Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
Am J Respir Cell Mol Biol. 2020 Nov;63(5):623-636. doi: 10.1165/rcmb.2020-0002OC.
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 , 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.
上皮-间充质相互作用异常在调节纤维化发展中起关键作用。细胞外囊泡（EVs），包括外泌体，在特发性肺纤维化（IPF）的发病机制中的作用仍有待阐明。在这里，我们发现 IPF 患者的肺成纤维细胞（LFs）通过 EV 介导的将致病货物转移到肺上皮细胞，诱导细胞衰老。在机制上，IPF LF 衍生的 EVs 增加了肺上皮细胞中线粒体活性氧和相关的线粒体损伤，导致 DNA 损伤反应的激活和随后的上皮细胞衰老。我们表明，IPF LF 衍生的 EVs 含有高水平的 microRNA-23b-3p（miR-23b-3p）和 miR-494-3p，它们抑制 Sirtuin 1 (SIRT1)，导致上皮 EV 诱导的表型变化。此外，在 IPF LF 衍生的 EVs 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，在 IPF 发病机制中观察到的加速的上皮细胞线粒体损伤和衰老，是由 IPF 成纤维细胞通过含有 microRNA 的 EV 发挥的一种新的旁分泌作用引起的。
