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.
【초록키워드】 Treatment, SARS-CoV-2, Inflammation, coronavirus, SARS-COV-2 infection, Respiratory complications, fibrosis, in vitro, pulmonary, angiotensin-converting enzyme 2, Disease progression, Region, infections, mice, human lung, Lung fibrosis, inhibitor, expression, Critical, mechanism, Lung epithelial cells, Pleiotropic effects, fibroblasts, Safe, transcription factor, tumor necrosis factor-α, acute respiratory syndrome, growth, causes, vascular endothelial cells, host protein, RUNX1, downstream, current, pathologic, reduced, reducing, subset, FES, overexpress, patients with HIV, Ro24-7429, 【제목키워드】 pulmonary, coronavirus 2, respiratory, mediator, Factor, targeting,