Pulmonary microRNA profiling in a mouse model of ventilator-induced lung injury

Abstract

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.

Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury

“…Vaporidi et al 49 demonstrated that ectopic expression of miR-21 reduced lung compliance and increased alveolar-arterial oxygen differences and protein levels in bronchoalveolar lavage in a ventilator-induced mouse ALI model. 49 Here, we observed that treatment with the miR-21 mimic abolished the protective effect of LXA 4 on LPSreduced ENaC-γ expression. In addition, both SR11302 and LXA 4 reversed LPS-decreased ENaC-γ protein expression.…”

“…Consistent with previous studies that upregulated miR-21 depressed PTEN mRNA and protein expression in ventilator-induced and OA-stimulated rat ALI model. 47,49 In addition, PTEN contains miR-21-binging site within 3′ UTR. 45 Hence, we provide evidence linking LPS-mediated upregulation of miR-21 with downregulation of PTEN mRNA and protein in alveolar epithelia.…”

Antisense Oligonucleotide Treatment Enhances the Recovery of Acute Lung Injury through IL-10–Secreting M2-like Macrophage-Induced Expansion of CD4+ Regulatory T Cells

“…Recent studies have revealed that miR-155 was involved in the development of inflammatory lung disease (20,21). For example, elevated miR-155 could promote inflammation in the lung in cystic fibrosis disease (22).…”

“…For example, elevated miR-155 could promote inflammation in the lung in cystic fibrosis disease (22). Global miRNA profile analysis showed that the expression of miR-155 was elevated in ALI (21,23). Furthermore, miR-155 could regulate the transduction of TLRs signaling on mouse and human immune cells such as macrophages (24,25), *Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China; which was critical for generation of proinflammatory cytokine storm and subsequently the development and recovery of ALI (26)(27)(28).…”

MicroRNA expression profiling studies on bronchopulmonary dysplasia: a systematic review and meta-analysis

“…Zhong et al (2012) and Liu et al (2013) further reported that miRNA-21 increased cell growth, promoted migration and invasion, and enhanced chemo-or radio-resistance of non-small cell lung cancer cells, mainly by acting on the phosphatase and tensin homolog signaling pathway and by down-regulating human mutS homolog 2, one of the core mismatch repair genes. In addi- tion, Vaporidi et al (2012) reported that miRNA-21 could be highly up-regulated by high tidal volume ventilation, and could exert a negative effect on lung compliance through increasing alveolar-arterial oxygen differences and the level of inflammation of the associated protein. Yang et al (2012a) further showed that miRNA-21 plays an important role in the pathogenesis of chronic hypoxia-induced pulmonary vascular remodeling.…”