MicroRNA-mRNA interactions in a murine model of hyperoxia-induced bronchopulmonary dysplasia.
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.


CONCLUSIONS
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.
Division of General Thoracic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA.
Jie
J
Dong
William A
WA
Carey
Stuart
S
Abel
Christopher
C
Collura
Guoqian
G
Jiang
Sandra
S
Tomaszek
Shari
S
Sutor
Anja C
AC
Roden
Yan W
YW
Asmann
Y S
YS
Prakash
Dennis A
DA
Wigle
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D018496:Hyperoxia; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D020813:Receptor, trkB
D008562:Membrane Glycoproteins; D035683:MicroRNAs; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; C547014:MIRN29 microRNA, mouse; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB