哮喘COPD重叠患者上调的微小RNA-125b-5p通过靶向IL6R/TRIAP1信号介导氧化应激和晚期细胞凋亡
2024/02/23
摘要
背景：在慢性阻塞性肺疾病（COPD）患者中，某些患者同时具有支气管哮喘和慢性阻塞性肺疾病的特征，这种情况被归类为哮喘-慢性阻塞性肺疾病重叠（ACO）。
目的：本研究旨在明确哮喘或COPD相关miRNA是否在ACO的发病机制中发挥作用。
方法：本研究共纳入22名健康受试者及27名ACO患者，并选择6种已发现与COPD和哮喘相关微小RNA（miRNA）。本研究采用定量逆转录聚合酶链式反应分析miRNA和靶基因表达水平，采用流式细胞术评估细胞凋亡和细胞内活性氧产生情况。通过香烟烟雾提取物（CSE）或卵清蛋白（OVA）过敏原或两者同时刺激体外人单核细胞THP-1细胞和原代正常人支气管上皮（NHBE）细胞来验证临床现象。
结果：本研究发现miR-125b-5p在ACO患者和CSE+OVA过敏原共同刺激THP-1细胞中上调。本研究共选择了16个与miR-125b-5p通路相关基因，并发现IL6R和TRIAP1在ACO患者和CSE+OVA共同刺激THP-1细胞中均下调。CSE和OVA刺激后，THP-1细胞模型中晚期凋亡细胞的百分比增加，且通过用miR-125b-5p小干扰RNA（siRNA）转染逆转上述作用。CSE和OVA刺激后，NHBE细胞模型中产生活性氧细胞的百分比增加，且miR-125b-5p siRNA转染可逆转上述作用。siRNA转染可逆转CSE+OVA共同刺激所致NHBE细胞中STAT3上调。
结论：本研究表明，ACO患者体内miR-125b-5p上调可靶向作用于IL6R和TRIAP1，进而介导THP-1细胞晚期凋亡和NHBE细胞氧化应激，同时STAT3表达也受miR-125b-5p调控。
Upregulated microRNA-125b-5p in patients with asthma-COPD overlap mediates oxidative stress and late apoptosis via targeting IL6R/TRIAP1 signaling.
Chang YP, Tsai YH, Chen YM, Huang KT, Lee CP, Hsu PY, Chen HC, Lin MC, Chen YC.
Abstract
BACKGROUND:Among patients with chronic obstructive pulmonary disease (COPD), some have features of both asthma and COPD-a condition categorized as asthma-COPD overlap (ACO).
OBJECTIVE:Our aim was to determine whether asthma- or COPD-related microRNAs (miRNAs) play a role in the pathogenesis of ACO.
METHODS: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.
RESULTS: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.
CONCLUSION: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.
背景：在慢性阻塞性肺疾病（COPD）患者中，某些患者同时具有支气管哮喘和慢性阻塞性肺疾病的特征，这种情况被归类为哮喘-慢性阻塞性肺疾病重叠（ACO）。
目的：本研究旨在明确哮喘或COPD相关miRNA是否在ACO的发病机制中发挥作用。
方法：本研究共纳入22名健康受试者及27名ACO患者，并选择6种已发现与COPD和哮喘相关微小RNA（miRNA）。本研究采用定量逆转录聚合酶链式反应分析miRNA和靶基因表达水平，采用流式细胞术评估细胞凋亡和细胞内活性氧产生情况。通过香烟烟雾提取物（CSE）或卵清蛋白（OVA）过敏原或两者同时刺激体外人单核细胞THP-1细胞和原代正常人支气管上皮（NHBE）细胞来验证临床现象。
结果：本研究发现miR-125b-5p在ACO患者和CSE+OVA过敏原共同刺激THP-1细胞中上调。本研究共选择了16个与miR-125b-5p通路相关基因，并发现IL6R和TRIAP1在ACO患者和CSE+OVA共同刺激THP-1细胞中均下调。CSE和OVA刺激后，THP-1细胞模型中晚期凋亡细胞的百分比增加，且通过用miR-125b-5p小干扰RNA（siRNA）转染逆转上述作用。CSE和OVA刺激后，NHBE细胞模型中产生活性氧细胞的百分比增加，且miR-125b-5p siRNA转染可逆转上述作用。siRNA转染可逆转CSE+OVA共同刺激所致NHBE细胞中STAT3上调。
结论：本研究表明，ACO患者体内miR-125b-5p上调可靶向作用于IL6R和TRIAP1，进而介导THP-1细胞晚期凋亡和NHBE细胞氧化应激，同时STAT3表达也受miR-125b-5p调控。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Respir Res. 2024 Feb 1;25(1):64. doi: 10.1186/s12931-024-02703-7.)
(Respir Res. 2024 Feb 1;25(1):64. doi: 10.1186/s12931-024-02703-7.)
Upregulated microRNA-125b-5p in patients with asthma-COPD overlap mediates oxidative stress and late apoptosis via targeting IL6R/TRIAP1 signaling.
Chang YP, Tsai YH, Chen YM, Huang KT, Lee CP, Hsu PY, Chen HC, Lin MC, Chen YC.
Abstract
BACKGROUND:Among patients with chronic obstructive pulmonary disease (COPD), some have features of both asthma and COPD-a condition categorized as asthma-COPD overlap (ACO).
OBJECTIVE:Our aim was to determine whether asthma- or COPD-related microRNAs (miRNAs) play a role in the pathogenesis of ACO.
METHODS: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.
RESULTS: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.
CONCLUSION: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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哮喘患者气道上皮细胞对RSV的反应主要受损于杯状细胞和多纤毛细胞
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