Pulmonary microRNA profiling in a mouse model of ventilator-induced lung injury.
The aim of this study was to investigate the changes induced by high tidal volume ventilation (HVTV) in pulmonary expression of micro-RNAs (miRNAs) and identify potential target genes and corresponding miRNA-gene networks. Using a real-time RT-PCR-based array in RNA samples from lungs of mice subjected to HVTV for 1 or 4 h and control mice, we identified 65 miRNAs whose expression changed more than twofold upon HVTV. An inflammatory and a TGF-β-signaling miRNA-gene network were identified by in silico pathway analysis being at highest statistical significance (P = 10(-43) and P = 10(-28), respectively). In the inflammatory network, IL-6 and SOCS-1, regulated by miRNAs let-7 and miR-155, respectively, appeared as central nodes. In TGF-β-signaling network, SMAD-4, regulated by miR-146, appeared as a central node. The contribution of miRNAs to the development of lung injury was evaluated in mice subjected to HVTV treated with a precursor or antagonist of miR-21, a miRNA highly upregulated by HVTV. Lung compliance was preserved only in mice treated with anti-miR-21 but not in mice treated with pre-miR-21 or negative-control miRNA. Both alveolar-arterial oxygen difference and protein levels in bronchoalveolar lavage were lower in mice treated with anti-miR-21 than in mice treated with pre-miR-21 or negative-control miRNA (D(A-a): 66 ± 27 vs. 131 ± 22, 144 ± 10 mmHg, respectively, P < 0.001; protein concentration: 1.1 ± 0.2 vs. 2.3 ± 1, 2.1 ± 0.4 mg/ml, respectively, P < 0.01). Our results show that HVTV induces changes in miRNA expression in mouse lungs. Modulation of miRNA expression can affect the development of HVTV-induced lung injury.
Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. vaporidi@med.uoc.gr
Katerina
K
Vaporidi
Eleni
E
Vergadi
Evangelos
E
Kaniaris
Maria
M
Hatziapostolou
Eleni
E
Lagoudaki
Dimitrios
D
Georgopoulos
Warren M
WM
Zapol
Kenneth D
KD
Bloch
Dimitris
D
Iliopoulos
D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D017403:In Situ Hybridization; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D055397:Ventilator-Induced Lung Injury / Q000209:etiology* / Q000473:pathology*
D015415:Biomarkers; D035683:MicroRNAs; D016212:Transforming Growth Factor beta