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Metabolomic profile perturbations of serum, lung, bronchoalveolar lavage fluid, spleen and feces in LPS-induced acute lung injury rats based on HPLC-ESI-QTOF-MS.

基于 HPLC-ESI-QTOF-MS 对 LPS 诱导的急性肺损伤大鼠血清、肺、支气管肺泡灌洗液、脾脏和粪便的代谢组学分析。

  • 影响因子:3.18
  • DOI:10.1007/s00216-019-02357-1
  • 作者列表:"Wang T","Lin S","Liu R","Li H","Liu Z","Zhang X","Xu H","Li Q","Bi K
  • 发表时间:2020-01-15

:Acute lung injury (ALI) is a clinically common and serious disease, underscoring the urgent need for clarification of its pathogenesis. According to traditional Chinese medicine (TCM) theories on the "lung-spleen-intestine axis" and its correlation with ALI, a high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS) metabolomic platform was applied to identify biomarkers from five bio-samples of control and model rats challenged with intratracheally administered lipopolysaccharide (LPS) based on multivariate mathematical statistical analysis. As a result, 19, 24, 24, 15 and 29 altered metabolites were identified in serum, lung, bronchoalveolar lavage fluid (BALF), spleen and feces samples, respectively. Metabolic pathway analysis showed that linoleic acid, sphingolipid, glycerophospholipid and bile acid metabolism pathways were mainly altered by ALI. Additionally, ROC curves were applied to assess the specificity and sensitivity of the biomarkers. ALI characteristic metabolomic spectra were then established to differentiate the control from the model group with a similarity discriminative threshold of 0.7. Additionally, to compare the metabolomic profiles of the five bio-samples and establish metabolic similarities and differences among them, correlation analysis was conducted in order to delineate an objective law of endogenous linkage along the lung-spleen-intestine axis. Therefore, this study provides insights into the mechanisms involved in ALI from a metabolomics perspective, which can be applied in characterization of the mechanism and early disease detection. Graphical abstract.


急性肺损伤 (ALI) 是临床常见而严重的疾病,迫切需要阐明其发病机制。根据中医关于 “肺-脾-肠轴” 及其与 ALI 相关性的理论, 高效液相色谱-四极杆飞行时间质谱法 (HPLC-QTOF-MS) 应用代谢组学平台,基于多元数学统计分析,从 5 个对照和模型大鼠的生物样本中鉴定生物标志物。结果,在血清、肺、支气管肺泡灌洗液 (BALF) 、脾脏和粪便样本中分别鉴定出 19 、 24 、 15 和 29 种改变的代谢物。代谢途径分析表明,亚油酸、鞘脂、甘油磷脂和胆汁酸代谢途径主要被 ALI 改变。此外,应用 ROC 曲线评估生物标志物的特异性和敏感性。然后建立 ALI 特征代谢组学谱,以 0.7 的相似性判别阈值区分对照和模型组。此外,为了比较五种生物样本的代谢组学特征,并建立它们之间的代谢异同, 进行相关分析,以描绘沿肺-脾-肠轴的内源性连锁的客观规律。因此,本研究从代谢组学的角度对 ALI 的参与机制提供了见解,可应用于机制的表征和疾病的早期检测。图形摘要。



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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