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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Activation Of Critical, Host-induced, Metabolic And Stress Pathways Marks Neutrophil Entry Into Cystic Fibrosis Lungs
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Activation Of Critical, Host-induced, Metabolic And Stress Pathways Marks Neutrophil Entry Into Cystic Fibrosis Lungs

机译:关键的,宿主诱导的,代谢和应激途径的激活标志着中性粒细胞进入囊性纤维化肺。

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摘要

Cystic fibrosis (CF) patients undergo progressive airway destruction caused in part by chronic neutrophilic inflammation. While opportunistic pathogens infecting CF airways can cause inflammation, we hypothesized that host-derived metabolic and stress signals would also play a role in this process. We show that neutrophils that have entered CF airways have increased phos-phorylation of the eukaryotic initiation factor 4E and its partner the 4E-binding protein 1; 2 key effectors in the growth factor- and amino acid-regulated mammalian target of rapamycin (mTOR) pathway. Furthermore CF airway neutrophils display increased phosphorylation of the cAMP response element binding protein (CREB), a major transcriptional coactivator in stress signaling cascades. These active intracellular pathways are associated with increased surface expression of critical adaptor molecules, including the growth factor receptor CD114 and the receptor for advanced glycation end-products (RAGE), a CREB inducer and sensor for host-derived damage-associated molecular patterns (DAMPs). Most CF airway fluids lack any detectable soluble RAGE, an inhibitory decoy receptor for DAMPs. Concomitantly, CF airway fluids displayed high and consequently unopposed levels of S100A12; a potent mucosa- and neutrophil-derived DAMP. CF airway neutrophils also show increased surface levels of 2 critical CREB targets, the purine-recycling enzyme CD39 and the multifunctional, mTOR-inducing CXCR4 receptor. This coordinated set of events occurs in all patients, even in the context of minimal airway inflammation and well-preserved lung function. Taken together, our data demonstrate an early and sustained activation of host-responsive metabolic and stress pathways upon neutrophil entry into CF airways, suggesting potential targets for therapeutic modulation.rnCFTR; EN-RAGE; flow cytometry; S6 ribosomal protein; stromal derived factor-1
机译:囊性纤维化(CF)患者经历进行性气道破坏,部分原因是慢性嗜中性粒细胞炎症。尽管感染CF气道的机会性病原体可能会引起炎症,但我们假设宿主衍生的代谢和应激信号也将在此过程中起作用。我们显示,进入CF气道的嗜中性粒细胞增加了真核生物起始因子4E及其伴侣4E结合蛋白1的磷酸化;雷帕霉素(mTOR)途径的生长因子和氨基酸调节的哺乳动物靶标中的2个关键效应子。此外,CF气道中性粒细胞显示出cAMP反应元件结合蛋白(CREB)的磷酸化增加,这是应激信号级联反应中的主要转录共激活因子。这些活跃的细胞内途径与关键衔接子分子的表面表达增加相关,包括生长因子受体CD114和晚期糖基化终产物的受体(RAGE),CREB诱导剂和宿主来源的损伤相关分子模式(DAMPs)的传感器。 )。大多数CF气道液缺乏任何可检测到的可溶性RAGE,这是DAMP的抑制性诱饵受体。随之而来的是,CF气道液显示出较高的水平,因此S100A12的水平保持不变。一种有效的黏膜和中性粒细胞衍生的DAMP。 CF气道中性粒细胞还显示2个关键CREB靶,嘌呤回收酶CD39和多功能,诱导mTOR的CXCR4受体的表面水平升高。即使在最小的气道炎症和肺功能良好的情况下,所有患者也会发生这种协调的事件。两者合计,我们的数据表明中性粒细胞进入CF气道后,宿主响应性代谢和应激途径的早期持续活化,暗示了治疗调节的潜在靶点。激怒;流式细胞仪S6核糖体蛋白;基质衍生因子-1

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    Departments of Pediatrics and Stanford University School of Medicine, Stanford, CA 94305;

    Departments of Pediatrics and Stanford University School of Medicine, Stanford, CA 94305;

    Departments of Pediatrics and Stanford University School of Medicine, Stanford, CA 94305;

    Departments of Pediatrics and Stanford University School of Medicine, Stanford, CA 94305;

    Departments of Pediatrics and Stanford University School of Medicine, Stanford, CA 94305;

    Departments of Pediatrics and Stanford University School of Medicine, Stanford, CA 94305;

    Departments of Pediatrics and Stanford University School of Medicine, Stanford, CA 94305;

    Departments of Pediatrics and Stanford University School of Medicine, Stanford, CA 94305;

    Departments of Genetics, Stanford University School of Medicine, Stanford, CA 94305;

    Departments of Genetics, Stanford University School of Medicine, Stanford, CA 94305;

    Departments of Pediatrics and Stanford University School of Medicine, Stanford, CA 94305;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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