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RAGE-induced ILC2 expansion in acute lung injury due to haemorrhagic shock.

出血休克引起的急性肺损伤中 RAGE 诱导的 ILC2 扩张。

  • 影响因子:4.63
  • DOI:10.1136/thoraxjnl-2019-213613
  • 作者列表:"Zhang K","Jin Y","Lai D","Wang J","Wang Y","Wu X","Scott M","Li Y","Hou J","Billiar T","Wilson M","Shu Q","Fang X","Fan J
  • 发表时间:2020-01-14

BACKGROUND:Type 2 immune dysfunction contributes to acute lung injury and lethality following haemorrhagic shock (HS) and trauma. Group 2 innate lymphoid cells (ILC2s) play a significant role in the regulation of type 2 immune responses. However, the role of ILC2 in post-HS acute lung injury and the underlying mechanism has not yet been elucidated. OBJECTIVE:To investigate the regulatory role of ILC2s in HS-induced acute lung injury and the underlying mechanism in patients and animal model. METHODS:Circulating markers of type 2 immune responses in patients with HS and healthy controls were characterised. Using a murine model of HS, the role of high-mobility group box 1 (HMGB1)-receptor for advanced glycation end products (RAGE) signalling in regulation of ILC2 proliferation, survival and function was determined. And the role of ILC2 in inducing type 2 immune dysfunction was assessed as well. RESULTS:The number of ILC2s was significantly increased in the circulation of patients with HS that was correlated with the increase in the markers of type 2 immune responses in the patients. Animal studies showed that HMGB1 acted via RAGE to induce ILC2 accumulation in the lungs by promoting ILC2 proliferation and decreasing ILC2 death. The expansion of ILC2s resulted in type 2 cytokines secretion and eosinophil infiltration in the lungs, both of which contributed to lung injury after HS. CONCLUSIONS:These results indicate that HMGB1-RAGE signalling plays a critical role in regulating ILC2 biological function that aggravates type 2 lung inflammation following HS.


背景: 2 型免疫功能紊乱导致失血性休克和创伤后的急性肺损伤和致死。第 2 组固有淋巴细胞 (ILC2s) 在调节 2 型免疫反应中起着重要作用。然而,ILC2 在 HS 后急性肺损伤中的作用及其机制尚未阐明。 目的: 探讨 ILC2s 在急性肺损伤中的调节作用及其机制。 方法: 对 HS 患者和健康对照者的循环 2 型免疫反应标志物进行表征。使用 HS 鼠模型,高迁移率族蛋白 b1 (HMGB1)-晚期糖基化终产物受体 (RAGE) 信号在 ILC2 增殖调控中的作用, 确定生存和功能。并评估 ILC2 在诱导 2 型免疫功能紊乱中的作用。 结果: HS 患者循环中 ILC2s 数量显著增加,与患者 2 型免疫反应标志物增加相关。动物研究表明,HMGB1 通过 RAGE 诱导 ILC2 在肺部蓄积,促进 ILC2 增殖,减少 ILC2 死亡。ILC2s 的扩张导致 2 型细胞因子的分泌和肺部嗜酸性粒细胞的浸润,这两者都有助于 HS 后的肺损伤。 结论: 这些结果表明,HMGB1-RAGE 信号在调节 ILC2 生物学功能中起关键作用,加重 HS 后 2 型肺部炎症。



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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