Thiols in sulfur mustard toxicity

硫芥中的硫醇毒性

• 批准号: 8115239
• 负责人: Carl W White
• 金额: $ 38.78万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8115239
• 关键词: 2-chloroethyl ethyl sulfide; Acute; Acute Lung Injury; Adult; Adult Respiratory Distress Syndrome; Affect; Animal Model; Antidotes; Asthma; Attenuated; Bacterial Pneumonia; Biological; Biological Availability; Bioterrorism; Blindness; Bronchiectasis; Bronchiolitis Obliterans; Bronchopneumonia; Burn injury; Chemical Warfare; Chemical Weapons; Chemicals; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Cicatrix; Clothing; Decontamination; Drug Kinetics; Edema; Effectiveness; Epithelial; Eye; Gas Masks; Guidelines; Home environment; Hour; Incidence; Individual; Inflammation; Inflammatory; Injury; Intervention; Iran; Iraq; Keratitis; Laboratories; Lead; Liquid substance; Long-Term Survivors; Lung; Lung diseases; Measurement; Medical; Military Personnel; Mono-S; Mustard; Mustard Gas; Newly Diagnosed; Nuclear Weapon; Oral; Organ; Pathology; Persons; Pharmaceutical Preparations; Pneumonia; Poisoning; Population; Preventive; Probability; Pulmonary Edema; Pulmonary Fibrosis; Rattus; Recording of previous events; Recovery; Reporting; Route; Secure; Skin; Soldier; Stenosis; Sulfhydryl Compounds; Supplementation; Supportive care; Survivors; Symptoms; Syndrome; Techniques; Terrorism; Testing; Thioctic Acid; Thioredoxin; Time; Toxic effect; Toxicology; Tracheobronchial; Tracheobronchomalacia; War; World Health Organization; aerosolized; airway hyperresponsiveness; airway inflammation; analog; combat; cytokine; dithiol; experience; in vivo; injured airway; killings; lung injury; medical complication; member; novel; prevent; respiratory; secondary infection; weapons

Sulfur mustard (HD, mustard gas) is the most highly utilized chemical weapon in history, and currently it poses a serious threat to both military and civilian populations. In addition to stockpiles, HD remains one of the easiest chemical weapons to make in large quantities, and it is included in the list of likely choices for terrorist organizations. HD can be a severely debilitating agent for those exposed to it. The primary organs affected by HD are the lungs, skin and eyes. It results in acute airway edema, ARDS, bronchopneumonia, tracheobronchomalacia and/or airway stenosis, bronchiolitis obliterans, bronchiectasis, pulmonary fibrosis, asthma, and other respiratory complications. There are no specific treatments or antidotes for HD nor preventive medications to minimize its effects. Decontamination and supportive care are the only interventions recommended by current medical guidelines and more of these protect the airways. Decontamination is effective for skin and eyes only if enacted very early (< 5 minutes). Unfortunately, recognition of the problem usually does not occur within this timeframe. We hypothesize that supplementation or augmentation of airway mono- or dithiols will prevent or limit sulfur mustard toxicity. Using an animal model employing 2-chloroethyl ethyl sulfide (CEES, "half-mustard"), a less toxic analog of sulfur mustard, we will: 1) Determine airway inflammation, pro-inflammatory cytokines, and principal thiols following half-mustard aerosolization in rat, 2) evaluate effectiveness of oral and aerosolized mono- (GSH) and dithiols (lipoic acid, thioredoxin) in attenuating halfmustard lung injury (inflammation, cytokines, thiols), 3) develop novel compounds to stimulate mono- and dithiol efflux into lung epithelial lining fluid, and 4) examine the efficacy of these novel compounds in vivo. The latter studies will help us establish optimal compounds, route and mode of delivery, pharmacokinetics, bioavailability, and toxicology. Our laboratories have exceptional experience in measurement of the relevant, potentially protective thiol compounds to be evaluated. We anticipate these studies will lead to testing of the most effective compounds using authentic mustard gas at appropriate facilities.

硫芥末（HD，芥末气）是历史上使用最多的化学武器，目前 对军事和平民构成严重威胁。除库存外，高清仍然是 大量制造的最简单的化学武器，它包含在可能的选择列表中 恐怖组织。高清可能是暴露于它的人的严重使人衰弱的代理。主要器官 受高清影响的是肺，皮肤和眼睛。它导致急性气道水肿，ARDS，支气管瘤， 气管脑弧菌和/或气道狭窄，支气管炎闭塞剂，支气管扩张，肺纤维化， 哮喘和其他呼吸并发症。没有针对高清的特定治疗方法或解毒剂 预防药物可最大程度地减少其影响。去污和支持护理是唯一的 当前的医疗指南和更多这些保护呼吸道建议采取的干预措施。 仅在非常早（<5分钟）制定时，才能对皮肤和眼睛有效。很遗憾， 识别问题通常不会在此期限内发生。我们假设这一点 呼吸道单或二硫醇的补充或增强将预防或限制硫磺芥末 毒性。使用采用2-氯乙基乙基硫化物（CEES，“ Half-mustard”）的动物模型，较少 硫芥末的有毒类似物，我们将：1）确定气道炎症，促炎症 大鼠半固定后的细胞因子和主硫醇，2）评估有效性 衰减半mustard的口服和雾化的单（GSH）和二硫醇（硫氧还蛋白） 肺损伤（炎症，细胞因子，硫醇），3）开发新型化合物以刺激 单二硫醇外排入肺上皮衬里流体，4）检查这些新型的功效 体内化合物。后者的研究将帮助我们建立最佳化合物，路线和模式 分娩，药代动力学，生物利用度和毒理学。我们的实验室在 测量要评估的相关，潜在的保护性硫醇化合物。我们期待这些 研究将在适当的 设施。