tetano
Editor, Senior Moderator
Am J Pathol
. 2021 Apr 21;S0002-9440(21)00161-9.
doi: 10.1016/j.ajpath.2021.04.006. Online ahead of print.
Targeting RUNX1 prevents pulmonary fibrosis and reduces expression of SARS-CoV-2 host mediators
Michael O'Hare[SUP] 1 [/SUP], Dhanesh Amarnani[SUP] 1 [/SUP], Hannah A B Whitmore[SUP] 1 [/SUP], Miranda An[SUP] 1 [/SUP], Claudia Marino[SUP] 1 [/SUP], Leslie Ramos[SUP] 1 [/SUP], Santiago Delgado-Tirado[SUP] 1 [/SUP], Xinyao Hu[SUP] 1 [/SUP], Natalia Chmielewska[SUP] 1 [/SUP], Anita Chandrahas[SUP] 1 [/SUP], Antonia Fitzek[SUP] 2 [/SUP], Fabian Heinrich[SUP] 2 [/SUP], Stefan Steurer[SUP] 3 [/SUP], Benjamin Ondruschka[SUP] 2 [/SUP], Markus Glatzel[SUP] 4 [/SUP], Susanne Krasemann[SUP] 4 [/SUP], Diego Sepulveda-Falla[SUP] 4 [/SUP], David Lagares[SUP] 5 [/SUP], Julien Pedron[SUP] 6 [/SUP], John H Bushweller[SUP] 6 [/SUP], Paul Liu[SUP] 7 [/SUP], Joseph F Arboleda-Velasquez[SUP] 8 [/SUP], Leo A Kim[SUP] 9 [/SUP]
Affiliations
Abstract
Pulmonary fibrosis (PF) can arise from unknown causes as in idiopathic pulmonary fibrosis (IPF), 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 RUNX1 inhibitor (Ro24-7429), previously found to be safe, though 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 pathological mediators of fibrosis and inflammation including TGF-?1 and TNF-? in cultured lung epithelial cells, fibroblasts, and vascular endothelial cells indicating pleiotropic effects. RUNX1 inhibition also reduced the expression of ACE2 and 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.
. 2021 Apr 21;S0002-9440(21)00161-9.
doi: 10.1016/j.ajpath.2021.04.006. Online ahead of print.
Targeting RUNX1 prevents pulmonary fibrosis and reduces expression of SARS-CoV-2 host mediators
Michael O'Hare[SUP] 1 [/SUP], Dhanesh Amarnani[SUP] 1 [/SUP], Hannah A B Whitmore[SUP] 1 [/SUP], Miranda An[SUP] 1 [/SUP], Claudia Marino[SUP] 1 [/SUP], Leslie Ramos[SUP] 1 [/SUP], Santiago Delgado-Tirado[SUP] 1 [/SUP], Xinyao Hu[SUP] 1 [/SUP], Natalia Chmielewska[SUP] 1 [/SUP], Anita Chandrahas[SUP] 1 [/SUP], Antonia Fitzek[SUP] 2 [/SUP], Fabian Heinrich[SUP] 2 [/SUP], Stefan Steurer[SUP] 3 [/SUP], Benjamin Ondruschka[SUP] 2 [/SUP], Markus Glatzel[SUP] 4 [/SUP], Susanne Krasemann[SUP] 4 [/SUP], Diego Sepulveda-Falla[SUP] 4 [/SUP], David Lagares[SUP] 5 [/SUP], Julien Pedron[SUP] 6 [/SUP], John H Bushweller[SUP] 6 [/SUP], Paul Liu[SUP] 7 [/SUP], Joseph F Arboleda-Velasquez[SUP] 8 [/SUP], Leo A Kim[SUP] 9 [/SUP]
Affiliations
- PMID: 33894177
- DOI: 10.1016/j.ajpath.2021.04.006
Abstract
Pulmonary fibrosis (PF) can arise from unknown causes as in idiopathic pulmonary fibrosis (IPF), 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 RUNX1 inhibitor (Ro24-7429), previously found to be safe, though 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 pathological mediators of fibrosis and inflammation including TGF-?1 and TNF-? in cultured lung epithelial cells, fibroblasts, and vascular endothelial cells indicating pleiotropic effects. RUNX1 inhibition also reduced the expression of ACE2 and 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.