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Lung-derived exosomes in phosgene-induced acute lung injury regulate the functions of mesenchymal stem cells partially via miR-28-5p.

光气诱导急性肺损伤的肺源性外泌体部分通过 miR-28-5p 调节间充质干细胞的功能。

  • 影响因子:3.78
  • DOI:10.1016/j.biopha.2019.109603
  • 作者列表:"Xu N","He D","Shao Y","Qu Y","Ye K","Memet O","Zhang L","Shen J
  • 发表时间:2020-01-01
Abstract

:Accidental phosgene exposure can result in acute lung injury (ALI). Mesenchymal stem cells (MSCs) have been found to alleviate phosgene-induced ALI. However, the mechanism of MSCs underlying such protective effect remains largely unexplored. Exosomes, important components of microenvironment, are closely associated with intercellular information transfer. In the present study, we isolated lung exosomes in rats after phosgene exposure by ultracentrifugation and explored their effects on MSCs in vitro. ALI exosomes were elliptical in shape and 50-200 nm in size. ALI exosomes could promote proliferation and migration of MSCs. Moreover, ALI exosomes increased the secretion of IL-10, leading to enhanced immunoregulatory properties of MSCs. The paracrine factors, VEGF, HGF, LL-37 and Ang-1, were also augmented by ALI exosomes. However, ALI exosomes had no effect on differentiation of MSCs towards lung alveolar cells. To identify the effective miRNAs in ALI exosomes, we performed miRNA profile analysis. MiR-28-5p was considered as a possible effective molecule. We further studied the effect of miR-28-5p on MSCs. MiR-28-5p mimic promoted proliferation, migration, immunomodulation of MSCs. MiR-28-5p mimic promoted the paracrine of VEGF, HGF, LL-37 and Ang-1. Besides, we explored molecular mechanism of miR-28-5p in MSCs. PI3K/Akt signaling pathway was found significantly augmented by miR-28-5p mimic, indicating the activation in this process. Taken together, our findings could help identify the effects of lung-derived exosomes on MSCs, and the effective molecule in exosomes, miR-28-5p, activated MSCs through PI3K/Akt signaling pathway.

摘要

意外光气暴露可导致急性肺损伤 (ALI)。间充质干细胞 (MSCs) 被发现可以缓解光气诱导的 ALI。然而,MSCs 这种保护作用的机制在很大程度上仍未被探索。外泌体是微环境的重要组成部分,与细胞间信息传递密切相关。在本研究中,我们通过超速离心法分离了光气暴露后大鼠的肺外泌体,并探讨了它们在体外对 MSCs 的影响。ALI 外泌体呈椭圆形,大小为 50-200 nm。ALI 外泌体可促进 MSCs 的增殖和迁移。此外,ALI 外泌体增加了 IL-10 的分泌,导致 MSCs 的免疫调节特性增强。ALI 外泌体也可增强旁分泌因子 VEGF 、 HGF 、 LL-37 和 Ang-1。而 ALI 外泌体对 MSCs 向肺泡细胞分化无影响。为了鉴定 ALI 外泌体中的有效 miRNAs,我们进行了 miRNA 谱分析。MiR-28-5p 被认为是一种可能的有效分子。我们进一步研讨了 miR-28-5p 对 MSCs 的影响。MiR-28-5p 模拟物促进 MSCs 的增殖、迁移、免疫调节。MiR-28-5p 模拟促进 VEGF,HGF,LL-37 和 Ang-1 的旁分泌。此外,我们还探讨了 MSCs miR-28-5p 的分子机制。PI3K/Akt 信号通路被 miR-28-5p 模拟物显著增强,表明这一过程中的激活。总之,我们的研究结果有助于确定肺来源的外泌体对 MSCs 的影响,外泌体中的有效分子 miR-28-5p 通过 PI3K/Akt 信号通路激活 MSCs。

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影响因子:3.94
发表时间:2020-01-15
DOI:10.1016/j.taap.2019.114847
作者列表:["Bernstein DM","Toth B","Rogers RA","Kling DE","Kunzendorf P","Phillips JI","Ernst H"]

METHODS::The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.

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影响因子:4.04
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DOI:10.1042/BST20191010
作者列表:["Zaragosi LE","Deprez M","Barbry P"]

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