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in members of the miR-34/449 family in asthmatic compared to healthy subjects, and miR-34/449 was found
to regulate epithelial cell differentiation in vitro [107] .

The asthma-chronic obstructive pulmonary disease overlap syndrome
The asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is a relatively new
definition and has clinical features of both asthma and COPD. It is likely that for ACOS, as for asthma and
COPD, a range of different underlying mechanisms will be identified.

Thus far, only one study has investigated the miRNA expression pattern in ACOS. Both miR-145 and miR-
338 were increased in serum and sputum supernatant from the disease compared to healthy subjects. They
could not find any differences between the expression of miRNA-145 and miRNA-338 in ACOS patients
compared to asthma or COPD patients. The authors considered this finding as a confirmation that ACOS
presents some overlapping characteristics between both diseases [108] .

Asthma phenotype not defined
CD4+ T cells from asthmatics demonstrated a negative correlation between miR-145 and runt-related
transcription factor 3 (RUNX3) mRNA. Using miR-145 mimics and inhibitors the study revealed that miR-
145 functions as a regulator of Th1/Th2 balance by targeting RUNX3 [109] . Increased expression of miR-323-
3p in peripheral blood mononuclear cells from patients with asthma was associated with IL-22 production
in T cells. miR-323-3p was found to act in a negative feedback loop to control the production of IL-22 in
IL-22/IL-17 producing T cells and thereby affecting T cell responses in asthma [110] . Network analysis was
used to identify a novel asthma-associated gene. The top ranked predicted target of the highly down-
regulated miRNA-203 in asthmatic cells was the aquaporin 4 (AQP4) gene. Its expression was confirmed
to be significantly higher in bronchial epithelial cells from patients with asthma. Up-regulation of AQP4
in the bronchial epithelial cells of patients with asthma may represent a mechanism, by which the lung is
attempting to clear excessive fluid [111] .

FUTURE PERSPECTIVES
As miRNAs are differentially expressed in various cells and time-points, there is much interest to use them
in the clinic as biomarkers for asthma. Indeed, various studies have used mouse models and human subjects
to explore the possibility of miRNA biomarkers in asthma [Table 1]. miRNAs are especially well suited for
the biomarker role as they have been shown to be extremely resistant to different conditions (such as pH,
heat, and freeze-thaw), likely due to their protection by various RNA binding proteins and/or the inclusion
into vesicles [112-114] . Furthermore, miRNAs have been found in virtually every tissue and bodily fluid
examined, meaning that they can be collected using both invasive and non-invasive methods. To date, a few
therapies using miRNA agonists are in clinical trials, mostly for the treatment of cancers [115-119] . As miRNAs
become bigger players in the asthma field, specific signatures and biomarkers to better define the disease
may lead to work to develop more directed therapies for future generations.

The current research direction in the asthma field in relation to miRNAs appears to be in the form of data
generation and a search for biomarkers. Although this generation of data is critical for advancement in the
field, there must be subsequent steps taken to validate these findings. Algorithms and machine learning
are an excellent second step to understand if there is a relationship between asthma and the miRNA(s)
in question, but one must take care to ensure that subject samples are utilized as well. It does no good for
a perfect relationship, as predicted by modeling, if that cannot be replicated in vivo. Several open access
programs are now helping researchers to better predict the targets of their miRNA of interest or the
pathways that they may be affecting [85,120-123] . Unfortunately, a combination of programs must often be used in
order to find potential miRNA-mRNA interactions, making it tedious and often unrewarding work during
the validation phase. Furthermore, miRNAs can bind a several different targets and several miRNAs can