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肺成纤维细胞转录组分析鉴定 PIM1 信号为与衰老相关的持续性纤维化的驱动因素。

Transcriptional analysis of lung fibroblasts identifies PIM1 signaling as a driver of aging-associated persistent fibrosis.

机构信息

Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA.

出版信息

JCI Insight. 2022 Mar 22;7(6):e153672. doi: 10.1172/jci.insight.153672.

Abstract

Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by myofibroblast accumulation and progressive lung scarring. To identify transcriptional gene programs driving persistent lung fibrosis in aging, we performed RNA-Seq on lung fibroblasts isolated from young and aged mice during the early resolution phase after bleomycin injury. We discovered that, relative to injured young fibroblasts, injured aged fibroblasts exhibited a profibrotic state characterized by elevated expression of genes implicated in inflammation, matrix remodeling, and cell survival. We identified the proviral integration site for Moloney murine leukemia virus 1 (PIM1) and its target nuclear factor of activated T cells-1 (NFATc1) as putative drivers of the sustained profibrotic gene signatures in injured aged fibroblasts. PIM1 and NFATc1 transcripts were enriched in a pathogenic fibroblast population recently discovered in IPF lungs, and their protein expression was abundant in fibroblastic foci. Overexpression of PIM1 in normal human lung fibroblasts potentiated their fibrogenic activation, and this effect was attenuated by NFATc1 inhibition. Pharmacological inhibition of PIM1 attenuated IPF fibroblast activation and sensitized them to apoptotic stimuli. Interruption of PIM1 signaling in IPF lung explants ex vivo inhibited prosurvival gene expression and collagen secretion, suggesting that targeting this pathway may represent a therapeutic strategy to block IPF progression.

摘要

特发性肺纤维化(IPF)是一种与年龄相关的疾病,其特征是肌成纤维细胞积聚和进行性肺瘢痕形成。为了确定导致衰老过程中持续肺纤维化的转录基因程序,我们对博来霉素损伤后早期恢复阶段从小鼠肺成纤维细胞中分离的年轻和老年小鼠的肺成纤维细胞进行了 RNA-Seq 分析。与年轻的受损成纤维细胞相比,我们发现受损的老年成纤维细胞表现出一种促纤维化状态,其特征是与炎症、基质重塑和细胞存活相关的基因表达上调。我们鉴定了莫洛尼鼠白血病病毒 1(PIM1)的前病毒整合位点及其靶基因激活 T 细胞核因子-1(NFATc1),它们是受损老年成纤维细胞中持续的促纤维化基因特征的潜在驱动因素。PIM1 和 NFATc1 的转录本在最近在 IPF 肺中发现的致病性成纤维细胞群体中富集,其蛋白表达在纤维母细胞灶中丰富。在正常的人肺成纤维细胞中过表达 PIM1 增强了它们的纤维化激活作用,而 NFATc1 抑制可减弱这种作用。PIM1 的药理学抑制减弱了 IPF 成纤维细胞的激活,并使它们对凋亡刺激敏感。在体外阻断 PIM1 信号通路可抑制 IPF 肺组织中的促生存基因表达和胶原蛋白分泌,提示靶向该通路可能是阻止 IPF 进展的一种治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1b30/8986080/d8f5ba5e503e/jciinsight-7-153672-g009.jpg

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