MicroRNA-486-5p Promotes Acute Lung Injury via Inducing Inflammation and Apoptosis by Targeting OTUD7B.

MicroRNA-486-5p 通过靶向 OTUD7B 诱导炎症和凋亡促进急性肺损伤。

  • 影响因子:2.84
  • DOI:10.1007/s10753-020-01183-3
  • 作者列表:"Luo Q","Zhu J","Zhang Q","Xie J","Yi C","Li T
  • 发表时间:2020-01-15

:The aim of this article is to study the effect of miR-486-5p in acute lung injury (ALI). MiR-486-5p expression in peripheral blood was determined in ALI patients and healthy volunteers by qRT-PCR. ALI mouse model were reproduced by LPS treatment, and miR-486-5p NC and miRNA-486 inhibitors were injected through trachea. ALI patients' peripheral blood and LPS-induced acute lung injury in mice had significantly higher miR-486-5p levels than control subjects. Inhibition of miR-486-5p by injection with antagomiR-486-5p markedly reduced LPS-induced lung inflammation. Moreover, knockdown of miR-486-5p can reduce protects A549 cell against LPS-induced injury and its corresponding inflammatory response. In addition, Mechanistic analysis indicated that miR-486-5p on the occurrence of ALI is related to the inhibition of OTUD7B activity, which induces the downregulation of inflammatory in ALI. Our results identified miR-486-5p independently associated with ALI. miR-486-5p can mediate the formation of ALI by promoting inflammation.


本文旨在研究 miR-486-5p 在急性肺损伤 (ALI) 中的作用。用 qRT-PCR 法测定 ALI 患者和健康志愿者外周血 MiR-486-5p 的表达。LPS 处理复制 ALI 小鼠模型,气管内注射 NC 和 miR-486-5p 抑制剂 miRNA-486。ALI 患者外周血和 LPS 诱导的小鼠急性肺损伤的 miR-486-5p 水平明显高于对照组。注射 miR-486-5p 抑制 antagomiR-486-5p 可显著降低 LPS 诱导的肺部炎症。此外,敲除 miR-486-5p 可降低 A549 细胞对 LPS 诱导的损伤及其相应的炎症反应的保护作用。此外,机制分析表明,miR-486-5p 对 ALI 的发生与抑制 OTUD7B 活性有关,从而诱导 ALI 的炎症下调。我们的结果确定了与 ALI 独立相关的 miR-486-5p。miR-486-5p 可以通过促进炎症介导 ALI 的形成。



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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