Inhibition and Role of let-7d in Idiopathic Pulmonary Fibrosis

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Show simple item record Pandit, KV Corcoran, D Yousef, H Yarlagadda, M Tzouvelekis, A Gibson, KF Konishi, K Yousem, SA Singh, M Handley, D Richards, T Selman, M Watkins, SC Ben-Yehudah, A Bouros, D Eickelberg, O Ray, P Benos, PV Kaminski, N Pardo-Cemo, Annie 2011-01-21T10:35:26Z 2011-01-21T10:35:26Z 2010
dc.identifier.issn 1073449X
dc.identifier.uri http://hdlhandlenet/123456789/268
dc.description.abstract Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal fibrotic lung disease characterized by profound changes in epithelial cell phenotype and fibroblast proliferation. Objectives. To determine changes in expression and role of microRNAs in IPF. Methods. RNA from 10 control and 10 IPF tissues was hybridized on Agilent microRNA microarrays and results were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. SMAD3 binding to the let-7d promoter was confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assay, luciferase assays, and reduced expression of let-7d in response to transforming growth factor-p. HMGA2, a let-7d target, was localized by immunohistochemistry. In mice, let-7d was inhibited by intratracheal administration of a let-7d antagomir and its effects were determined by immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, and morphometry. Measurements and Main Results. Eighteen microRNAs including let-7d were significantly decreased in IPF. Transforming growth factor-beta down-regulated let-7d expression, and SMAD3 binding to the let-7d promoter was demonstrated. Inhibition of let-7d caused increases in mesenchymal markers N-cadherin-2, vimentin, and a-smooth muscle actin (ACTA2) as well as HMGA2 in multiple epithelial cell lines. let-7d was significantly reduced in IPF lungs and the number of epithelial cells expressing let-7d correlated with pulmonary functions. HMGA2 was increased in alveolar epithelial cells of IPF lungs. let-7d inhibition in vivo caused alveolar septal thickening and increases in collagen, ACTA2 and S100A4 expression in SFTPC (pulmonary-associated surfactant protein C) expressing alveolar epithelial cells. Conclusions: Our results indicate a role for microRNAs in IPF. The down-regulation of let-7d in IPF and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key regulatory role for this microRNA in preventing lung fibrosis. en_US
dc.language.iso en en_US
dc.title Inhibition and Role of let-7d in Idiopathic Pulmonary Fibrosis
dc.type Artículo de investigación en_US
dc.identifier.idprometeo 148
dc.identifier.doi 10.1164/rccm.200911-1698OC
dc.source.novolpages 182(2):220-229
dc.subject.wos Critical Care Medicine
dc.subject.wos Respiratory System
dc.description.index WoS: SCI, SSCI o AHCI
dc.subject.keywords epithelial-mesenchymal transition
dc.subject.keywords HMGA2 (high-mobility group AT-hook 2)
dc.subject.keywords microRNA
dc.subject.keywords transforming growth factor-beta
dc.relation.journal American Journal of Respiratory and Critical Care Medicine
dc.description.Departamento Departamento de Biología Comparada

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