Contact and respiratory sensitizers can be identified by cytokine profiles following inhalation exposure
Contact and respiratory sensitizers can be identified by cytokine profiles following inhalation exposure
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DOI：
10.1016/j.tox.2009.04.057
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发表时间：
2009-07-10
期刊：
影响因子：
4.5
通讯作者：
Van Loveren, Henk
中科院分区：
文献类型：
--
作者：
De Jong, Wim H.;Arts, Josje H. E.;Van Loveren, Henk
目前没有经过验证的动物模型可以识别低分子量（LMW）呼吸道致敏物。局部淋巴结试验（LLNA）是一种经验证的动物模型，开发用于使用皮肤暴露检测接触性致敏物，但迄今为止检测的所有LMW呼吸道致敏物在该试验中也呈阳性。通过评估细胞因子谱可以区分接触性和呼吸道致敏物。在使用吸入途径的LLNA中，接触和呼吸致敏剂均增强引流淋巴结的增殖。问题是他们的细胞因子谱是否受到暴露途径的影响。雄性BALB/c小鼠在连续3天期间仅头部/鼻子暴露于呼吸致敏剂偏苯三酸酐、邻苯二甲酸酐、甲苯二异氰酸酯、邻苯二甲酸二异氰酸酯（HDI）和异佛尔酮二异氰酸酯;接触致敏剂二硝基氯苯（DNCB）、恶唑酮（OXA）和甲醛（FA）以及刺激性水杨酸甲酯（MS）。最后一次暴露后三天，切除引流淋巴结，用伴刀豆球蛋白A离体刺激后测量细胞因子产生。皮肤应用用作阳性对照。吸入暴露后，呼吸道致敏剂诱导更多的白细胞介素-4（IL-4）和白细胞介素（IL-10）相比，接触致敏剂，而接触致敏剂，除甲醛，诱导相对更多的干扰素-γ（IFN-γ）的生产。当IL-4和IFN-γ作为增殖反应的函数作图时，显示IL-4可用于鉴定除HDI以外的呼吸敏化剂，其浓度水平诱导中间刺激指数。在高SI值下，HDI可与DNCB和OXA区分开。相比之下，接触致敏剂只能确定当IFN-γ在高刺激指数测量。在高浓度下检测的皮肤阳性对照显示出IL-4和IL-10的相当结果，而IFN-γ水平不能用于区分呼吸道和接触性致敏物。接触致敏剂FA和刺激剂MS在吸入和皮肤暴露后未诱导显著的细胞因子产生。总之，呼吸LLNA能够识别和区分强接触和呼吸致敏剂时，同时增殖和细胞因子的生产进行评估，在上呼吸道引流LN。(c)2009爱思唯尔爱尔兰有限公司保留所有权利。
There are currently no validated animal models that can identify low molecular weight (LMW) respiratory sensitizers. The Local Lymph Node Assay (LLNA) is a validated animal model developed to detect contact sensitizers using skin exposure, but all LMW respiratory sensitizers tested so far were also positive in this assay. Discrimination between contact and respiratory sensitizers can be achieved by the assessment of cytokine profiles. In a LLNA using the inhalation route, both contact and respiratory sensitizers enhanced proliferation in the draining lymph nodes. The question was if their cytokine profiles were affected by the route of exposure. Male BALB/c mice were exposed head/nose-only during 3 consecutive days to the respiratory sensitizers trimellitic anhydride, phthalic anhydride, toluene diisocyanate, hexamethylene diisocyanate (HDI), and isophorone diisocyanate; the contact sensitizers dinitrochlorobenzene (DNCB), oxazolone (OXA) and formaldehyde (FA), and the irritant methyl salicylate (MS). Three days after the last exposure the draining lymph nodes were excised and cytokine production was measured after ex vivo stimulation with Concanavalin A. Skin application was used as a positive control. After inhalation exposure the respiratory sensitizers induced more interleukin-4 (IL-4) and interleukin (IL-10) compared to the contact sensitizers, whereas the contact sensitizers, except formaldehyde, induced relatively more interferon-gamma (IFN-gamma) production. When IL-4 and IFN-gamma were plotted as a function of the proliferative response, it was shown that IL-4 could be used to identify respiratory sensitizers, except HDI, at concentration levels inducing intermediate stimulation indices. HDI could be distinguished from DNCB and OXA at high SI values. In contrast, contact sensitizers could only be identified when IFN-gamma was measured at high stimulation indices. The skin positive control, tested at high concentrations, showed comparable results for IL-4 and IL-10, whereas IFN-gamma levels could not be used to discriminate between respiratory and contact sensitizers. The contact sensitizer FA and the irritant MS did not induce significant cytokine production after inhalation and skin exposure. In conclusion, the respiratory LLNA is able to identify and distinguish strong contact and respiratory sensitizers when simultaneously proliferation and cytokine production are assessed in the upper respiratory tract draining LNs. (c) 2009 Elsevier Ireland Ltd. All rights reserved.