Monteiro-Riviere Nancy A, Baynes Ronald E, Riviere Jim E
Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA.
Toxicology. 2003 Feb 1;183(1-3):15-28. doi: 10.1016/s0300-483x(02)00421-3.
Gulf War personnel were given pyridostigmine bromide (PB) as a prophylactic treatment against organophosphate nerve agent exposure, and were exposed to the insecticide permethrin and the insect repellent N,N-diethyl-m-toluamide (DEET). The purpose of this study was to assess the effects of PB to modulate release of inflammatory biomarkers after topical chemical exposure to chemical mixtures containing permethrin and DEET applied in ethanol or water vehicles. Treatments were topically applied to isolated perfused porcine skin flaps (IPPSFs). Concentrations of interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E(2) (PGE(2)) were assayed in perfusate to probe for potential inflammatory effects after complex mixture application. IPPSFs (n=4/treatment) were topically dosed with mixtures of permethrin, DEET, and permethrin/DEET, in ethanol. Each treatment was repeated with perfusate spiked with 50 ng/ml of PB. Perfusate was also spiked with 30 ng/ml diisopropylfluorophosphate to simulate low level organophosphate nerve agent exposure. Timed IPPSF venous effluent samples (0.5,1,2,4, and 8 h) were assayed by ELISA for IL-8 and TNF-alpha and by EIA for PGE(2). Overall, PB infusion caused a decrease or IL-8 and PGE(2) release. Effects on TNF-alpha were vehicle dependent. To probe the potential mechanism of this PB effect, human epidermal keratinocyte HEK cell cultures were exposed to permethrin DEET permethrin/DEET, with and without PB in DMSO. IL-8 was assayed at 1, 2, 4, 8, 12 and 24 h. PB suppressed IL-8 in permethrin and ethanol treatment from 4 to 24 h confirming the IPPSF results. In conclusion, these studies suggest that systemic exposure to PB suppressed IL-8 release at multiple time points in two skin model systems. This interaction merits further study.
海湾战争时期的人员曾服用溴化吡啶斯的明（PB）作为预防有机磷酸酯类神经毒剂暴露的治疗手段，并且接触过杀虫剂氯菊酯和驱蚊剂N，N - 二乙基 - m - 甲苯胺（避蚊胺，DEET）。本研究的目的是评估在局部化学暴露于含氯菊酯和避蚊胺的化学混合物（以乙醇或水为载体）后，PB对调节炎症生物标志物释放的影响。将处理剂局部应用于离体灌注猪皮瓣（IPPSF）。检测灌注液中白细胞介素 - 8（IL - 8）、肿瘤坏死因子 - α（TNF - α）和前列腺素E2（PGE2）的浓度，以探究复合混合物应用后的潜在炎症效应。IPPSF（每组n = 4）局部给予氯菊酯、避蚊胺以及氯菊酯/避蚊胺的乙醇混合物。每种处理均在灌注液中加入50 ng/ml的PB后重复进行。灌注液中还加入30 ng/ml的二异丙基氟磷酸酯以模拟低水平有机磷酸酯类神经毒剂暴露。通过ELISA法检测定时采集的IPPSF静脉流出液样本（0.5、1、2、4和8小时）中的IL - 8和TNF - α，通过EIA法检测PGE2。总体而言，注入PB导致IL - 8和PGE2释放减少。对TNF - α的影响取决于载体。为探究PB这种作用的潜在机制，将人表皮角质形成细胞HEK细胞培养物暴露于氯菊酯、避蚊胺、氯菊酯/避蚊胺，同时在二甲基亚砜中加入或不加入PB。在1、2、4、8、12和24小时检测IL - 8。PB在4至24小时内抑制了氯菊酯和乙醇处理组中的IL - 8，证实了IPPSF实验结果。总之，这些研究表明，在两个皮肤模型系统中，全身性暴露于PB在多个时间点抑制了IL - 8的释放。这种相互作用值得进一步研究。
