A Role for Mitochondrial Oxidative Stress in Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide-Induced Lung Cell Injury and Antioxidant Protection
A Role for Mitochondrial Oxidative Stress in Sulfur Mustard Analog 2-Chloroethyl Ethyl Sulfide-Induced Lung Cell Injury and Antioxidant Protection
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DOI：
10.1124/jpet.108.145037
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发表时间：
2009-03-01
影响因子：
3.5
通讯作者：
Day, Brian J.
中科院分区：
文献类型：
--
作者：
Gould, Neal S.;White, Carl W.;Day, Brian J.
硫磺芥菜（SMs）自第一次世界大战以来一直被用作战剂，至今仍对平民和军事人员构成重大威胁。接触SM会导致皮肤明显起泡、呼吸损伤和纤维化。目前还没有针对SM暴露的解药，但最近的研究，使用SM类似物2-氯乙基乙基硫醚（CEES），集中在抗氧化剂预防毒性的能力上。虽然抗氧化剂可以预防cees引起的毒性，但这些化合物有效对抗SM的机制在很大程度上是未知的。使用人支气管上皮细胞（16HBE）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，在暴露后12小时达到峰值。我们还发现了一种催化抗氧化剂金属卟啉，在暴露于CEES 1小时后加入它可以拯救气道细胞免受CEES诱导的毒性。此外，催化抗氧化剂的细胞保护作用与纠正线粒体功能障碍ROS、DNA氧化和细胞内GSH降低有关。这些发现提示氧化应激在CEES毒性中的作用，并为研究抗氧化剂作为SM暴露的救援剂提供了理论依据。
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.