RNA 测序检测到的脂联素 2 调节 COPD 中的细胞凋亡和铁死亡。
Increased Lipocalin 2 detected by RNA sequencing regulates apoptosis and ferroptosis in COPD.
机构信息
Department of Pulmonary and Critical Care Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences,Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030032, China.
Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
出版信息
BMC Pulm Med. 2024 Oct 26;24(1):535. doi: 10.1186/s12890-024-03357-3.
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a complex respiratory condition influenced by environmental and genetic factors. Using next-generation sequencing, we aimed to identify dysregulated genes and potential therapeutic targets for COPD.
METHODS
Peripheral blood leukocyte RNA profiles from COPD patients and healthy controls were analyzed using next-generation sequencing. Key genes involved in COPD pathogenesis were identified through protein-protein interaction network analysis. In vitro, bronchial epithelial cells treated with cigarette smoke extract (CSE) were used to study the effects on gene expression, cell viability, apoptosis, and ferroptosis. Additionally, Lipocalin 2 (LCN2) inhibition experiments were conducted to elucidate its role in COPD-related cellular processes.
RESULTS
Analysis of RNA profiles revealed consistent downregulation of 17 genes and upregulation of 21 genes across all COPD groups. Among these, Cathelicidin Antimicrobial Peptide(CAMP), Defensin Alpha 4(DEFA4), Neutrophil Elastase(ELANE), LCN2 and Lactotransferrin(LTF) were identified as potentially important players in COPD pathogenesis. Particularly, LCN2 exhibited a close association with COPD and was found to be involved in cellular processes. In vitro experiments demonstrated that CSE treatment significantly increased LCN2 expression in bronchial epithelial cells in a concentration-dependent manner. Moreover, CSE-induced apoptosis and ferroptosis were observed, along with alterations in cell viability, Glutathione content, Fe2 + accumulation, ROS: Reactive Oxygen Species and Malondialdehyde levels, Lactate Dehydrogenase(LDH) release and Glutathione Peroxidase 4(GPX4) expression. Inhibition of LCN2 expression partially reversed these effects, indicating the pivotal role of LCN2 in COPD-related cellular processes.
CONCLUSION
Our study identified six candidate genes: CAMP, DEFA4, ELANE, LCN2, and LTF were upregulated, HSPA1B was downregulated. Notably, LCN2 emerges as a significant biomarker in COPD pathogenesis, exerting its effects by promoting apoptosis and ferroptosis in bronchial epithelial cells.
背景
慢性阻塞性肺疾病（COPD）是一种受环境和遗传因素影响的复杂呼吸系统疾病。本研究采用下一代测序技术，旨在鉴定 COPD 的失调基因和潜在治疗靶点。
方法
采用下一代测序技术分析 COPD 患者和健康对照者的外周血白细胞 RNA 谱。通过蛋白质-蛋白质相互作用网络分析鉴定参与 COPD 发病机制的关键基因。在体外，用香烟烟雾提取物（CSE）处理支气管上皮细胞，研究其对基因表达、细胞活力、细胞凋亡和铁死亡的影响。此外，进行脂钙蛋白 2（LCN2）抑制实验以阐明其在 COPD 相关细胞过程中的作用。
结果
RNA 谱分析显示，所有 COPD 组均存在 17 个基因下调和 21 个基因上调。其中，Cathelicidin Antimicrobial Peptide（CAMP）、Defensin Alpha 4（DEFA4）、Neutrophil Elastase（ELANE）、LCN2 和 Lactotransferrin（LTF）被鉴定为 COPD 发病机制中的潜在重要参与者。特别是 LCN2 与 COPD 密切相关，并且参与细胞过程。体外实验表明，CSE 处理以浓度依赖性方式显著增加支气管上皮细胞中的 LCN2 表达。此外，观察到 CSE 诱导的细胞凋亡和铁死亡，以及细胞活力、谷胱甘肽含量、Fe2+积累、活性氧（ROS）和丙二醛水平、乳酸脱氢酶（LDH）释放和谷胱甘肽过氧化物酶 4（GPX4）表达的改变。LCN2 表达抑制部分逆转了这些效应，表明 LCN2 在 COPD 相关细胞过程中具有关键作用。
结论
本研究鉴定了 6 个候选基因：CAMP、DEFA4、ELANE、LCN2 和 LTF 上调，HSPA1B 下调。值得注意的是，LCN2 作为 COPD 发病机制中的重要生物标志物，通过促进支气管上皮细胞的细胞凋亡和铁死亡发挥作用。
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