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Targeting RUNX1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators.

Authors
  • O'Hare, Michael1
  • Amarnani, Dhanesh1
  • Whitmore, Hannah A B1
  • An, Miranda1
  • Marino, Claudia1
  • Ramos, Leslie1
  • Delgado-Tirado, Santiago1
  • Hu, Xinyao1
  • Chmielewska, Natalia1
  • Chandrahas, Anita1
  • Fitzek, Antonia2
  • Heinrich, Fabian2
  • Steurer, Stefan3
  • Ondruschka, Benjamin2
  • Glatzel, Markus4
  • Krasemann, Susanne4
  • Sepulveda-Falla, Diego4
  • Lagares, David5
  • Pedron, Julien6
  • Bushweller, John H6
  • And 3 more
  • 1 Schepens Eye Research Institute of Mass Eye and Ear and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts.
  • 2 Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. , (Germany)
  • 3 Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. , (Germany)
  • 4 Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. , (Germany)
  • 5 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • 6 Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia.
  • 7 National Institutes of Health, National Human Genome Research Institute, Bethesda, Maryland.
  • 8 Schepens Eye Research Institute of Mass Eye and Ear and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts. Electronic address: [email protected]
  • 9 Schepens Eye Research Institute of Mass Eye and Ear and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts. Electronic address: [email protected]
Type
Published Article
Journal
American Journal Of Pathology
Publisher
Elsevier
Publication Date
Apr 21, 2021
Identifiers
DOI: 10.1016/j.ajpath.2021.04.006
PMID: 33894177
Source
Medline
Language
English
License
Unknown

Abstract

Pulmonary fibrosis (PF) can arise from unknown causes, as in idiopathic PF, or as a consequence of infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current treatments for PF slow, but do not stop, disease progression. We report that treatment with a RUNX1 inhibitor (Ro24-7429), previously found to be safe, although ineffective, as a Tat inhibitor in patients with HIV, robustly ameliorates lung fibrosis and inflammation in the bleomycin-induced PF mouse model. RUNX1 inhibition blunted fundamental mechanisms downstream pathologic mediators of fibrosis and inflammation, including transforming growth factor-β1 and tumor necrosis factor-α, in cultured lung epithelial cells, fibroblasts, and vascular endothelial cells, indicating pleiotropic effects. RUNX1 inhibition also reduced the expression of angiotensin-converting enzyme 2 and FURIN, host proteins critical for SARS-CoV-2 infection, in mice and in vitro. A subset of human lungs with SARS-CoV-2 infection overexpress RUNX1. These data suggest that RUNX1 inhibition via repurposing of Ro24-7429 may be beneficial for PF and to battle SARS-CoV-2, by reducing expression of viral mediators and by preventing respiratory complications. Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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