DIFFERENTIALLY EXPRESSED CIRCULATING LONG-NONCODING RNAS IN PREMATURE INFANTS WITH RESPIRATORY DISTRESS SYNDROME
Bao ZD, Wan J, Zhu W, Shen JX, Yang Y, Zhou XY
*Corresponding Author: Dr. Yang Yang and Dr. Zhou Xiao‑Yu, E‑mail: yy860507@126.com (YY) and xyzhou161@163.com (XYZ), Tel:+ 86-25-83117362, Department of Neonatology, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
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DISCUSSION
RDS is one of the most common respiratory disorders
in preterm infants, which can induce acute respiratory
failure [16]. Currently, it has been proven that RDS is a
complex disease characterized by immature lung development.
The embryonic phase of human lung development
begins approximately at the gestational age of 3-4
weeks and originates from the endoderm. Immature fetal
embryonic lung development has been recognized in the
pseudo‑glandular period (7‑16 weeks of gestation), canalicular
period (16‑25 weeks of gestation), and terminal
saccular period (25 weeks of gestation to full term) [17].
Yet the specific molecular regulatory mechanism of RDS
has not yet been fully understood.
LncRNAs are related to many biologic processes,
such as cell differentiation and proliferation [18]. Previous
studies have indicated that lncRNAs are involved in
lung development by regulating tracheal branches and
differentiation of lung epithelial progenitor cells [19-20].
Few studies, however, have investigated the role of lncRNAs
in RDS patients. Our study found that lncRNA
and mRNA profiles exhibited differential expressions in
the plasma of RDS patients. Our results further showed
that the expression patterns of mRNAs and lncRNAs were
consistent (Figures 2 and 4). Further function analysis of
target lncRNAs and mRNAs described that PI3K-Akt,
RAS, MAPK, and metabolic pathways might be downstream
of the significant lncRNAs, and were potentially
involved in the development of RDS.
Interestingly, we found that the expression level of
lncRNA ENST00000470527.1, ENST00000504497.1,
ENST00000417781.5, and ENST00000440408.5 was
increased in the plasma of RDS patients, compared with
non-RDS controls. Additionally, the level of those four
lncRNAs was significantly higher in the severe patients,
compared with the mild RDS group. The above results
suggest that these four lncRNAs were possibly related to
the severity of RDS.
A few studies have investigated lncRNA
ENST00000440408.5, also known as Testis-specific transcript
Y-linked 15 (TTTY15). A study reported by Zhang et
al. demonstrated that TTTY15 knockdown can protect cardiomyocytes
against hypoxia-induced apoptosis and mitochondrial
energy metabolism dysfunction in vitro through
the let-7i-5p/TLR3/NF-κB pathway [21]. The let‑7 family
has been demonstrated to be important in lung development
and regulate RAS gene expression [22]. Fabro et al.
further reported that circulating miRNA-let-7i-5p significantly
changed in patients with acute pulmonary embolism
and idiopathic pulmonary arterial hypertension compared
with healthy controls [23]. Let-7i-5p were just regulators
of pulmonary arterial adventitial fibroblasts, pulmonary artery
endothelial cells, and pulmonary artery smooth muscle
cells. Thus, we thought that lncRNA ENST00000440408.5
may be involved in lung development by interacting with
miRNA let-7 directly or indirectly.
To our knowledge, the other three lncRNAs
(ENST00000470527.1, ENST00000504497.1, and
ENST00000417781.5) were reported for the first time.
Bioinformatics analysis showed that they may be associated
with PI3K-Akt, RAS, MAPK, and TGF-β signaling pathways,
which could regulate lung development and PS secretion.
Furthermore, the process of transdifferentiation from
alveolar epithelial type II to type I cells is also controlled
by TGF-β and BMP signaling pathways [24]. In our previous
study, the results indicated that SMAD4 negatively
regulates the expression of surfactant proteins (SPs), and
that miR‑431 negatively regulates the expression of SPs by
inhibiting the BMP4/activin/ TGF-β signaling pathway by
targeting SMAD4 [25]. In addition, the PI3K-Akt signaling
pathway synergistically regulates epithelial-mesenchymal
transition [26], which is also essential for lung development
[27]. Zhao M et al. reported that naringenin pre-treatment
ameliorated LPS-induced acute lung injury through its antioxidative
and anti-inflammatory activity and by inhibition
of the PI3K/AKT pathway in mice [28]. As far as Ras/
MAPK signaling pathway is concerned, it affects the FGF
signaling cascade, while the FGF signaling pathway is crucial
for the dynamic and reciprocal communication between
epithelium and mesenchyme during lung development [29].
There were several limitations in our study. Firstly, the
sample size is relatively small, a larger sample study could
validate the results further. Secondly, the specific functions
of four differentially expressed lncRNAs should be deeply
explored in future studies to clarify the pathogenesis of RDS.
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