Upregulated microRNA-125b-5p in patients with asthma-COPD overlap mediates oxidative stress and late apoptosis via targeting IL6R/TRIAP1 signaling

IF 4.7 2区医学 Q1 RESPIRATORY SYSTEM

Respiratory Research Pub Date : 2024-02-01 DOI:10.1186/s12931-024-02703-7

Yu-Ping Chang, Yi-Hsuan Tsai, Yu-Mu Chen, Kuo-Tung Huang, Chiu-Ping Lee, Po-Yuan Hsu, Hung-Chen Chen, Meng-Chih Lin, Yung-Che Chen

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Abstract

Among patients with chronic obstructive pulmonary disease (COPD), some have features of both asthma and COPD—a condition categorized as asthma-COPD overlap (ACO). Our aim was to determine whether asthma- or COPD-related microRNAs (miRNAs) play a role in the pathogenesis of ACO. A total of 22 healthy subjects and 27 patients with ACO were enrolled. We selected 6 miRNAs that were found to correlate with COPD and asthma. The expression of miRNAs and target genes was analyzed using quantitative reverse-transcriptase polymerase chain reaction. Cell apoptosis and intracellular reactive oxygen species production were evaluated using flow cytometry. In vitro human monocytic THP-1 cells and primary normal human bronchial epithelial (NHBE) cells under stimuli with cigarette smoke extract (CSE) or ovalbumin (OVA) allergen or both were used to verify the clinical findings. We identified the upregulation of miR-125b-5p in patients with ACO and in THP-1 cells stimulated with CSE plus OVA allergen. We selected 16 genes related to the miR-125b-5p pathway and found that IL6R and TRIAP1 were both downregulated in patients with ACO and in THP-1 cells stimulated with CSE plus OVA. The percentage of late apoptotic cells increased in the THP-1 cell culture model when stimulated with CSE plus OVA, and the effect was reversed by transfection with miR-125b-5p small interfering RNA (siRNA). The percentage of reactive oxygen species-producing cells increased in the NHBE cell culture model when stimulated with CSE plus OVA, and the effect was reversed by transfection with miR-125b-5p siRNA. In NHBE cells, siRNA transfection reversed the upregulation of STAT3 under CSE+OVA stimulation. Our study revealed that upregulation of miR-125b-5p in patients with ACO mediated late apoptosis in THP-1 cells and oxidative stress in NHBE cells via targeting IL6R and TRIAP1. STAT3 expression was also regulated by miR-125b-5p.

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哮喘-慢性阻塞性肺病重叠患者体内上调的 microRNA-125b-5p 通过靶向 IL6R/TRIAP1 信号介导氧化应激和晚期细胞凋亡

在慢性阻塞性肺病（COPD）患者中，有些同时具有哮喘和慢性阻塞性肺病的特征--这种情况被归类为哮喘-慢性阻塞性肺病重叠（ACO）。我们的目的是确定哮喘或慢性阻塞性肺病相关的微 RNA（miRNA）是否在 ACO 的发病机制中发挥作用。我们共招募了 22 名健康受试者和 27 名 ACO 患者。我们选择了 6 个与慢性阻塞性肺病和哮喘相关的 miRNA。我们使用反转录聚合酶链式反应定量分析了 miRNAs 和靶基因的表达。使用流式细胞术评估了细胞凋亡和细胞内活性氧的产生。体外人单核细胞THP-1细胞和原代正常人支气管上皮细胞（NHBE）在香烟烟雾提取物（CSE）或卵清蛋白（OVA）过敏原或两者的刺激下，被用来验证临床研究结果。我们发现，在 ACO 患者中，以及在用 CSE 和 OVA 过敏原刺激的 THP-1 细胞中，miR-125b-5p 上调。我们选取了与 miR-125b-5p 通路相关的 16 个基因，发现在 ACO 患者和受到 CSE 加 OVA 刺激的 THP-1 细胞中，IL6R 和 TRIAP1 均出现下调。在 THP-1 细胞培养模型中，当 CSE 加 OVA 刺激时，晚期凋亡细胞的比例增加，转染 miR-125b-5p 小干扰 RNA（siRNA）可逆转这种效应。在 NHBE 细胞培养模型中，当 CSE 加 OVA 刺激时，产生活性氧的细胞比例增加，转染 miR-125b-5p siRNA 后可逆转这种效应。在 NHBE 细胞中，转染 siRNA 逆转了 STAT3 在 CSE+OVA 刺激下的上调。我们的研究表明，ACO 患者体内 miR-125b-5p 的上调通过靶向 IL6R 和 TRIAP1 介导了 THP-1 细胞的晚期凋亡和 NHBE 细胞的氧化应激。STAT3 的表达也受到 miR-125b-5p 的调控。

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来源期刊

Respiratory Research 医学-呼吸系统

自引率

1.70%

发文量

314

期刊介绍： Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.