Transcriptional analysis of lung fibroblasts identifies PIM1 signaling as a driver of aging-associated persistent fibrosis.
Transcriptional analysis of lung fibroblasts identifies PIM1 signaling as a driver of aging-associated persistent fibrosis.
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肺成纤维细胞的转录分析将PIM 1信号转导鉴定为衰老相关的持续性纤维化的驱动因素。
DOI：
10.1172/jci.insight.153672
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发表时间：
2022-03-22
期刊：
影响因子：
8
通讯作者：
Ligresti G
中科院分区：
文献类型：
--
作者：
Pham TX;Lee J;Guan J;Caporarello N;Meridew JA;Jones DL;Tan Q;Huang SK;Tschumperlin DJ;Ligresti G
特发性肺纤维化（IPF）是一种以肌成纤维细胞积累和进行性肺瘢痕为特征的衰老相关疾病。为了确定在衰老过程中驱动持续性肺纤维化的转录基因程序，我们对博来霉素损伤后早期分离的年轻和老年小鼠的肺成纤维细胞进行了RNA-Seq分析。我们发现，相对于受伤的年轻成纤维细胞，受伤的老年成纤维细胞表现出以炎症、基质重塑和细胞存活相关基因表达升高为特征的促纤维化状态。我们确定了Moloney小鼠白血病病毒1 （PIM1）的前整合位点及其靶核因子活化T细胞-1 （NFATc1）可能是损伤的衰老成纤维细胞中持续的促纤维化基因特征的驱动因素。PIM1和NFATc1转录本在最近在IPF肺中发现的致病性成纤维细胞群中富集，它们的蛋白表达在成纤维细胞灶中丰富。在正常人肺成纤维细胞中，PIM1的过表达增强了它们的成纤维活化，而这种作用通过抑制NFATc1而减弱。药理抑制PIM1可减弱IPF成纤维细胞的激活并使其对凋亡刺激敏感。体外IPF肺外植体中PIM1信号通路的中断抑制了促生存基因的表达和胶原分泌，表明靶向这一途径可能是阻断IPF进展的一种治疗策略。
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.
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影响因子：
--
作者：
Habiel DM;Hogaboam CM
通讯作者：
Hogaboam CM
DOI：
10.1002/path.4749
发表时间：
2016-09
期刊：
The Journal of pathology
影响因子：
--
作者：
Im J;Kim K;Hergert P;Nho RS
通讯作者：
Nho RS
影响因子：
4.8
作者：
Gabriel, Christian H.;Gross, Fridolin;Baumgrass, Ria
通讯作者：
Baumgrass, Ria
影响因子：
7.8
作者：
Caporarello, Nunzia;Meridew, Jeffrey A.;Ligresti, Giovanni
通讯作者：
Ligresti, Giovanni
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK