Abstract

<b>Introduction:</b> Idiopathic pulmonary fibrosis (IPF) is a lethal and chronic lung disease characterized by injury and activation of the lung epithelium, (myo)fibroblast and immune cells all leading to extracellular matrix deposition and non-functional lung tissue. Extracellular vesicles (EVs) accumulate within the lung during IPF. Here, we investigate the proteome cargo of these vesicles. <b>Methods:</b> EVs were isolated from broncho-alveolar lavage fluid (BALF) collected from mice with bleomycin-induced pulmonary fibrosis and culture media from primary fibroblasts using ultracentrifugation. These vesicles were analyzed by nanoparticle tracking analysis, Western Blotting and a label-free mass spectrometry. The functional effects of the EVs were studied using organoid assays and with the bleomycin mouse model. <b>Results:</b> Our proteomic approach identified 107 proteins specifically enriched in fibrotic BALF-EVs. This signature was associated with wound healing, extracellular matrix organization and cell motility. Fibroblasts expressed high levels of proteins specific to fibrotic BALF-EVs such as Secreted Frizzled Related Protein (SFRP)1. In the lung of patients with IPF, SFRP1 was significantly increased in mesenchymal cells. Functionally, fibrotic BALF-EVs increased WNT/β-catenin signaling and impaired organoid development. Furthermore, Sfrp1 deficiency impaired the ability of fibroblast-derived EVs to potentiate bleomycin-induced lung fibrosis. <b>Conclusion:</b> During pulmonary fibrosis, EVs carry specific protein cargos to contribute to organ remodeling. Our data support that proteins enriched in EVs during fibrosis, such as SFRP1, may represent therapeutic targets.

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