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Activation of aryl hydrocarbon receptor by benzo[a]pyrene increases interleukin 33 expression and eosinophil infiltration in a mouse model of allergic airway inflammation.

苯并 [a] 芘激活芳香烃受体增加变应性气道炎症小鼠模型白细胞介素 33 表达和嗜酸性粒细胞浸润。

  • 影响因子:3.14
  • DOI:10.1002/jat.4017
  • 作者列表:"Tajima H","Tajiki-Nishino R","Watanabe Y","Kurata K","Fukuyama T
  • 发表时间:2020-06-18

:We recently demonstrated that benzo[a]pyrene (BaP), the aryl hydrocarbon receptor (AhR) ligand, directly contributes to aggravation of cutaneous allergy in a mouse model of allergic dermatitis. The present study aimed to determine whether BaP-induced AhR activation results in development of airway inflammation. Initially, the potential for a direct relationship between BaP-induced AhR activation and airway inflammation was investigated in vivo, using a mouse model of type 2 helper T cell (Th2) hapten toluene-2,4-diisocyanate (TDI)-induced airway inflammation. Mice were orally administered BaP at 48, 24, and 4 h before the final allergen challenge. Oral administration of BaP showed a significant increase in lung inflammation and eosinophil infiltration. While expression of Th2 cytokines such as interleukin 4 (IL-4) and IL-13 was not affected by exposure to BaP, AhR activation significantly increased IL-33 expression. To confirm the in vivo results, in vitro experiments were performed using the human eosinophilic leukemia cell line (EOL-1), human bronchial epithelial cell line (BEAS-2B), and human lung adenocarcinoma epithelial cell line (A549). Results indicated that pre-treatment with BaP increased expression of IL-8 in house dust mite-activated EOL-1, BEAS-2B, and A549 cells. In addition, IL-33 levels in BEAS-2B cells were significantly increased after BaP exposure. Our findings indicated that BaP-induced AhR activation is involved in the pro-inflammatory response in respiratory allergy, and that this effect may be mediated by increased IL-33 expression and eosinophil infiltration.


: 我们最近证明,芳基烃受体 (AhR) 配体苯并 [a] 芘 (BaP) 直接有助于过敏性皮炎小鼠模型皮肤过敏的加重。本研究旨在确定 BaP 诱导的 AhR 激活是否导致气道炎症的发生。最初,使用 2 型辅助性 T 细胞 (Th2) 半抗原甲苯-2 的小鼠模型,在体内研究了 BaP 诱导的 AhR 活化与气道炎症之间直接关系的潜力,4-二异氰酸酯 (TDI) 诱导的气道炎症。小鼠在最终过敏原激发前 48 、 24 和 4 h 经口给予 BaP。口服 BaP 表现为肺部炎症和嗜酸性粒细胞浸润明显增加。而 Th2 细胞因子如白细胞介素 4 (IL-4) 和 IL-13 的表达不受暴露于 BaP 的影响,AhR 激活显著增加 IL-33 表达。为了证实体内结果,使用人嗜酸性粒细胞白血病细胞系 (EOL-1) 、人支气管上皮细胞系 (BEAS-2B) 进行体外实验,和人肺腺癌上皮细胞系 (A549)。结果表明,BaP 预处理可增加屋尘螨活化 IL-8 、 EOL-1 和 A549 细胞中 BEAS-2B 的表达。此外,BaP 暴露后 IL-33 细胞中 BEAS-2B 水平显著升高。我们的研究结果表明,BaP 诱导的 AhR 激活参与了呼吸道过敏的促炎症反应,这种作用可能是通过增加 IL-33 表达和嗜酸性粒细胞浸润介导的。



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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