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MicroRNA-mRNA interactions in a murine model of hyperoxia-induced bronchopulmonary dysplasia
Jie Dong1, William A Carey, Stuart Abel
1Division of General Thoracic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA.
Background:
Bronchopulmonary dysplasia is a chronic lung disease of premature neonates characterized by arrested pulmonary alveolar development. There is increasing evidence that microRNAs (miRNAs) regulate translation of messenger RNAs (mRNAs) during lung organogenesis. The potential role of miRNAs in the pathogenesis of BPD is unclear.
Results:
Following exposure of neonatal mice to 80% O2 or room air (RA) for either 14 or 29 days, lungs of hyperoxic mice displayed histological changes consistent with BPD. Comprehensive miRNA and mRNA profiling was performed using lung tissue from both O2 and RA treated mice, identifying a number of dynamically regulated miRNAs and associated mRNA target genes. Gene ontology enrichment and pathway analysis revealed that hyperoxia modulated genes involved in a variety of lung developmental processes, including cell cycle, cell adhesion, mobility and taxis, inflammation, and angiogenesis. MiR-29 was prominently increased in the lungs of hyperoxic mice, and several predicted mRNA targets of miR-29 were validated with real-time PCR, western blotting and immunohistochemistry. Direct miR-29 targets were further validated in vitro using bronchoalveolar stem cells.
Conclusion:
In newborn mice, prolonged hyperoxia induces an arrest of alveolar development similar to that seen in human neonates with BPD. This abnormal lung development is accompanied by significant increases in the levels of multiple miRNAs and corresponding decreases in the levels of predicted mRNA targets, many of which have known or suspected roles in pathways altered in BPD. These data support the hypothesis that dynamic regulation of miRNAs plays a prominent role in the pathophysiology of BPD.
Insights
MicroRNAs (miRNAs) are implicated in the lung disease bronchopulmonary dysplasia (BPD). Hyperoxia in neonatal mice increased miRNAs, leading to arrested alveolar development, suggesting miRNAs play a key role in BPD.
Area of Science:
- Pulmonary Medicine
- Developmental Biology
- Molecular Biology
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants characterized by impaired alveolar development.
- MicroRNAs (miRNAs) are known regulators of gene expression during lung development.
- The specific role of miRNAs in BPD pathogenesis remains largely unknown.
Purpose of the Study:
- To investigate the role of miRNAs in the pathogenesis of hyperoxia-induced lung injury resembling BPD in neonatal mice.
- To identify specific miRNAs and their mRNA targets affected by hyperoxia during lung development.
Main Methods:
- Neonatal mice were exposed to hyperoxia (80% O2) or room air (RA) for 14 or 29 days.
- Comprehensive miRNA and mRNA profiling of lung tissue was performed.
- Gene ontology and pathway analyses were conducted to identify affected biological processes.
- Validation of miRNA-mRNA interactions was performed using molecular and cellular assays.
Main Results:
- Hyperoxia induced histological changes in mouse lungs consistent with BPD.
- Dynamic regulation of multiple miRNAs and their predicted mRNA targets was observed.
- Hyperoxia modulated genes involved in lung development, including cell cycle, adhesion, inflammation, and angiogenesis.
- miR-29 levels were significantly increased in hyperoxic lungs, with validated mRNA targets.
Conclusions:
- Prolonged hyperoxia in newborn mice causes arrested alveolar development, mirroring human BPD.
- Increased miRNA levels and decreased mRNA targets are associated with this abnormal lung development.
- These findings support the hypothesis that dynamic miRNA regulation is a key factor in BPD pathophysiology.
