Repurposing thiosulfate for chlorine gas exposure

氯气是一种化学战剂和有毒工业化学品(TIC)，会导致呼吸衰竭和 由化学烧伤引起的呼吸道和肺泡上皮的浮肿。化学战剂是一种重要的 对军事人员和平民的威胁。这项计划的长远目标是发展医疗 对产生肺部毒素的化学制剂的对策。氯气和其他抽搐可以 增加氧化损伤，导致细胞损伤和炎症。氯气暴露对细胞的损伤 据信是由于它的快速水合作用产生了次氯酸(漂白剂)和盐酸。 硫代硫酸钠是FDA批准的治疗氰化物中毒的药物，但也被用作有效的 脱氯剂。我们假设硫代硫酸钠的脱氯和抗氧化作用 以氯气接触过程中产生的次氯酸和次氯酸以及其他氧化剂为目标 是在与氯气接触相关的氧化应激和炎症过程中产生的。我们将测试我们的 有两个具体目标的假设。第一个目标是建立氯气致急性肺损伤的猪模型。 损伤模型。第二个目标是优化硫代硫酸钠的剂量、给药方案和抢救窗口。 猪模。这些数据将被用作原则研究的证据，以支持监管部门批准使用 根据FDA动物规则，硫代硫酸钠作为氯气肺损伤的药物对策。如果 如果成功，这种FDA批准的产品可能会被迅速开发出来，作为对抗氯的医学对策 毒气伤。

Chlorine gas is a chemical warfare agent and toxic industrial chemical (TIC) that produces respiratory failure and edema due to chemical burns of the airway and alveolar epithelium. Chemical warfare agents are an important threat to military personnel and civilians. The broad long-term goal of this project is to develop medical countermeasures against chemical agents that produce a lung toxidrome. Chlorine gas and other TICs can elevate oxidative damage leading to cellular injury and inflammation. Cellular injury from chlorine gas exposure is believed to result from its rapid hydration that generates hypochlorous acid (bleach) and hydrochloric acid. Sodium thiosulfate is an FDA approved treatment for cyanide poisoning, but also is used as an effective dechlorinating agent. We hypothesize that the dechlorinating and antioxidant actions of sodium thiosulfate will target hypochlorous acid and hypochloric acid generated during chlorine exposure along with other oxidants that are produced during oxidative stress and inflammation associated with a chlorine gas exposure. We will test our hypothesis with two specific aims. The first aim will develop a swine model of chlorine gas-induced acute lung injury model. The second aim will optimize dose, dose regimen, and rescue window of sodium thiosulfate in this swine model. These data will be used as proof of principle studies to support regulatory approval for the use of sodium thiosulfate as a medical countermeasure for chlorine gas lung injury under the FDA animal rule. If successful this FDA approved product could be rapidly developed as a medical countermeasure against chlorine gas injury.