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Weidner et al. J Transl Genet Genom 2019;3:2. I https://doi.org/10.20517/jtgg.2018.30 Page 5 of 16
[2]
recently reported that up to 20% of school aged children in Europe have asthma . Asthma often manifests
during childhood, with males being more affected than females. Additionally, there is a strong link between
[59]
childhood asthma and atopy and Th2-based immunological responses . To date, there have been very few
studies examining the role of miRNAs in the pediatric asthma population. Thus, studies to understand the
causes and molecular mechanisms of the disease are important for future treatments and diagnoses.

miRNAs in lung development
Even before birth, miRNAs play a major role in the developing lung. During organogenesis the miRNA
processing enzymes Dicer and Ago have been shown to be greatly expressed in the branching regions
[60]
of the lung, suggesting that these areas are major sites of miRNA regulation . These findings were later
expanded when array studies examining the miRNA, mRNA and protein expression during murine lung
[61]
organogenesis were performed. Dong et al. were able to show that changes in miRNA expression appeared
to be a prominent mechanism during lung development with miRs-21, -167, and -198 being differentially
expressed. Shortly thereafter, differential expression of several miRNAs during development in both the
[62]
mouse and human lung were observed . Overall, the expression patterns between mouse and human
tissue was similar, signifying that the expression pattern of miRNAs in lung development is evolutionarily
[63]
conserved. Furthermore, in transgenic mice where the miR-17~92 cluster was overexpressed, Lu et al.
observed that lung epithelial progenitor cells were unable to differentiate, thus, suggesting a role for miRNAs
[64]
in promoting cell differentiation in lung cells. Using rat lung at different developmental stages, Bhaskaran et al.
showed the temporal nature of miRNA expression. They focused on miR-127, which was highly expressed in
late stage lung development. Further analysis of miR-127 showed a shift of this miRNA during development
from mesenchymal to epithelial cells and overexpression of miR-127 in fetal lung cultures caused improper
bud formation, suggesting the importance of this miRNA in lung development. With the knowledge gained
of differential miRNA expression during lung development, perhaps we can start to pinpoint early signs of
potential disease or abnormal embryonic development via the miRNA signatures in amniotic fluid, placenta
or cord blood.

Comparisons of pediatric asthma to murine models
[65]
In an early study, Liu et al. performed microarrays to identify miRNA expression differences between
blood lymphocytes in young asthmatic and non-asthmatic children, where 36 miRNAs were significantly
upregulated and 47 miRNAs were significantly downregulated. They then went on to compare miRNAs
found in asthmatic children with OVA-induced murine models and found that miR-221 and miR-485-
3p were upregulated in both instances. Furthermore, using in silico analysis, they found that a common
predicted target of both miRNAs, sprouty-related, EVH1 domain-containing protein 2. This gene was later
found to be downregulated in the murine asthma model, thus suggesting a valid miRNA-mRNA interaction
that may have important implications in the development or persistence of childhood asthma. In order to
[66]
determine biomarkers for young children with potential asthma, Jiang et al. examined children with
recurrent wheeze. Recurrent wheeze is regarded as an important risk factor for developing asthma and so a
biomarker to help identify asthma, which would be helpful in early diagnosis. Plasma was collected from 140
children ranging from 0 to 12 years of age, with half having recurrent wheeze or asthma and half acting as
controls. Eleven miRNAs were chosen based on their association to asthma and miR-21 and miR-26a proved
to be significantly different between the control and recurrent wheeze group. Moreover, this increase in miR-
21 and miR-26a expression could be replicated in the plasma and bronchoalveolar lavage fluid (BALF) of rats
with both acute and chronic pulmonary inflammation. Thus, these miRNAs could be of interest for future
studies in the development of asthma in children.

Circulating miRNAs as potential biomarkers in pediatric asthma
Several studies have addressed the potential for miRNAs to act as biomarkers in childhood asthma cohorts.
Due to the ease of collection, blood has often been used to identify miRNAs as potential biomarkers in