Ban M, Hettich D, Goutet M, Bonnet P
Institut National de Recherche et de Securite, Vandoeuvre, France.
Toxicol Lett. 1997 Dec;93(2-3):185-94. doi: 10.1016/s0378-4274(97)00091-x.
Toluene diisocyanate (TDI) can cause occupational asthma, but the mechanism underlying sensitization to this chemical compound remains controversial. The present study aims to investigate whether tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) liberated in the lungs after TDI inhalation can contribute to the migration of dendritic cells from respiratory airways towards lung associated lymph nodes for presentation of TDI hapten. Exposure was studied in two modes: (1) acute exposure (experiment no. 1, 2 and 3) where animals were exposed to 2.962, 1.060, and 1.076 ppm TDI for 1, 4, and two periods of 4 h, respectively; (2) subacute exposure (experiment no. 4, 5 and 6) where animals were exposed to 0.066, 0.110, and 0.999 ppm TDI for 48 h for the two lower doses and 5 days for the highest dose. Depending on the modes of exposure, two to four post exposure times were selected. After acute exposure to 2.962 ppm TDI for 1 h, the increase in TNF-alpha and IL-6 levels in bronchoalveolar lavage (BAL) fluid was observed immediately at the end of inhalation exposure, whereas the maximum number of dendritic cells and total cells occurred at post exposure times of 48 h and 5 days, respectively. In two other acute exposures, the peak increases in TNF-alpha, IL-6 and total cell numbers were observed at 48 h post exposure time, whereas the peak increase in dendritic cells occurred at 24 h. After subacute exposure to 48 h TDI, where TDI concentrations were relatively low (0.006 or 0.110 ppm), a parallel increase in TNF-alpha and IL-6 levels, dendritic and total cell numbers were observed at 0 h post exposure time. This phenomenon was also apparent at 24 h post exposure time when the animals had been exposed to 1.999 ppm TDI for 5 days. From these results, we can conclude that dendritic cells could play a key role as antigen presenting cells in the development of TDI-induced respiratory sensitization, and that their migration toward lung-associated lymph nodes is probably conditioned by cytokine release in their micro-environment. Future work must delineate whether TNF-alpha and IL-6 are solely responsible for the migration of dendritic cells after TDI inhalation, for example by using antibodies to neutralize these cytokines.
甲苯二异氰酸酯（TDI）可引发职业性哮喘，但对这种化合物致敏的潜在机制仍存在争议。本研究旨在探究吸入TDI后肺中释放的肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）是否有助于树突状细胞从呼吸道向肺相关淋巴结迁移，以呈递TDI半抗原。研究了两种暴露模式：（1）急性暴露（实验1、2和3），动物分别暴露于2.962、1.060和1.076 ppm的TDI中1小时、4小时以及两个4小时时间段；（2）亚急性暴露（实验4、5和6），较低剂量组动物暴露于0.066、0.110 ppm的TDI中48小时，最高剂量组动物暴露于0.999 ppm的TDI中5天。根据暴露模式，选择了两到四个暴露后时间点。急性暴露于2.962 ppm的TDI 1小时后，在吸入暴露结束时立即观察到支气管肺泡灌洗（BAL）液中TNF-α和IL-6水平升高，而树突状细胞和总细胞的最大数量分别出现在暴露后48小时和5天。在另外两次急性暴露中，TNF-α、IL-6和总细胞数的峰值增加出现在暴露后48小时，而树突状细胞的峰值增加出现在24小时。亚急性暴露于TDI 48小时（TDI浓度相对较低，为0.006或0.110 ppm）后，在暴露后0小时观察到TNF-α和IL-6水平、树突状细胞和总细胞数平行增加。当动物暴露于1.999 ppm的TDI 5天时，在暴露后24小时也出现了这种现象。从这些结果可以得出结论，树突状细胞可能作为抗原呈递细胞在TDI诱导的呼吸道致敏过程中发挥关键作用，并且它们向肺相关淋巴结的迁移可能受其微环境中细胞因子释放的调节。未来的工作必须明确TNF-α和IL-6是否是TDI吸入后树突状细胞迁移的唯一原因，例如通过使用抗体中和这些细胞因子来进行研究。
