Hyperoxia‐induced miR‐342‐5p down‐regulation exacerbates neonatal bronchopulmonary dysplasia via the Raf1 regulator Spred3

Abstract

Background and Purpose Bronchopulmonary dysplasia (BPD) is the most prevalent chronic paediatric lung disease and is linked to the development of chronic obstructive pulmonary disease. MicroRNA‐based regulation of type II alveolar epithelial cell (T2AEC) proliferation and apoptosis is an important factor in the pathogenesis of BPD and warrants further investigation. Experimental Approach Two murine models of hyperoxic lung injury (with or without miR‐342‐5p or Sprouty‐related, EVH1 domain‐containing protein 3 [Spred3] modulation) were employed: a hyperoxia‐induced acute lung injury model (100% O2 on postnatal days 1–7) and the BPD model (100% O2 on postnatal days 1–4, followed by room air for 10 days). Tracheal aspirate pellets from healthy control and moderate/severe BPD neonates were randomly selected for clinical miR‐342‐5p analysis. Key Results Hyperoxia decreased miR‐342‐5p levels in primary T2AECs, MLE12 cells and neonatal mouse lungs. Transgenic miR‐342 overexpression in neonatal mice ameliorated survival rates and improved the BPD phenotype and BPD‐associated pulmonary arterial hypertension (PAH). T2AEC‐specific miR‐342 transgenic overexpression, as well as miR‐342‐5p mimic therapy, also ameliorated the BPD phenotype and associated PAH. miR‐342‐5p targets the 3′UTR of the Raf1 regulator Spred3, inhibiting Spred3 expression. Treatment with recombinant Spred3 exacerbated the BPD phenotype and associated PAH. Notably, miR‐342‐5p inhibition under room air conditions did not mimic the BPD phenotype. Moderate/severe BPD tracheal aspirate pellets exhibited decreased miR‐342‐5p levels relative to healthy control pellets. Conclusion and Implications These findings suggest that miR‐342‐5p mimic therapy may show promise in the treatment or prevention of BPD.

CREB1 Transcriptionally Activates LTBR to Promote the NF-κB Pathway and Apoptosis in Lung Epithelial Cells

“…LTBR expression was also increased by hyperoxia-stimulated A549 and ATII cells in this study. Apoptosis of ATII is observed in hyperoxiastimulated BPD model [19]. Our work supports that hyperoxia decreases cell viability and promotes apoptosis in A549 and ATII cells.…”

“…Despite studies on LTBR in lung development or lung cancer [9,26,27], its role in BPD remains unknown. We used a mouse model of BPD by exposure to 100% O 2 on postnatal day 4 followed by recovering for 10 days [19] and found that LTBR expression was increased in lungs of BPD mouse model compared with normal control mice. ATII cells are pulmonary epithelial progenitor cells and exist in the corners of alveoli, taking up only 5% of alveolar surface area in healthy adults with many functions including synthesizing and secreting surfactants, transporting intrapulmonary fluid and ion, supporting immune modulation, and regenerating alveolar epithelium after injury [28].…”

“…Mice were randomly divided into the BPD model group (n = 8) or the control group (n = 8). To establish the BPD model, mice were exposed to 100% O 2 in a medium-sized airtight polypropylene chamber on postnatal days 1-4, followed by recovering for 10 days [19]. Neonatal pups were given adequate nutrition by lactating dam during experimental time to avoid death.…”

“…This study is aimed at evaluating the expression of LTBR in the BPD lung injury mouse model in vivo and its role in the apoptosis of lung epithelial cells in vitro. Hyperoxiastimulated A549 and ATII cells were used as the in vitro model of BPD [18,19]. The potential binding of CREB1 on LTBR promoter as well as the downstream NF-κB pathway was assessed, providing new ideas for understanding the pathogenesis of BPD.…”

MicroRNA in Extracellular Vesicles from Patients with Pulmonary Arterial Hypertension Alters Endothelial Angiogenic Response

“…Moreover, none of the differentially expressed miRs have thus far been found to be directly associated with PAH pathology. Nevertheless, some of the miRs that are found to be affected in PAH EVs are known to be involved in other lung diseases; for example, miR-342, found to be down-regulated in PAH EVs in the present study, has been shown to exacerbate neonatal broncho-pulmonary dysplasia [ 32 ]. Likewise, miR-486 carrying EVs was more recently exhibited to promote angiogenesis after myocardial infarction in mice [ 18 ], whereas miR-26a, found to be upregulated in the present study, was identified as inhibiting angiogenesis in a cellular model of hepatic carcinoma [ 33 ].…”