡辅助性T细胞、δT细胞、M0巨噬细胞和CD8 T细胞在COPD患者中存在显著差异。ECT2和MMP9的ROC曲线显示，它们在区分COPD患者和正常样本方面具有较高的能力。此外，我们收集了临床样本并分析了核心基因表达，结果显示枢纽基因ECT2和MMP9在COPD样本中具有较高的鉴别能力。通过构建动物模型、病理切片、qPCR、免疫印迹、免疫组化等方法进一步验证了ECT2和MMP9的上位性。数据表明MMP9在香烟烟雾提取物（CSC）诱导的氧化应激损伤中起关键作用。敲低MMP9可减轻CSC诱导的损伤，并促进巨噬细胞向M2巨噬细胞极化。MMP9缺失可保护细胞免受CSC诱导的损伤，这主要与BEAS-2B细胞凋亡、细胞炎症和活性氧损伤的减少有关。它促进巨噬细胞从M1向M2极化。综上所述，我们发现ECT2和MMP9与COPD中的氧化应激有关，MMP9与BEAS-2B细胞凋亡、细胞炎症和活性氧损伤以及巨噬细胞从M1向M2极化有关。
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