Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators
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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.
in: AM J PATHOL, Jahrgang 191, Nr. 7, 07.2021, S. 1193-1208.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators
AU - O'Hare, Michael
AU - Amarnani, Dhanesh
AU - Whitmore, Hannah A B
AU - An, Miranda
AU - Marino, Claudia
AU - Ramos, Leslie
AU - Delgado-Tirado, Santiago
AU - Hu, Xinyao
AU - Chmielewska, Natalia
AU - Chandrahas, Anita
AU - Fitzek, Antonia
AU - Heinrich, Fabian
AU - Steurer, Stefan
AU - Ondruschka, Benjamin
AU - Glatzel, Markus
AU - Krasemann, Susanne
AU - Sepulveda-Falla, Diego
AU - Lagares, David
AU - Pedron, Julien
AU - Bushweller, John H
AU - Liu, Paul
AU - Arboleda-Velasquez, Joseph F
AU - Kim, Leo A
N1 - Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
KW - Angiotensin-Converting Enzyme 2/metabolism
KW - Animals
KW - Bleomycin
KW - COVID-19/metabolism
KW - Cells, Cultured
KW - Core Binding Factor Alpha 2 Subunit/antagonists & inhibitors
KW - Disease Models, Animal
KW - Epithelial Cells/drug effects
KW - Female
KW - Furin/metabolism
KW - Lung/drug effects
KW - Male
KW - Mice
KW - Pulmonary Fibrosis/chemically induced
KW - Treatment Outcome
U2 - 10.1016/j.ajpath.2021.04.006
DO - 10.1016/j.ajpath.2021.04.006
M3 - SCORING: Journal article
C2 - 33894177
VL - 191
SP - 1193
EP - 1208
JO - AM J PATHOL
JF - AM J PATHOL
SN - 0002-9440
IS - 7
ER -