MicroRNA-146a-5p alleviates bronchopulmonary dysplasia in neonatal mice by modulating the TGF-?1/SMAD4 pathway

Bronchopulmonary dysplasia (BPD) is a common and challenging disease that affects newborns and infants, characterized by alveolar dysplasia and reduced pulmonary function.Various microRNAs (miRNAs) have been found to be deferentially expressed during the progression of BPD.The interaction between SMAD4 and miR-146a-5p was identified using a dual-luciferase reporter assay.A mouse model of BPD was established through hyperoxia induction, where the expression pattern of miR-146a-5p, pathological manifestations, and fibrosis factors were assessed over 14 days.Additionally, lentivirus-packed vectors were used to modulate miR-146a-5p expression in mice to observe its effects.SRI-011381 was employed to activate TGF-1, confirming that miR-146a-5p targets SMAD4 and influences the TGF- pathway in BPD progression.The expressions of miR-146a-5p, TGF-1, and SMAD4 in BPD neonatal mice were determined using RT-qPCR and Western blot analysis, while TGF-1, COL I, and COL III levels were evaluated through immunohistochemistry semi-quantification.We found miR-146a-5p was up-regulated in the lung tissues of hyperoxia-induced BPD neonatal mice over time.SMAD4 was identified as a target of miR-146a-5p which was shown to down-regulate SMAD4, thereby inactivating the TGF- signaling pathway.This resulted in decreased expression of fibrosis factors and restoration of alveolarization in BPD neonatal mice.Our findings demonstrate that miR-146a-5p facilitates alveolarization in preterm neonates with BPD by suppressing the SMAD4-dependent TGF- pathway.