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
  • 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: [email protected].
  • 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: [email protected].
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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