2. Academic Validation
  3. Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators

Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators

  • Am J Pathol. 2021 Jul;191(7):1193-1208. doi: 10.1016/j.ajpath.2021.04.006.
Michael O'Hare 1,  Dhanesh Amarnani 1,  Hannah A B Whitmore 1,  Miranda An 1,  Claudia Marino 1,  Leslie Ramos 1,  Santiago Delgado-Tirado 1,  Xinyao Hu 1,  Natalia Chmielewska 1,  Anita Chandrahas 1,  Antonia Fitzek 2,  Fabian Heinrich 2,  Stefan Steurer 3,  Benjamin Ondruschka 2,  Markus Glatzel 4,  Susanne Krasemann 4,  Diego Sepulveda-Falla 4,  David Lagares 5,  Julien Pedron 6,  John H Bushweller 6,  Paul Liu 7,  Joseph F Arboleda-Velasquez 8,  Leo A Kim 9
Affiliations

Affiliations

  • 1 Schepens Eye Research Institute of Mass Eye and Ear, Boston, Massachusetts, and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts.
  • 2 Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 3 Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 4 Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, 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, Boston, Massachusetts, and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts. Electronic address: joseph_arboleda@meei.harvard.edu.
  • 9 Schepens Eye Research Institute of Mass Eye and Ear, Boston, Massachusetts, and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts. Electronic address: leo_kim@meei.harvard.edu.
PMID: 33894177 DOI: 10.1016/j.ajpath.2021.04.006
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 runt-related transcription factor 1 (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 FES Upstream Region (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.

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