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. 2017 Oct 27;8:1173. doi: 10.1038/s41467-017-01349-y

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© The Author(s) 2017

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 10 — Lungs of infants with RDS and BPD have increased miR-34a expression. a miR-34a expression in cell pellets obtained from tracheal aspirates of neonates in the first PN week, who subsequently did or did not develop BPD. b Next, we used ISH to detect miR-34a in human neonatal lungs. As noted in the representative microphotographs, there was increased violet staining (miR-34a-positive) of the cells in the lungs of RDS and BPD neonates, compared to controls. c Western blot analysis of Tie2 and Ang1 was performed on total homogenates from human lung samples. d, e Densitometric analysis of Tie2 and Ang1 expression from infants born near term with no lung disease compared to near or post term with mild RDS, evolving BPD and established BPD. f A proposed schema for the role of miR-34a in the pathogenesis of BPD. Hyperoxia exposure to the developing lung leads to production and release of the primary (Pri-miR-34a), which is processed into the mature form of miR-34a. Downstream targets of the miR34a signaling pathway include Ang1 and its receptor Tie2, and the anti-apoptotic protein Bcl2; decreased expression of both are known to increase cell death in hyperoxia-induced lung injury models and BPD. In addition, hyperoxia decreases cell proliferation via CDK4 and cyclin D1, both targets of miR34a. The class III histone deacetylator, Sirt1 is also a downstream target of miR-34a, and a decrease in Sirt1 has been associated with enhanced transcription of pro-inflammatory mediators and BPD. The combined effect of enhanced cell death and decreased cell proliferation would be impaired alveolarization in the lung. In addition, miR34a, by suppressing the Ang1/Tie2 signaling pathway and enhancing cell death, results in dysregulated vascularization in the lung. Hence, increased miR-34a results in increased inflammation, impaired alveolarization and dysregulated vascularization in the developing lung—the hallmarks of “new” BPD. RDS: respiratory distress syndrome; BPD: bronchopulmonary dysplasia; Ang1: angiopoietin 1; Sirt1: Sirtuin 1. *P <0.05, **P <0.01, compared with controls, 1-way ANOVA