Inflammatory biomarkers of sulfur mustard analog 2-chloroethyl ethyl sulfide-induced skin injury in SKH-1 hairless mice.
Inflammatory biomarkers of sulfur mustard analog 2-chloroethyl ethyl sulfide-induced skin injury in SKH-1 hairless mice.
复制标题
硫芥类似物 2-氯乙基乙基硫醚诱导 SKH-1 无毛小鼠皮肤损伤的炎症生物标志物。
DOI：
10.1093/toxsci/kfn261
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Agarwal,Rajesh
中科院分区：
文献类型：
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作者：
Tewari-Singh,Neera;Rana,Sumeet;Gu,Mallikarjuna;Pal,Arttatrana;Orlicky,DavidJ;White,CarlW;Agarwal,Rajesh
硫芥（HD）是一种烷基化和细胞毒性化学战剂，可引起严重的皮肤毒性和炎症反应。由于对HD引起的皮肤毒性的相关机制了解有限，缺乏有效的医学对策，这主要归因于需要更适用和有效的动物皮肤毒性模型。使用HD的毒性较小的类似物，氯乙基乙基硫醚（CEES），我们在剂量-（0.05-2 mg）和时间-（3-168 h）反应实验中鉴定了CEES诱导的皮肤损伤的可定量的炎症生物标志物，并开发了CEES诱导的皮肤毒性SKH-1无毛小鼠模型。高剂量的局部CEES治疗引起皮肤双倍厚度的显著剂量依赖性增加，表明水肿。CEES处理的皮肤切片的组织病理学评估显示表皮和真皮厚度、固缩的基底角质形成细胞、真皮毛细血管、中性粒细胞、巨噬细胞、肥大细胞数量增加，以及表皮脱落。CEES诱导的表皮细胞凋亡和基底细胞增殖的剂量依赖性增加分别通过末端脱氧核苷酸转移酶（tdt）介导的dUTP-生物素缺口末端标记和增殖细胞核抗原染色来证明。肥大细胞增加后，炎症皮肤中的髓过氧化物酶活性在CEES暴露后24小时达到峰值，与中性粒细胞浸润一致。皮肤外皮的F4/80染色显示CEES暴露24小时后巨噬细胞数量增加。总之，这些结果在更适用和有效的SKH-1无毛小鼠模型中建立了CEES诱导的可量化炎症生物标志物，这对于药物疗效研究开发HD诱导的皮肤毒性的潜在预防和治疗干预措施可能是有价值的。
Sulfur mustard (HD) is an alkylating and cytotoxic chemical warfare agent, which inflicts severe skin toxicity and an inflammatory response. Effective medical countermeasures against HD-caused skin toxicity are lacking due to limited knowledge of related mechanisms, which is mainly attributed to the requirement of more applicable and efficient animal skin toxicity models. Using a less toxic analog of HD, chloroethyl ethyl sulfide (CEES), we identified quantifiable inflammatory biomarkers of CEES-induced skin injury in dose- (0.05–2 mg) and time- (3–168 h) response experiments, and developed a CEES-induced skin toxicity SKH-1 hairless mouse model. Topical CEES treatment at high doses caused a significant dose-dependent increase in skin bi-fold thickness indicating edema. Histopathological evaluation of CEES-treated skin sections revealed increases in epidermal and dermal thickness, number of pyknotic basal keratinocytes, dermal capillaries, neutrophils, macrophages, mast cells, and desquamation of epidermis. CEES-induced dose-dependent increases in epidermal cell apoptosis and basal cell proliferation were demonstrated by the terminal deoxynucleotidyl transferase (tdt)-mediated dUTP-biotin nick end labeling and proliferative cell nuclear antigen stainings, respectively. Following an increase in the mast cells, myeloperoxidase activity in the inflamed skin peaked at 24 h after CEES exposure coinciding with neutrophil infiltration. F4/80 staining of skin integuments revealed an increase in the number of macrophages after 24 h of CEES exposure. In conclusion, these results establish CEES-induced quantifiable inflammatory biomarkers in a more applicable and efficient SKH-1 hairless mouse model, which could be valuable for agent efficacy studies to develop potential prophylactic and therapeutic interventions for HD-induced skin toxicity.