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Functional contribution of sphingosine-1-phosphate to airway pathology in cigarette smoke-exposed mice.

Sphingosine-1-phosphate 对香烟烟雾暴露小鼠气道病理的功能贡献。

  • 影响因子:6.12
  • DOI:10.1111/bph.14861
  • 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
  • 发表时间:2020-01-01
Abstract

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.

摘要

背景与目的: 在呼吸系统疾病中,鞘氨醇激酶/sphingosine-1-phosphate (S1P) 通路在控制气道功能中发挥关键作用。在此,我们讨论 S1P 在轻度慢性阻塞性肺疾病 (COPD) 小鼠模型中的贡献。 实验方法: C57BL/6J 小鼠暴露在室内空气或香烟烟雾中长达 11 个月,并在不同时间点处死。已经进行了功能和分子研究。 关键结果: 香烟烟雾引起整个肺实质的气肿性改变,在细支气管周围和支气管周围区域伴有进行性胶原沉积。高和低气道对胆碱能刺激和 α-平滑肌肌动蛋白过表达表现出反应性增加。同样,S1P 激发后,吸烟小鼠的气道反应性和肺阻力增加。在吸烟小鼠肺内检测到 S1P 、 Sph-K2 和 S1P 受体 (S1P2 和 S1P3) 的高表达。鞘氨醇激酶抑制逆转了吸烟小鼠气道胆碱能反应的增加。 结论和意义: S1P 信号上调遵循吸烟小鼠的疾病进展,并参与气道高反应性的发展。我们的研究定义了 S1P 抑制剂在管理与哮喘和 COPD 吸烟者肺气肿相关的气道高反应性中的治疗潜力。

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影响因子:6.12
发表时间:2020-01-01
DOI:10.1111/bph.14861
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.

关键词: 暂无
翻译标题与摘要 下载文献
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.

关键词: 暂无
翻译标题与摘要 下载文献
影响因子:4.04
发表时间:2020-01-10
DOI:10.1042/BST20191010
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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