Idiopathic Pulmonary Fibrosis (IPF) is a fatal, aging-related disease characterized by persistent lung fibroblast activation, progressive lung scarring and several vascular abnormalities. We have previously demonstrated that aging-associated vascular dysfunction drives maladaptive endothelial responses to injury and exacerbates lung fibrosis via secretion of pro-fibrotic endothelial-derived factors. However, regulatory mechanisms governing endothelial dysfunction during progressive lung fibrosis remain poorly understood. Here, using preclinical mouse models of progressive lung fibrosis as well as human IPF lungs, we demonstrate that miR-205-5p is overexpressed in lung ECs from fibrotic lungs, and coordinates gene expression programs implicated in endothelial dysfunction and progressive fibrosis. Mechanistically, miR-205-5p induces senescence in lung ECs, mirroring the senescent phenotype of IPF lung ECs. Consistently, conditioned medium derived from lung ECs overexpressing miR-205-5p promotes lung fibroblast activation. Importantly, miR-205-5p inhibition in IPF lung ECs attenuates endothelial senescence and limits paracrine fibroblast activation. Finally, inhibition of miR-205-5p in vivo preserves the pulmonary vascular network and attenuates lung fibrosis progression in aged mice challenged with bleomycin. Collectively, our findings support a novel connection between lung endothelial miR-205-5p, endothelial senescence and pro-fibrotic alteration of the endothelial secretome, and highlight miR-205-5p inhibition as a potential therapeutic intervention for pulmonary fibrosis.
Muscato et al. (Thu,) studied this question.