Department of Critical Care Medicine, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, 650 Xinsongjiang Road, Shanghai, 201620, China.
Department of Intensive Care Medicine, Wuxi People's Hospital, Nanjing Medical University, Wuxi, 214021, Jiangsu, China.
Arch Toxicol. 2024 May;98(5):1399-1413. doi: 10.1007/s00204-024-03700-x. Epub 2024 Mar 9.
Pulmonary fibrosis involves destruction of the lung parenchyma and extracellular matrix deposition. Effective treatments for pulmonary fibrosis are lacking and its pathogenesis is still unclear. Studies have found that epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AECs) plays an important role in progression of pulmonary fibrosis. Thus, an in-depth exploration of its mechanism might identify new therapeutic targets. In this study, we revealed that a novel circular RNA, MKLN1 (circMKLN1), was significantly elevated in two pulmonary fibrosis models (intraperitoneally with PQ, 50 mg/kg for 7 days, and intratracheally with BLM, 5 mg/kg for 28 days). Additionally, circMKLN1 was positively correlated with the severity of pulmonary fibrosis. Inhibition of circMKLN1 expression significantly reduced collagen deposition and inhibited EMT in AECs. EMT was aggravated after circMKLN1 overexpression in AECs. MiR-26a-5p/miR-26b-5p (miR-26a/b), the targets of circMKLN1, were confirmed by luciferase reporter assays. CircMKLN1 inhibition elevated miR-26a/b expression. Significantly decreased expression of CDK8 (one of the miR-26a/b targets) was observed after inhibition of circMKLN1. EMT was exacerbated again, and CDK8 expression was significantly increased after circMKLN1 inhibition and cotransfection of miR-26a/b inhibitors in AECs. Our research indicated that circMKLN1 promoted CDK8 expression through sponge adsorption of miR-26a/b, which regulates EMT and pulmonary fibrosis. This study provides a theoretical basis for finding new targets or biomarkers in pulmonary fibrosis.
肺纤维化涉及肺实质和细胞外基质的破坏。目前缺乏有效的肺纤维化治疗方法，其发病机制仍不清楚。研究发现，肺泡上皮细胞（AEC）的上皮-间充质转化（EMT）在肺纤维化的进展中起着重要作用。因此，深入探讨其机制可能为新的治疗靶点提供依据。在这项研究中，我们发现一种新型环状 RNA，MKLN1（circMKLN1），在两种肺纤维化模型（腹腔注射博来霉素，50mg/kg，7 天；气管内滴注博来霉素，5mg/kg，28 天）中显著升高。此外，circMKLN1 与肺纤维化的严重程度呈正相关。抑制 circMKLN1 的表达可显著减少胶原沉积，抑制 AEC 中的 EMT。在 AEC 中转染 circMKLN1 过表达后，EMT 加重。circMKLN1 的靶基因 miR-26a-5p/miR-26b-5p（miR-26a/b）通过荧光素酶报告基因实验得到证实。circMKLN1 抑制 miR-26a/b 的表达。抑制 circMKLN1 后，观察到 CDK8（miR-26a/b 的靶基因之一）的表达显著下降。EMT 再次加剧，在 AEC 中转染 miR-26a/b 抑制剂后抑制 circMKLN1，CDK8 表达显著增加。我们的研究表明，circMKLN1 通过海绵吸附 miR-26a/b 促进 CDK8 的表达，从而调节 EMT 和肺纤维化。这项研究为寻找肺纤维化的新靶点或生物标志物提供了理论依据。
