MicroRNA modulate alveolar epithelial response to cyclic stretch

Department of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 South 33rd Street, Philadelphia, PA 19104-6321, USA.
BMC Genomics (Impact Factor: 3.99). 04/2012; 13(1):154. DOI: 10.1186/1471-2164-13-154
Source: PubMed


MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression implicated in multiple cellular processes. Cyclic stretch of alveoli is characteristic of mechanical ventilation, and is postulated to be partly responsible for the lung injury and inflammation in ventilator-induced lung injury. We propose that miRNAs may regulate some of the stretch response, and therefore hypothesized that miRNAs would be differentially expressed between cyclically stretched and unstretched rat alveolar epithelial cells (RAECs).
RAECs were isolated and cultured to express type I epithelial characteristics. They were then equibiaxially stretched to 25% change in surface area at 15 cycles/minute for 1 hour or 6 hours, or served as unstretched controls, and miRNAs were extracted. Expression profiling of the miRNAs with at least 1.5-fold change over controls revealed 42 miRNAs were regulated (34 up and 8 down) with stretch. We validated 6 of the miRNAs using real-time PCR. Using a parallel mRNA array under identical conditions and publicly available databases, target genes for these 42 differentially regulated miRNAs were identified. Many of these genes had significant up- or down-regulation under the same stretch conditions. There were 362 down-regulated genes associated with up-regulated miRNAs, and 101 up-regulated genes associated with down-regulated miRNAs. Specific inhibition of two selected miRNAs demonstrated a reduction of the increased epithelial permeability seen with cyclic stretch.
We conclude that miRNA expression is differentially expressed between cyclically stretched and unstretched alveolar epithelial cells, and may offer opportunities for therapeutic intervention to ameliorate stretch-associated alveolar epithelial cell dysfunction.

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Available from: Adi Yerrapureddy, Dec 31, 2013
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    • "Target prediction and functional enrichment of differentially expressed miRNAs TargetScan (Lewis et al. 2005) was used to predict the targets of differentially expressed miRNAs. TargetScan allows identification of target mRNAs for any specific microRNA based on the context score percentile (Grimson et al. 2007), and we set context score percentile of 50 as threshold value to filter the prediction results (Yehya et al. 2012). To discover the function of those differential expressed miRNAs, gene ontology (GO) analysis was applied to reveal the functions of the target genes of the differential expressed miRNAs. "
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    • "Since miRs regulate 30% of human gene expression [14], the miR expression signatures can be employed as biomarkers for tissue functions and diseases. In airway cells, miR expression profiles can be regulated by multiple factors, including growth factors [15], inflammatory agents [16], mechanical force [17], and hypoxia [18]. miRs have been demonstrated to play critical roles in many inflammatory diseases and asthma [19], [20], but the roles of miRs in regulating the mechanical pathobiology of the lung remain to be established. "
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    • "Other miRNAs associated with inflammation, such as miR-155, let-7 and miR-146, are similarly deregulated upon HVTV treatment[170] (Table 1). Another expression analysis on the effects of stress ventilation was performed by stretching rat alveolar epithelial cells to mimic mechanical ventilation.[171] In this study, the majority of miRNAs were again found to be upregulated.[171] "
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