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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

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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, Vol. 191, No. 7, 07.2021, p. 1193-1208.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

O'Hare, M, Amarnani, D, Whitmore, HAB, An, M, Marino, C, Ramos, L, Delgado-Tirado, S, Hu, X, Chmielewska, N, Chandrahas, A, Fitzek, A, Heinrich, F, Steurer, S, Ondruschka, B, Glatzel, M, Krasemann, S, Sepulveda-Falla, D, Lagares, D, Pedron, J, Bushweller, JH, Liu, P, Arboleda-Velasquez, JF & Kim, LA 2021, 'Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators', AM J PATHOL, vol. 191, no. 7, pp. 1193-1208. https://doi.org/10.1016/j.ajpath.2021.04.006

APA

O'Hare, M., Amarnani, D., Whitmore, H. A. B., An, M., Marino, C., Ramos, L., Delgado-Tirado, S., Hu, X., Chmielewska, N., Chandrahas, A., Fitzek, A., Heinrich, F., Steurer, S., Ondruschka, B., Glatzel, M., Krasemann, S., Sepulveda-Falla, D., Lagares, D., Pedron, J., ... Kim, L. A. (2021). Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators. AM J PATHOL, 191(7), 1193-1208. https://doi.org/10.1016/j.ajpath.2021.04.006

Vancouver

O'Hare M, Amarnani D, Whitmore HAB, An M, Marino C, Ramos L et al. 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. https://doi.org/10.1016/j.ajpath.2021.04.006

Bibtex

@article{fd675b4d64a54675b536e1783bdffb67,
title = "Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators",
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.",
keywords = "Angiotensin-Converting Enzyme 2/metabolism, Animals, Bleomycin, COVID-19/metabolism, Cells, Cultured, Core Binding Factor Alpha 2 Subunit/antagonists & inhibitors, Disease Models, Animal, Epithelial Cells/drug effects, Female, Furin/metabolism, Lung/drug effects, Male, Mice, Pulmonary Fibrosis/chemically induced, Treatment Outcome",
author = "Michael O'Hare and Dhanesh Amarnani and Whitmore, {Hannah A B} and Miranda An and Claudia Marino and Leslie Ramos and Santiago Delgado-Tirado and Xinyao Hu and Natalia Chmielewska and Anita Chandrahas and Antonia Fitzek and Fabian Heinrich and Stefan Steurer and Benjamin Ondruschka and Markus Glatzel and Susanne Krasemann and Diego Sepulveda-Falla and David Lagares and Julien Pedron and Bushweller, {John H} and Paul Liu and Arboleda-Velasquez, {Joseph F} and Kim, {Leo A}",
note = "Copyright {\textcopyright} 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.",
year = "2021",
month = jul,
doi = "10.1016/j.ajpath.2021.04.006",
language = "English",
volume = "191",
pages = "1193--1208",
journal = "AM J PATHOL",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "7",

}

RIS

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 -