Mechanisms of Sulfur Mustard Toxicology

硫芥毒理学机制

• 批准号: 7851214
• 负责人: YIHUA JAN
• 金额: $ 5.67万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851214
• 关键词: 2-chloroethyl ethyl sulfide; A549; Alkylation; Antioxidants; Apoptosis; Cell Survival; Cell physiology; Cells; Chemical Weapons; Cysteine; Development; Drug Delivery Systems; Enzyme Inhibition; Enzyme Kinetics; Enzymes; Epithelial Cells; Exposure to; Homeostasis; Human; Inflammation; Inhibition of Cell Proliferation; Injury; Lead; Link; Lung; Mechlorethamine; Mediating; Military Personnel; Modeling; Molecular; Mustard; Mustard Agent; Mustard Gas; NADP; Necrosis; Oxidation-Reduction; Oxidative Stress; Play; Poisoning; Proteins; Rattus; Research; Rodent; Role; Site; Small Interfering RNA; Structure of parenchyma of lung; Sulfhydryl Compounds; System; Technology; Testing; Thioredoxin; Time; Toxic effect; Toxicology; Vesicants; World War I; adduct; cell growth regulation; cytotoxic; cytotoxicity; design; effective therapy; inhibitor/antagonist; knock-down; protein expression; public health relevance; research study; thioredoxin reductase

DESCRIPTION (provided by applicant): The overall aim of our proposed studies is to reveal the molecular mechanisms of cytotoxicity induced by mustard agents such as sulfur mustard (2, 2'-dichlorodiethyl sulfide). Sulfur mustard is a potent vesicant known to damage lung tissue. Toxicity is the result of alkylation of critical proteins that maintain the integrity of the lung, resulting in inflammation and oxidative stress. However, the underlying mechanisms mediating the actions of sulfur mustard are not fully understood. The thioredoxin (Trx) system, composed of thioredoxin reductase (TrxR) and thioredoxin, is a major thiol-regulating system in cells and plays an important role in many cellular functions including antioxidant defense, redox regulation, and cell growth control. Inhibition of this system can lead to oxidative stress and inhibition of cell proliferation as well as necrosis and apoptosis. In preliminary experiments we found that 2-chloroethyl ethyl sulfide (GEES), a model sulfur mustard vesicant, is a potent inhibitor of thioredoxin reductase in lung epithelial cells. We hypothesize that vesicants target critical sulfhydryl's in thioredoxin reductase and/or thioredoxin resulting in enzyme inhibition and in turn creating oxidative stress in target cells. To test our hypothesis, we initially plan to examine the link between cytotoxicity and the function of the thioredoxin system after vesicant exposure (using the monofunctional vesicant CEES and a bifunctional nitrogen mustard HN-2) in lung epithelial cells. Then, the interaction between vesicants and thioredoxin reductase and/or thioredoxin will be characterized using purified enzymes. PUBLIC HEALTH RELEVANCE: Sulfur mustard, a vesicant first employed during World War I as a chemical weapon, remains a significant civilian and military threat. There are currently no approved treatments for exposure to sulfur mustard and related vesicants. Successful therapy for sulfur mustard poisoning will depend on the development of drugs that target one or more of its sites of action. This research is designed to identify sites of action of sulfur mustard that can be targeted for drug treatment.

描述（由申请人提供）：我们拟定研究的总体目的是揭示芥子类药物（如硫芥子（2，2 '-二氯二乙基硫醚））诱导细胞毒性的分子机制。芥子气是一种强力的致疱剂，已知会损害肺组织。毒性是维持肺完整性的关键蛋白质烷基化的结果，导致炎症和氧化应激。然而，介导硫芥作用的潜在机制尚未完全了解。硫氧还蛋白（Trx）系统由硫氧还蛋白还原酶（TrxR）和硫氧还蛋白组成，是细胞内主要的巯基调节系统，在细胞的抗氧化防御、氧化还原调节和细胞生长调控等方面发挥重要作用。该系统的抑制可导致氧化应激和细胞增殖抑制以及坏死和凋亡。在初步的实验中，我们发现2-氯乙基乙基硫醚（GEES），一种模型硫芥发泡剂，是肺上皮细胞中硫氧还蛋白还原酶的有效抑制剂。我们假设，起泡剂靶向硫氧还蛋白还原酶和/或硫氧还蛋白中的关键巯基，导致酶抑制，进而在靶细胞中产生氧化应激。为了验证我们的假设，我们最初计划检查肺上皮细胞中的细胞毒性和起泡剂暴露后硫氧还蛋白系统的功能（使用单功能起泡剂CEES和双功能氮芥HN-2）之间的联系。然后，将使用纯化的酶表征起泡剂与硫氧还蛋白还原酶和/或硫氧还蛋白之间的相互作用。公共卫生相关性：芥子气是一种在第一次世界大战期间首次用作化学武器的起泡剂，仍然是一个重大的民用和军事威胁。目前还没有批准的治疗暴露于硫芥和相关的起疱剂。硫芥中毒的成功治疗将取决于针对其一个或多个作用部位的药物的开发。这项研究旨在确定硫芥的作用位点，可以作为药物治疗的靶点。