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.