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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

: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.


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。



作者列表:["De Cunto G","Brancaleone V","Riemma MA","Cerqua I","Vellecco V","Spaziano G","Cavarra E","Bartalesi B","D'Agostino B","Lungarella G","Cirino G","Lucattelli M","Roviezzo F"]

METHODS:BACKGROUND AND PURPOSE:A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). EXPERIMENTAL APPROACH:C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. KEY RESULTS:Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. CONCLUSIONS AND IMPLICATIONS:S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.

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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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作者列表:["Zaragosi LE","Deprez M","Barbry P"]

METHODS::The respiratory tract is lined by a pseudo-stratified epithelium from the nose to terminal bronchioles. This first line of defense of the lung against external stress includes five main cell types: basal, suprabasal, club, goblet and multiciliated cells, as well as rare cells such as ionocytes, neuroendocrine and tuft/brush cells. At homeostasis, this epithelium self-renews at low rate but is able of fast regeneration upon damage. Airway epithelial cell lineages during regeneration have been investigated in the mouse by genetic labeling, mainly after injuring the epithelium with noxious agents. From these approaches, basal cells have been identified as progenitors of club, goblet and multiciliated cells, but also of ionocytes and neuroendocrine cells. Single-cell RNA sequencing, coupled to lineage inference algorithms, has independently allowed the establishment of comprehensive pictures of cell lineage relationships in both mouse and human. In line with genetic tracing experiments in mouse trachea, studies using single-cell RNA sequencing (RNAseq) have shown that basal cells first differentiate into club cells, which in turn mature into goblet cells or differentiate into multiciliated cells. In the human airway epithelium, single-cell RNAseq has identified novel intermediate populations such as deuterosomal cells, 'hybrid' mucous-multiciliated cells and progenitors of rare cells. Novel differentiation dynamics, such as a transition from goblet to multiciliated cells have also been discovered. The future of cell lineage relationships in the respiratory tract now resides in the combination of genetic labeling approaches with single-cell RNAseq to establish, in a definitive manner, the hallmarks of cellular lineages in normal and pathological situations.

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