Novel antioxidant therapeutics for sulfur mustard toxicity (U54)

描述(申请人提供)：硫磺芥末(HD，芥子气)是历史上使用率最高的化学武器，目前它对军事和平民人口都构成了严重威胁。除了库存，HD仍然是最容易大量制造的化学武器之一，它被列入恐怖组织的可能选择名单。对于那些接触它的人来说，HD可能是一个严重的衰弱因素。受HD影响的主要器官是肺、皮肤和眼睛。它会导致急性呼吸道水肿、ARDS、支气管肺炎、气管支气管软化和/或呼吸道狭窄、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的特效药或解毒剂，也没有预防性药物来将其影响降至最低。净化和支持性护理是当前医疗指南建议的唯一干预措施，其中更多的是保护呼吸道。只有在很早的时候(5分钟)去污才能对皮肤和眼睛有效。不幸的是，认识到这个问题通常不会在这个时间框架内发生。我们假设，补充或增加呼吸道一硫醇或二硫醇可预防或限制硫芥子气的毒性。使用毒性较低的硫芥类似物2-氯乙基乙硫醚(CEES，“半芥子”)制作的动物模型，我们将：1)测定半芥末雾化后大鼠的气道炎症、促炎细胞因子和主要硫醇，2)评估口服和雾化单一硫醇(GSH)和二硫醇(硫辛酸、硫氧还蛋白)在减轻半芥末肺损伤(炎症、细胞因子、硫醇)中的有效性，3)开发新型化合物以刺激单、二硫醇外排进入肺上皮细胞衬里液体，以及4)在体内检测这些新型化合物的有效性。后一项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的潜在保护性硫醇化合物方面拥有非凡的经验。我们预计这些研究将导致在适当的设施中使用正宗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.