Unidad de Investigación, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas. Calzada de Tlalpan 4502, Colonia Sección XVI, 14080 Mexico City, Mexico.
Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica, Periférico Sur 4809, Arenal Tepepan, Tlalpan, 14610 Mexico City, Mexico.
Cells. 2020 Jun 26;9(6):1556. doi: 10.3390/cells9061556.
Interstitial lung abnormalities (ILA) are observed in around 9% of older respiratory asymptomatic subjects, mainly smokers. Evidence suggests that ILA may precede the development of interstitial lung diseases and may evolve to progressive fibrosis. Identifying biomarkers of this subclinical status is relevant for early diagnosis and to predict outcome. We aimed to identify circulating microRNAs (miRNAs) associated to ILA in a cohort of respiratory asymptomatic subjects older than 60 years. We identified 81 subjects with ILA from our Lung-Aging Program in Mexico City ( = 826). We randomly selected 112 subjects without ILA (Ctrl) from the same cohort. Using polymerase chain reaction PCR-Array technology (24 ILA and 24 Ctrl, screening cohort) and reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) (57 ILA and 88 Ctr, independent validation cohort) we identified seven up-regulated miRNAs in serum of ILA compared to Ctrl (miR-193a-5p, < 0.0001; miR-502-3p, < 0.0001; miR-200c-3p, = 0.003; miR-16-5p, = 0.003; miR-21-5p, = 0.002; miR-126-3p, = 0.004 and miR-34a-5p, < 0.005). Pathways regulated by these miRNAs include transforming growth factor beta (TGF-β), Wnt, mammalian target of rapamycin (mTOR), Insulin, mitogen-activated protein kinase (MAPK) signaling, and senescence. Receiver operator characteristic (ROC) curve analysis indicated that miR-193a-5p (area under the curve AUC: 0.75) and miR-502-3p (AUC 0.71) have acceptable diagnostic value. This is the first identification of circulating miRNAs associated to ILA in respiratory asymptomatic subjects, providing potential non-invasive biomarkers and molecular targets to better understand the pathogenic mechanisms associated to ILA.
间质性肺异常 (ILA) 在约 9%的无呼吸系统症状的老年人群中被观察到，主要为吸烟者。有证据表明，ILA 可能先于间质性肺疾病的发生，并可能进展为进行性纤维化。识别这种亚临床状态的生物标志物对于早期诊断和预测结局至关重要。我们旨在确定墨西哥城呼吸无症状老年人队列中与 ILA 相关的循环 microRNAs (miRNAs)。我们从我们的肺老化计划中确定了 81 名 ILA 患者（n = 826）。我们从同一队列中随机选择了 112 名无 ILA 患者（Ctrl）。使用聚合酶链反应聚合酶链反应 (PCR-Array) 技术（筛查队列中的 24 名 ILA 和 24 名 Ctrl）和逆转录定量聚合酶链反应 (RT-qPCR)（独立验证队列中的 57 名 ILA 和 88 名 Ctrl），我们确定了与 Ctrl 相比，血清中 7 种上调的 miRNAs 在 ILA 中上调（miR-193a-5p， < 0.0001；miR-502-3p， < 0.0001；miR-200c-3p， = 0.003；miR-16-5p， = 0.003；miR-21-5p， = 0.002；miR-126-3p， = 0.004 和 miR-34a-5p， < 0.005）。这些 miRNA 调节的途径包括转化生长因子-β（TGF-β）、Wnt、雷帕霉素靶蛋白（mTOR）、胰岛素、丝裂原激活蛋白激酶（MAPK）信号转导和衰老。受试者工作特征 (ROC) 曲线分析表明，miR-193a-5p（曲线下面积 AUC：0.75）和 miR-502-3p（AUC 0.71）具有可接受的诊断价值。这是首次确定与呼吸无症状患者的 ILA 相关的循环 miRNAs，为更好地理解与 ILA 相关的发病机制提供了潜在的非侵入性生物标志物和分子靶点。
