Novel antioxidant therapeutics for sulfur mustard toxicity (U54)

描述（申请方提供）：硫芥子气（HD，芥子气）是历史上使用率最高的化学武器，目前对军事和平民都构成严重威胁。除了库存，HD仍然是最容易大量制造的化学武器之一，并被列入恐怖组织可能选择的名单。对于暴露于HD的人来说，HD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。它导致急性气道水肿、ARDS、支气管扩张、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、哮喘和其他呼吸系统并发症。没有特定的治疗方法或解毒剂，也没有预防性药物，以尽量减少其影响。净化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。去污只有在非常早的时候（< 5分钟）才对皮肤和眼睛有效。不幸的是，问题的认识通常不会在这个时间范围内发生。我们假设补充或增加气道单硫醇或二硫醇将预防或限制硫芥毒性。使用使用2-氯乙基乙基硫醚的动物模型，（CEES，“半芥末”），一种毒性较小的硫芥子气类似物，我们将：1）在大鼠中测定半芥子气雾化后的气道炎症、促炎细胞因子和主要硫醇，2）评估口服和雾化的单（GSH）和二硫醇的有效性硫氧还蛋白减轻半芥子气肺损伤（炎症、细胞因子、硫醇），3）开发新的化合物以刺激单硫醇和二硫醇流出到肺上皮衬里液中，和4）检查这些新化合物在体内的功效。后者的研究将帮助我们建立最佳的化合物，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待评估的相关、潜在保护性硫醇化合物方面拥有卓越的经验。我们预计这些研究将导致在适当的设施中使用真实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.