4. DISCUSSION
At present, the pathogenesis of BPD has not yet been fully elucidated.
Most scholars believe that BPD is a multifactorial disease-causing
syndrome. Type II epithelial cells (alveolar epithelial II cells, AEC
II) apoptosis dominated immature lung injury, its pathological feature
is alveolar developmental block with increased alveolar epithelial cell
apoptosis 18, 19. AEC II is a stem cell of alveolar
epithelial cells, which has the ability of immortal proliferation and
differentiation 20, 21. During lung development, AEC
II continuously differentiates into alveolar epithelial cell I (AEC I)
to promote alveolar formation and complete alveolar remodeling after
epithelial injury 22. AEC II is an important effector
cell in the pathological process of lung injury. Its function and status
determine the pathological outcome of lung injury; AEC II’s survival and
apoptosis affect the outcome of lung injury repair.
Lung development is an intricate process. From a genetic perspective, it
is the result of the expression, regulation and interaction of key lung
development genes at different times and in different spaces. A slight
abnormality in any link may disrupt normal lung development and cause
varying degrees lung injury 23. With the rapid
development of molecular genetics research, a number of genes closely
related to BPD have been discovered, such as VEGF-α, TGF-β, IGF-1,
fibronectin 1, p21, FoxA1, etc. The expression level of these genes in
lung tissues To a certain extent, the changes in BPD can reflect the
development trend of BPD 23. Studies have reported
that non-coding RNA is also involved in the pathogenesis of BPD. For
example, miRNA-29 is highly expressed in the lung tissue of newborn mice
with BPD, and it participates in the occurrence and development of BPD
by down-regulating the expression of Ntrk2 and disrupting various
biological processes of lung development 24; Recent
studies have also reported that lncRNA MALAT1 can protect BPD by
inhibiting cell apoptosis 25. Although scholars at
home and abroad have done a lot of meaningful work on the pathogenesis
of BPD, providing molecular basis and clues for understanding the
formation process of BPD, the pathogenesis of BPD is still inaccurate,
and the existing pathogenesis cannot provide it. Effective clinical
interventions, so in-depth exploration of new mechanisms of BPD
pathogenesis is urgent.
uc.375 is a lncRNA with unknown function that is highly conserved among
different species, differentially lowly expressed in BPD lung tissue,
localized in alveolar type II epithelial cells, and obtained through
microarray technology screening. Regarding the biological information,
function and role of uc.375 in BPD, there are currently no relevant
reports at home and abroad, and there is no report on the function and
mechanism of uc.375 involved in the process of BPD alveolar development.
Our research found that silencing uc.375 in the mouse alveolar type II
epithelial cell line (MLE 12) can significantly promote its apoptosis
and inhibit its proliferation; uc.375 negatively regulates the
expression of FoxA1, affects the development of alveoli, and occurs in
BPD. Play an important role in development.
The FoxA family is a class of proteins with important functions, which
are involved in the regulation of cell proliferation, differentiation,
embryonic development and other important life activities. Some members
of the FoxA family play an important role in the regulation of
apoptosis-related genes. For example, FoxA2 can significantly inhibit
the expression of SP-A in A549, and SP-A is an apoptosis inhibitor of
alveolar epithelial cells 26; 2-Acetylaminofluorene
promotes bile duct cell apoptosis through FoxA3 27.
FoxA1’s nuclear localization sequence, DNA binding domain, and NH2
terminal transcription activation are highly homologous to FoxA2 and 3.
FoxA1 is closely related to the embryonic development of
endoderm-derived tissues and organs. Lee CS et al. 28revealed that the initiation of liver development during embryonic
development is FoxA1-dependent, and the development of fetal lungs is
also regulated by FoxA1, and FoxA1 is only found in the lungs. It is
expressed in airway epithelial cells and alveolar type II epithelial
cells in tissues 29. Studies have also found that the
loss of FoxA1 in mouse lung tissue AEC II and bronchial Clara cells will
delay cell development and maturation. In addition, the expression of
SP-B and SP-C in mice lacking FoxA1 is significantly lower than that in
wild-type mice, eventually leading to increased susceptibility to
respiratory diseases after birth 30, 31. It is more
reported in the literature that FoxA1 inhibits its expression by
combining with the anti-apoptotic genes bcl2 and FoxA1 binding elements
in the promoter region of UCP2, thereby promoting AEC II apoptosis and
playing a role in BPD 32. In this study, we identified
that FoxA1 is the regulatory target of uc.375.