Aberrant epithelial–mesenchymal interactions have critical roles in regulating fibrosis development. The involvement of extracellular vesicles (EVs), including exosomes, remains to be elucidated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we found that lung fibroblasts (LFs) from patients with IPF induce cellular senescence via EV-mediated transfer of pathogenic cargo to lung epithelial cells. Mechanistically, IPF LF–derived EVs increased mitochondrial reactive oxygen species and associated mitochondrial damage in lung epithelial cells, leading to activation of the DNA damage response and subsequent epithelial-cell senescence. We showed that IPF LF-derived EVs contain elevated levels of microRNA-23b-3p (miR-23b-3p) and miR-494-3p, which suppress SIRT3, resulting in the epithelial EV-induced phenotypic changes. Furthermore, the levels of miR-23b-3p and miR-494-3p found in IPF LF–derived EVs correlated positively with IPF disease severity. These findings reveal that the accelerated epithelial-cell mitochondrial damage and senescence observed during IPF pathogenesis are caused by a novel paracrine effect of IPF fibroblasts via microRNA-containing EVs.

异常的上皮-间质相互作用在调节纤维化发展中起关键作用。在特发性肺纤维化（IPF）的发病机理中尚需阐明包括囊泡在内的细胞外囊泡（EVs）的参与。在这里，我们发现IPF患者的肺成纤维细胞（LFs）通过EV介导的病原体转移到肺上皮细胞而诱导细胞衰老。从机理上讲，IPF LF衍生的电动汽车增加了肺上皮细胞中的线粒体活性氧种类和相关的线粒体损伤，从而导致DNA损伤反应的激活和随后的上皮细胞衰老。我们发现IPF LF衍生的电动汽车含有升高水平的microRNA-23b-3p（miR-23b-3p）和miR-494-3p，可抑制SIRT3，导致EV上皮引起的表型改变。此外，在IPF LF衍生的电动汽车中发现的miR-23b-3p和miR-494-3p的水平与IPF疾病严重程度呈正相关。这些发现表明IPF发病机理中观察到的加速的上皮细胞线粒体损伤和衰老是由IPF成纤维细胞通过含microRNA的EV产生的新旁分泌作用引起的。