Abstract
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 (n = 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, p < 0.0001; miR-502-3p, p < 0.0001; miR-200c-3p, p = 0.003; miR-16-5p, p = 0.003; miR-21-5p, p = 0.002; miR-126-3p, p = 0.004 and miR-34a-5p, p < 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.
Highlights
Interstitial lung abnormalities (ILA) are defined as specific patterns of increased lung densities identified on high-resolution computed tomography (HRCT) scans, usually in subjects without previous diagnosis of pulmonary disease
We identified 81 subjects from this cohort that presented interstitial lung abnormalities (ILA) defined as asymptomatic respiratory individuals that showed by high resolution computed tomography (HRCT) some or a combination of the following images: ground glass attenuation, diffuse nodules
We identified the differentially expressed miRNAs in ILA compared to Ctrl (p < 0.05 and log2 Fold Change > 1.4) and further validated the candidate miRNAs with reverse-transcriptase quantitative polymerase chain reactions (RT-qPCR) using individual samples from the independent validation cohort consisting of 57 ILA
Summary
Interstitial lung abnormalities (ILA) are defined as specific patterns of increased lung densities identified on high-resolution computed tomography (HRCT) scans, usually in subjects without previous diagnosis of pulmonary disease. ILA are frequently observed with advanced age and are associated with smoking history and environmental pollution [1,2,3]. ILA are observed in non-smokers and in some studies the development of these abnormalities was not dependent. Subjects with ILA show a higher frequency of the gain-of-function MUC5B common variant gene [5,6,7]. ILA are associated with reduced lung function and exercise capacity, and increased risk of all-cause and respiratory mortality [1,9,10,11]. Several recent studies linked ILA to increased risk for progressive pulmonary fibrosis, lung cancer and lung cancer-associated mortality [12]
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