Gould Neal S, White Carl W, Day Brian J
Department of Pharmaceutical Sciences, University ofColorado Health Sciences Center, Denver, Colorado, USA.
J Pharmacol Exp Ther. 2009 Mar;328(3):732-9. doi: 10.1124/jpet.108.145037. Epub 2008 Dec 8.
Sulfur mustards (SMs) have been used as warfare agents since World War I and still pose a significant threat against civilian and military personnel. SM exposure can cause significant blistering of the skin, respiratory injury, and fibrosis. No antidote currently exists for SM exposure, but recent studies, using the SM analog 2-chloroethyl ethyl sulfide (CEES), have focused on the ability of antioxidants to prevent toxicity. Although antioxidants can prevent CEES-induced toxicity, the mechanisms by which these compounds are effective against SM agents are largely unknown. Using human bronchial epithelial (16HBE) cells and primary small airway epithelial cells, we show that CEES causes a significant increase in mitochondrial dysfunction as early as 4 h, which is followed by increases in mitochondrial reactive oxygen species (ROS), peaking 12 h after exposure. We also have identified a catalytic antioxidant metalloporphyrin that can rescue airway cells from CEES-induced toxicity when added 1 h after CEES exposure. In addition, the cytoprotective effects of the catalytic antioxidant are associated with correcting mitochondrial dysfunction ROS, DNA oxidation, and decreases in intracellular GSH. These findings suggest a role for oxidative stress in CEES toxicity and provide a rationale to investigate antioxidants as rescue agents in SM exposures.
自第一次世界大战以来，硫芥气（SMs）就一直被用作战争毒剂，至今仍对平民和军事人员构成重大威胁。接触硫芥气会导致皮肤严重起泡、呼吸道损伤和纤维化。目前尚无针对硫芥气接触的解毒剂，但最近使用硫芥气类似物2-氯乙基乙基硫醚（CEES）的研究聚焦于抗氧化剂预防毒性的能力。尽管抗氧化剂可预防CEES诱导的毒性，但这些化合物有效对抗硫芥气毒剂的机制在很大程度上尚不清楚。利用人支气管上皮（16HBE）细胞和原代小气道上皮细胞，我们发现CEES早在4小时就会导致线粒体功能障碍显著增加，随后线粒体活性氧（ROS）增加，在接触后12小时达到峰值。我们还鉴定出一种催化性抗氧化金属卟啉，在CEES接触1小时后添加时，它可使气道细胞免受CEES诱导的毒性。此外，催化性抗氧化剂的细胞保护作用与纠正线粒体功能障碍、ROS、DNA氧化以及细胞内谷胱甘肽减少有关。这些发现表明氧化应激在CEES毒性中起作用，并为研究将抗氧化剂作为硫芥气接触时的救援剂提供了理论依据。
