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MicroRNAs in idiopathic pulmonary fibrosis

  • Kusum V. Pandit
    Affiliations
    Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Jadranka Milosevic
    Affiliations
    Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Naftali Kaminski
    Correspondence
    Reprint requests: Naftali Kaminski, MD, University of Pittsburgh Medical Center, NW 628 MUH, 3459 5th Avenue, Pittsburgh, PA 15261
    Affiliations
    Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
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Published:February 07, 2011DOI:https://doi.org/10.1016/j.trsl.2011.01.012
      In this review, we describe the recent advances in the understanding of the role of microRNAs in idiopathic pulmonary fibrosis (IPF), a chronic progressive and lethal fibrotic lung disease. Approximately 10% of the microRNAs are significantly changed in IPF lungs. Among the significantly downregulated microRNAs are members of let-7, mir-29, and mir-30 families as well as miR-17∼92 cluster among the upregulated mir-155 and mir-21. Downregulation of let-7 family members leads to changes consistent with epithelial mesenchymal transition in lung epithelial cells both in vitro and in vivo, whereas inhibition of mir-21 modulates fibrosis in the bleomycin model of lung fibrosis. Perturbations of mir-155 and mir-29 have profibrotic effects in vitro but have not yet been assessed in vivo in the context of lung fibrosis. A recurrent global theme is that many microRNAs studied in IPF are both regulated by transforming growth factor β1 (TGFβ1) and regulate TGFβ1 signaling pathway by their target genes. As a result, their aberrant expression leads to a release of inhibitions on the TGFβ1 pathway and to the creation of feed-forward loops. Coanalysis of published microRNA and gene expression microarray data in IPF reveals enrichment of the TGFβ1, Wnt, sonic hedgehog, p53, and vascular endothelial growth factor pathways and complex regulatory networks. The changes in microRNA expression in the IPF lung and the evidence for their role in the fibrosis suggest that microRNAs should be evaluated as therapeutic targets in IPF.

      Abbreviations:

      AP-1 (activation protein-1), AT1R (angiotensin II type I receptor), EMT (epithelial mesenchymal transition), HMGA2 (h mobility group AT-hook 2), IGF1 (insulin-like growth factor 1), IL (interleukin), IPF (idiopathic pulmonary fibrosis), LNA (locked nucleic acid), MMP (metalloproteinases), PDCD4 (programmed cell death 4), PTEN (phosphatase and tensin homolog), RECK (reversion-inducing-cysteine-rich protein with kazal motifs), SBE (SMAD binding elements), TGFβ1 (transforming growth factor β1), TIMP3 (tissue inhibitor of metalloproteinases 3), VEGF (vascular endothelial growth factor)
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