Endothelial Microparticles are Associated to Pathogenesis of Idiopathic Pulmonary Fibrosis
Endothelial Microparticles are Associated to Pathogenesis of Idiopathic Pulmonary Fibrosis
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DOI：
10.1007/s12015-017-9778-5
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发表时间：
2018-04-01
影响因子：
4.8
通讯作者：
Smadja, David M.
中科院分区：
文献类型：
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作者：
Bacha, Nour C.;Blandinieres, Adeline;Smadja, David M.
特发性肺纤维化（IPF）是一种毁灭性的疾病，其特征是肺泡结构的消失，导致肺功能下降并最终导致死亡。致病机制尚不清楚，但涉及疤痕组织的伴随积累以及肌成纤维细胞的激活。微粒（MP）已在多种人类肺部疾病中作为可能的致病因素、预后标志物和治疗靶点进行了研究。我们假设循环 MP 的水平和细胞起源可能作为 IPF 患者的生物标志物和/或纤维形成的活跃参与者。流式细胞术分析显示，与 22 名健康志愿者相比，41 名 IPF 患者的膜联蛋白 V 阳性内皮细胞和血小板 MP 水平更高。此外，在一氧化碳肺弥散能力较低（DLCO < 40%）的 IPF 患者中，内皮 MP（EMP）显着高于 DLCO > 40% 的患者（p = 0.02）。然后，我们使用从 IPF 患者或对照中提取的内皮祖细胞 (ECFC) 中分离出的 EMP 来调节正常人肺成纤维细胞 (NHLF) 的特性。我们发现电磁脉冲不会改变增殖、胶原沉积和肌成纤维细胞转分化。然而，IPF患者的EMP刺激了NHLF的迁移能力。我们假设这种效应可能是由 EMP 的纤溶特性引起的，并且发现与从健康对照 MP 中分离的那些相比，IPF 患者发出的总循环 MP 和 ECFC 衍生的 MP 中的纤溶酶原激活潜力确实更高。我们的研究表明，IPF 与最严重患者的 EMP 水平升高相关，这突显了后者的内皮激活过程。内皮微粒可能至少部分地通过纤溶活性介导肺成纤维细胞侵袭。
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by obliteration of alveolar architecture, resulting in declining lung function and ultimately death. Pathogenic mechanisms remain unclear but involve a concomitant accumulation of scar tissue together with myofibroblasts activation. Microparticles (MPs) have been investigated in several human lung diseases as possible pathogenic elements, prognosis markers and therapeutic targets. We postulated that levels and cellular origins of circulating MPs might serve as biomarkers in IPF patients and/or as active players of fibrogenesis. Flow cytometry analysis showed a higher level of Annexin-V positive endothelial and platelet MPs in 41 IPF patients compared to 22 healthy volunteers. Moreover, in IPF patients with a low diffusing capacity of the lung for carbon monoxide (DLCO < 40%), endothelial MPs (EMPs) were found significantly higher compared to those with DLCO > 40% (p = 0.02). We then used EMPs isolated from endothelial progenitor cells (ECFCs) extracted from IPF patients or controls to modulate normal human lung fibroblast (NHLF) properties. We showed that EMPs did not modify proliferation, collagen deposition and myofibroblast transdifferentiation. However, EMPs from IPF patients stimulated migration capacity of NHLF. We hypothesized that this effect could result from EMPs fibrinolytic properties and found indeed higher plasminogen activation potential in total circulating MPs and ECFCs derived MPs issued from IPF patients compared to those isolated from healthy controls MPs. Our study showed that IPF is associated with an increased level of EMPs in the most severe patients, highlighting an active process of endothelial activation in the latter. Endothelial microparticles might contribute to the lung fibroblast invasion mediated, at least in part, by a fibrinolytic activity.