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Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators.
O'Hare, Michael; Amarnani, Dhanesh; Whitmore, Hannah A B; An, Miranda; Marino, Claudia; Ramos, Leslie; Delgado-Tirado, Santiago; Hu, Xinyao; Chmielewska, Natalia; Chandrahas, Anita; Fitzek, Antonia; Heinrich, Fabian; Steurer, Stefan; Ondruschka, Benjamin; Glatzel, Markus; Krasemann, Susanne; Sepulveda-Falla, Diego; Lagares, David; Pedron, Julien; Bushweller, John H; Liu, Paul; Arboleda-Velasquez, Joseph F; Kim, Leo A.
  • O'Hare M; Schepens Eye Research Institute of Mass Eye and Ear, Boston, Massachusetts, and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts.
  • Amarnani D; Schepens Eye Research Institute of Mass Eye and Ear, Boston, Massachusetts, and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts.
  • Whitmore HAB; Schepens Eye Research Institute of Mass Eye and Ear, Boston, Massachusetts, and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts.
  • An M; Schepens Eye Research Institute of Mass Eye and Ear, Boston, Massachusetts, and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts.
  • Marino C; Schepens Eye Research Institute of Mass Eye and Ear, Boston, Massachusetts, and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts.
  • Ramos L; Schepens Eye Research Institute of Mass Eye and Ear, Boston, Massachusetts, and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts.
  • Delgado-Tirado S; Schepens Eye Research Institute of Mass Eye and Ear, Boston, Massachusetts, and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts.
  • Hu X; Schepens Eye Research Institute of Mass Eye and Ear, Boston, Massachusetts, and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts.
  • Chmielewska N; Schepens Eye Research Institute of Mass Eye and Ear, Boston, Massachusetts, and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts.
  • Chandrahas A; Schepens Eye Research Institute of Mass Eye and Ear, Boston, Massachusetts, and the Department of Ophthalmology at Harvard Medical School, Boston, Massachusetts.
  • Fitzek A; Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Heinrich F; Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Steurer S; Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Ondruschka B; Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Glatzel M; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Krasemann S; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Sepulveda-Falla D; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Lagares D; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Pedron J; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia.
  • Bushweller JH; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia.
  • Liu P; National Institutes of Health, National Human Genome Research Institute, Bethesda, Maryland.
  • Arboleda-Velasquez JF; 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.
  • Kim LA; 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.
Am J Pathol ; 191(7): 1193-1208, 2021 07.
Статья в английский | MEDLINE | ID: covidwho-1283899
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-ß1 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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Полный текст: Имеется в наличии Коллекция: Международные базы данных база данных: MEDLINE Основная тема: Pulmonary Fibrosis / Furin / Core Binding Factor Alpha 2 Subunit / Angiotensin-Converting Enzyme 2 / COVID-19 / Lung Тип исследования: Прогностическое исследование Пределы темы: Животные Язык: английский Журнал: Am J Pathol Год: 2021 Тип: Статья

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Полный текст: Имеется в наличии Коллекция: Международные базы данных база данных: MEDLINE Основная тема: Pulmonary Fibrosis / Furin / Core Binding Factor Alpha 2 Subunit / Angiotensin-Converting Enzyme 2 / COVID-19 / Lung Тип исследования: Прогностическое исследование Пределы темы: Животные Язык: английский Журнал: Am J Pathol Год: 2021 Тип: Статья