Circulating microRNA Signature Associated to Interstitial Lung Abnormalities in Respiratory Asymptomatic Subjects

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.

Telomere Shortening and Its Association with Cell Dysfunction in Lung Diseases

“…Furthermore, a high TS rate in IPF patients <60 years old is considered a poor prognosis because these patients present with more nonspecific hematological and/or immunological abnormalities [ 64 ]. Although there is limited information regarding the role of circulating microRNAs in the induction of TS and its link with the regulation of senescence in lung diseases, a recent report suggests that the upregulation of circulating microRNAs is associated with the regulation of critical signaling pathways, including senescence, which is in agreement with a previous report that indicated that miR-34a regulates c-Myc and FoxM1; interestingly, both molecules have a role in hTERT transcription [ 119 , 120 ].…”

Urine-derived exosomes from individuals with IPF carry pro-fibrotic cargo

“…2E). These selected miRNAs have also been shown to be expressed in lung tissue and serum from individuals with IPF (Casanova et al, 2021; Omote & Sauler, 2020; Ortiz-Quintero et al, 2020). These data suggest that composition of urine exosomes from individuals with IPF is the same as the composition from serum-derived exosomes in the same individual.…”

Interstitial lung abnormalities – current knowledge and future directions

“…Among other possible biomarkers, the adhesion molecule sICAM-1 has been associated with ILA [ 41 ] as well as pro-inflammatory molecule resistin [ 17 ]. Additionally, leptin and the metabolites phosphatidylcholine, phosphatidic acid, betaine aldehyde, phosphatidylethanolamine, and 1-acylglycerophosphocholine [ 42–44 ] have been linked with ILA and certain microRNAs, in particular miR-193a-5p and miR–502–5p, have been shown to be upregulated in ILA and suggested as ILA biomarkers [ 45 ]. Rheumatoid arthritis (RA) related autoantibodies and anti-cyclic citrullinated peptide have been associated with ILA among smokers and rheumatoid factor IgA are associated with ILA regardless of smoking history [ 46 ].…”