Toluene diisocyanate (TDI), a highly reactive industrial chemical is one of the leading causes of occupation-related asthma in industrialized countries. The pathophysiology of TDI-induced asthma, however, remains poorly understood, in part due to a lack of appropriate animal models. In this study, four models of TDI-sensitised mice were investigated. In model number 1, the mice were sensitised for 4 h/day on four consecutive days to 3 ppm inhaled TDI and challenged twice for 4 h each time with 0.3 ppm inhaled TDI. In model number 2, the sensitising condition was similar to that of model 1, but the challenge conditions involved an initial inhalation of 2 ppmTDI for 4h and then tracheal instillation with 50 microg/mouse albumin-TDI. In model number 3, the mice were sensitised first to 25% TDI (sc) and then three times for 4 h each time to 1 ppm inhaled TDI and challenged twice for 4h each time with 0.1 ppm inhalated TDI. In model number 4, the mice were first sensitised to 1% TDI by skin application and then with 0.2% TDI by tracheal instillation and challenged tree times by tracheal instillation of 0.1% TDI. In model number 4, skin application followed by tracheal instillations of TDI led to local and systemic Th2-dominated immune responses that were characterized: (1) in the lung-associated lymph nodes by a decrease in Th1 cytokine (IFN-gamma) production associated with an increase in Th2 cytokine (IL-4, IL-5, IL-3) production; (2) in the lungs by an allergic inflammation throughout the conducting airways: goblet cell proliferation and eosinophil influx and; (3) in the serums by increased total and specific IgE levels, 17.5- and 3.5-fold higher than that of the controls, respectively. The conditions used for sensitisation in the other models, i.e. inhalation or subcutaneous administration plus inhalation, failed to induce a strong Th2 response like that observed in model number 4. The findings indicate that TDI can induce a Th2-dominated response in mice when administered by topical application plus tracheal instillation for sensitisation and by intra-tracheal instillation for challenge (model number 4). This mouse Th2 model of TDI-induced airway allergy can, in several aspects, mimic occupational TDI asthma in humans and may prove to be useful in determining the mechanistic basis behind this disease.

译文

甲苯二异氰酸酯 (TDI) 是一种高反应性的工业化学品,是工业化国家与职业相关的哮喘的主要原因之一。然而,TDI诱导的哮喘的病理生理学仍然知之甚少,部分原因是缺乏合适的动物模型。在这项研究中,研究了四种TDI致敏小鼠模型。在模型1中,小鼠连续4天对3 ppm吸入的TDI致敏4小时/天,并用0.3 ppm吸入的TDI攻击两次,每次4小时。在模型2中,致敏条件与模型1相似,但是攻击条件包括最初吸入2 ppmTDI 4小时,然后气管滴注50 microg/小鼠白蛋白-TDI。在模型3中,首先使小鼠致敏以25% TDI (sc),然后三次,每次4小时,以lppm吸入TDI,并且用0.1 ppm吸入TDI攻击两次,每次4小时。在模型4中,首先通过皮肤施用使小鼠对1% TDI敏感,然后通过气管滴注0.2% TDI,并通过气管滴注0.1% TDI来激发树时间。在4号模型中,皮肤应用,然后气管滴注TDI导致局部和全身Th2-dominated免疫反应,其特征是 :( 1) 在肺相关淋巴结中,Th1细胞因子 (IFN-γ) 的产生减少,Th2细胞因子的增加 (IL-4,IL-5,IL-3) 产生; (2) 在肺部通过整个传导气道的过敏性炎症: 杯状细胞增殖和嗜酸性粒细胞流入; (3) 在血清中通过增加总IgE水平和特异性IgE水平,分别比对照组高17.5倍和3.5倍。在其他模型中用于致敏的条件,即吸入或皮下给药加吸入,未能像在模型4中观察到的那样引起强烈的Th2反应。研究结果表明,当通过局部应用加气管滴注致敏和气管内滴注致敏 (模型4) 给药时,TDI可以在小鼠中诱导Th2-dominated反应。这种TDI诱导的气道过敏的小鼠Th2模型可以在几个方面模仿人类的职业性TDI哮喘,并且可能被证明可用于确定该疾病背后的机制基础。

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