Vascular protection by young circulating extracellular vesicles ameliorates aging-related pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal, aging-related disease characterized by aberrant lung remodeling and progressive scarring, leading to organ failure and death. Current FDA-approved antifibrotic treatments are unable to reverse established disease, highlighting the need for innovative therapeutic approaches targeting novel pathways and cell types. Mounting evidence, including our own, has recently highlighted the pathogenic role of aging-related endothelial abnormalities, including vascular inflammation and oxidative stress, in the progression of lung fibrosis, offering new therapeutic opportunities to block IPF progression. Unexplored, however, are the modalities to restore vascular abnormalities associated with progressive lung fibrosis, representing a critical gap to effective treatments for IPF. In this study, we demonstrate that circulating extracellular vesicles (cEVs) isolated from young mice are capable of reversing the aging-associated transcriptional alterations of the pulmonary vasculature, reducing transcripts associated with innate immunity, oxidative stress, and senescence, while simultaneously increasing transcripts linked to endothelial identity. Using the bleomycin model of persistent lung fibrosis in aged mice, we then demonstrate that pretreatment with cEVs improves the vascular response to injury and attenuates lung fibrosis progression, as demonstrated by reduced lung collagen content and preserved vascular network and lung architecture. These findings support the efficacy of interventions targeting endothelial aging-associated transcriptional alterations, such as young cEV delivery, in mitigating pulmonary fibrosis progression in animal models of persistent fibrosis and indicate the potential benefits of combined therapies that simultaneously address vascular and nonvascular aspects of IPF.<b>NEW & NOTEWORTHY</b> This study demonstrates that circulating extracellular vesicles (cEVs) isolated from young mice reverse the transcriptional alterations of the aged mouse pulmonary vasculature, leading to a more youthful endothelial transcriptional phenotype. As a result of this vascular phenotype, aged mice are protected from bleomycin-induced pulmonary fibrosis. These findings highlight the therapeutic potential of targeting vascular aging to alleviate pulmonary fibrosis.