Investigation of a UPR-Related Gene Signature Identifies the Pro-Fibrotic Effects of Thrombospondin-1 by Activating CD47/ROS/Endoplasmic Reticulum Stress Pathway in Lung Fibroblasts.
Investigation of a UPR-Related Gene Signature Identifies the Pro-Fibrotic Effects of Thrombospondin-1 by Activating CD47/ROS/Endoplasmic Reticulum Stress Pathway in Lung Fibroblasts.
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对UPR相关基因特征的研究确定了血栓反应蛋白-1通过激活肺成纤维细胞CD47/ROS/内质网应激途径的促纤维化作用。
DOI：
10.3390/antiox12122024
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发表时间：
2023-11-21
期刊：
影响因子：
--
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中科院分区：
文献类型：
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未折叠蛋白反应（UPR）信号和内质网（ER）应激与肺纤维化有关。然而，特发性肺纤维化（IPF）患者UPR状态与肺功能和预后之间的关系仍不清楚。通过一系列生物信息学分析，我们建立了IPF患者UPR状态与肺功能之间的相关性。此外，血小板反应蛋白-1（TSP-1）被确定为IPF患者预后评估的潜在生物标志物。通过利用批量RNA分析和单细胞RNA测序数据，我们证明了肺纤维化期间肺成纤维细胞中TSP-1的上调。基因集富集分析（GSEA）结果表明，肺成纤维细胞中TSP-1表达与活性氧（ROS）通路相关的基因集之间呈正相关。TSP-1单独过表达可诱导轻度ER应激和肺纤维化，甚至可加重博莱霉素诱导的ER应激和肺纤维化。从机制上讲，TSP-1通过CD 47依赖性ROS产生促进ER应激和成纤维细胞活化。用TSP-1抑制剂或CD 47抑制剂治疗显著减弱BLM诱导的ER应激和肺纤维化。总的来说，这些发现表明肺纤维化期间TSP-1的升高不仅是一种生物标志物，而且可能在肺纤维化变化中起致病作用。
Unfolded protein response (UPR) signaling and endoplasmic reticulum (ER) stress have been linked to pulmonary fibrosis. However, the relationship between UPR status and pulmonary function and prognosis in idiopathic pulmonary fibrosis (IPF) patients remains largely unknown. Through a series of bioinformatics analyses, we established a correlation between UPR status and pulmonary function in IPF patients. Furthermore, thrombospondin-1 (TSP-1) was identified as a potential biomarker for prognostic evaluation in IPF patients. By utilizing both bulk RNA profiling and single-cell RNA sequencing data, we demonstrated the upregulation of TSP-1 in lung fibroblasts during pulmonary fibrosis. Gene set enrichment analysis (GSEA) results indicated a positive association between TSP-1 expression and gene sets related to the reactive oxygen species (ROS) pathway in lung fibroblasts. TSP-1 overexpression alone induced mild ER stress and pulmonary fibrosis, and it even exacerbated bleomycin-induced ER stress and pulmonary fibrosis. Mechanistically, TSP-1 promoted ER stress and fibroblast activation through CD47-dependent ROS production. Treatment with either TSP-1 inhibitor or CD47 inhibitor significantly attenuated BLM-induced ER stress and pulmonary fibrosis. Collectively, these findings suggest that the elevation of TSP-1 during pulmonary fibrosis is not merely a biomarker but likely plays a pathogenic role in the fibrotic changes in the lung.
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