Novel antioxidant therapeutics for sulfur mustard toxicity (U54)

描述（由申请人提供）：硫磺芥子气（HD, mustard gas）是历史上利用率最高的化学武器，目前对军队和平民都构成严重威胁。除了库存之外，HD仍然是最容易大量制造的化学武器之一，它被列入恐怖组织可能选择的清单。对于那些接触到HD的人来说，它可能是一种严重的衰弱剂。受HD影响的主要器官是肺、皮肤和眼睛。它可导致急性气道水肿、急性呼吸窘迫综合征、支气管肺炎、气管支气管软化和/或气道狭窄、闭塞性细支气管炎、支气管扩张、肺纤维化、哮喘和其他呼吸道并发症。目前还没有针对HD的特殊治疗方法或解毒剂，也没有预防药物来减少其影响。去污和支持性护理是目前医疗指南推荐的唯一干预措施，其中更多的是保护气道。只有在非常早（< 5分钟）进行去污才对皮肤和眼睛有效。不幸的是，通常不会在这个时间范围内发现问题。我们假设补充或增加气道单或二硫醇将防止或限制芥子气毒性。使用2-氯乙基乙基硫醚（CEES，“半芥子气”）（一种毒性较小的芥子气类似物）的动物模型，我们将：1)确定半芥菜雾化后大鼠气道炎症、促炎细胞因子和主要硫醇；2)评估口服和雾化单硫醇（GSH）和二硫醇（硫辛酸、硫氧还蛋白）减轻半芥菜肺损伤（炎症、细胞因子、硫醇）的有效性；3)开发新化合物刺激单硫醇和二硫醇外排到肺上皮衬里液中；4)检查这些新化合物在体内的功效。后一项研究将帮助我们建立最佳化合物、给药途径和方式、药代动力学、生物利用度和毒理学。我们的实验室在测量相关的、潜在的保护性硫醇化合物方面有丰富的经验。我们预计这些研究将导致在适当的设施中使用真正的芥子气测试最有效的化合物。

Description (provided by applicant): 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.