1. INTRODUCTION
Bronchopulmonary dysplasia (BPD) is one of the common chronic lung diseases in preterm infants, and its incidence is as high as 52% in extremely low birth weight infants 1, 2. With the increasing maturity of critical care and management techniques for premature infants, the survival rate of very low and extremely low birth weight infants has increased significantly, but with it, the incidence of BPD has also shown a continuous upward trend 3. Children with this disease not only suffer from repeated respiratory infections and varying degrees of pulmonary dysfunction, but also increase the risk of asthma and chronic obstructive pulmonary disease (COPD) in adulthood 4. Therefore, BPD has become an important medical problem that endangers the health of newborns, affects the quality of our nationals, and causes a heavy family and socioeconomic burden.
LncRNAs are a type of non-coding transcript that is greater than 200 nucleotides in length and does not have the ability to encode proteins. In recent years, with the rapid development of genetic information technology and the wide application of next-generation sequencing and gene chip technology, scholars’ understanding of the pathogenesis of many human diseases has gradually expanded to the level of lncRNA and has become a research hotspot in many fields of life medicine. It has also become a new direction for us to explore the pathogenesis of BPD. LncRNAs have abundant biological functions in cell development and metabolism, such as genetic imprinting 5, chromatin modification 6, cell cycle regulation7, transcription regulation 8, and participation in mRNA degradation 9 Etc. These are closely related to the occurrence, development and prevention of many human diseases. Studies on the role and mechanism of lncRNA in lung development and lung diseases have become a hot spot of increasing attention by scholars. Herriges MJ et al. 10identified 363 lncRNAs in embryonic mouse lungs, which interact with transcription factors spatially to regulate lung development. The lack of certain lncRNAs in the lungs can lead to alveolar capillary dysplasia and pulmonary vein dislocation (ACD/MPV) 11. Studies have also confirmed that lncRNA plays the role of ”inducers and terminators” of vascular development 12, affects the biological functions of endothelial cells, and can be used as a target for vascular diseases 13. Although there have been preliminary studies of lncRNA in the field of lung development, further exploration of the role and mechanism of lncRNA in the formation of BPD will inevitably promote neonatal scholars’ in-depth understanding of the pathogenesis of BPD.
In this study, we identified a molecular effector mechanism of the lncRNA uc.375 in lung tissue of BPD using lncRNA microarray, bioinformatics, and functional studies. We found that uc.375 is mainly distributed in AEC II, and low expression in BPD mice AEC II. Silencing uc.375 promoted the apoptosis of MLE 12 cells, reduced their proliferation and differentiation, and promoted the apoptosis-related factor caspase 3, inhibited the expression of MLE 12 specific secretion SP-C, bcl2 and UCP2. On the contrary, after overexpressing uc.375, the opposite results were obtained. Silencing uc.375 while silencing FoxA1 inhibited MLE 12 apoptosis, promoted their proliferation, inhibited apoptosis-related factor caspase3, and promoted the expression of MLE 12-specific secretions SP-C , bcl2 and UCP2. On the contrary, overexpression of uc.375 and FoxA1 at the same time, the result is opposite. uc.375 negatively regulates FoxA1 expression, affects alveolar development, and plays an important role in the occurrence and development of BPD. In summary, this study clarified the exact mechanism of uc.375 in the occurrence and development of BPD. we identified that it may provide a new molecular target for the prevention and treatment of BPD.