MiR-1307-5p enhances fibroblast transdifferentiation to exacerbate chronic obstructive pulmonary disease through regulating FBXL16/HIF1α axis.

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-10-17 DOI:10.1186/s12931-024-03007-6
Li-Peng Yao, Zheng-Kai Wang, Xin-Qing Jiang, Beier Jiang, Si-Jia Chen, Zhi-Dan Hua, Dan-Dan Gao, Quan Zheng, Sheng-Mei Zhu, Mao-Xiang Qian, Feng Zhang, Li-Feng Xu, Cheng-Shui Chen, Fang Lu
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Abstract

Chronic obstructive pulmonary disease (COPD) is an irreversible and progressive chronic inflammatory lung disease which affects millions of people worldwide. Activated fibroblasts are observed to accumulate in lung of COPD patients and promote COPD progression through aberrant extracellular matrix (ECM) deposition. In this study, we identified that miR-1307-5p expression was significantly increased in lung fibroblasts derived from COPD patients. Mechanistically, we found that upregulation of miR-1307-5p promoted TGF-β induced lung fibroblast activation and transdifferentiation. We also identified FBXL16 as a direct target for miR-1307-5p mediated myofibroblast activation in COPD. Knockdown of FBXL16 by siRNA prominently increased the expression of myofibroblast markers in MRC-5 fibroblasts after TGF-β administration. Ectopic expression of FBXL16 in MRC-5 counteracted miR-1307-5p agomir-induced fibroblast transdifferentiation. Furthermore, We found that miR-1307-5p promoted pulmonary fibroblast transdifferentiation through FBXL16 regulated HIF1α degradation. In general, our findings indicate that miR-1307-5p is important for COPD pathogenesis, and may serve as a potential target for COPD treatment.

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MiR-1307-5p通过调节FBXL16/HIF1α轴增强成纤维细胞的转分化,从而加重慢性阻塞性肺病。
慢性阻塞性肺病(COPD)是一种不可逆的进行性慢性炎症性肺病,影响着全球数百万人。据观察,活化的成纤维细胞在慢性阻塞性肺病患者的肺部聚集,并通过细胞外基质(ECM)的异常沉积促进慢性阻塞性肺病的进展。在这项研究中,我们发现在慢性阻塞性肺病患者的肺成纤维细胞中,miR-1307-5p 的表达明显增加。从机理上讲,我们发现 miR-1307-5p 的上调促进了 TGF-β 诱导的肺成纤维细胞活化和转分化。我们还发现 FBXL16 是 miR-1307-5p 介导的慢性阻塞性肺疾病肌成纤维细胞活化的直接靶点。在给予 TGF-β 后,通过 siRNA 敲除 FBXL16 能显著增加 MRC-5 成纤维细胞中肌成纤维细胞标记物的表达。FBXL16 在 MRC-5 中的异位表达抵消了 miR-1307-5p agomir 诱导的成纤维细胞转分化。此外,我们还发现,miR-1307-5p 通过 FBXL16 调控 HIF1α 降解促进了肺成纤维细胞的转分化。总之,我们的研究结果表明,miR-1307-5p 对慢性阻塞性肺病的发病机制非常重要,可作为治疗慢性阻塞性肺病的潜在靶点。
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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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