Advanced TRPA1 Inhibitor for the Treatment of Chlorine Inhalation Injury

总结 氯气在战争中被用作恐怖分子的武器， 交通或工业事故。尽管其破坏性的影响，没有机制为基础的治疗一直是 开发在本申请中，我们假设暴露后靶向TRPA 1离子通道将 改善氯对肺、心血管和神经系统的急性影响， 发病率和改善恢复。TRPA 1是一种化学刺激受体，引起疼痛、水肿、血管舒张， 心律失常、炎症和白细胞浸润。我们对小鼠的初步研究表明TRPA 1 氯暴露后给予抑制剂，可防止氯诱导的血液循环下降， 氧合，改善肺功能和减轻炎症。 在这里，我们建议测试第三代TRPA 1抑制剂的功效，发现其阻断小鼠、人和小鼠的神经细胞。 和猪TRPA 1，在小鼠和猪氯吸入性损伤模型中，目的是开发这种 作为未来人类的对策提出了以下目标：目标1：筛选潜力 第三代TRPA 1抑制剂在Cl2气体吸入性损伤小鼠模型中的治疗作用。目标二： 确定TRPA 1抑制剂在猪体内的药代动力学和毒理学特性。目标3：测试TRPA1 抑制剂在氯气吸入性损伤猪模型中应用

Summary Chlorine gas has been used as a terrorist weapon, in warfare and has injured many Americans in transportation or industrial accidents. Despite its devastating effects, no mechanism-based treatment has been developed. In this application, we hypothesize that targeting the TRPA1 ion channel post-exposure will ameliorate the acute pulmonary, cardiovascular and neurological effects of chlorine, leading to decreased morbidity and improved recovery. TRPA1 is a chemical irritant receptor eliciting pain, edema, vasodilation, cardiac arrhythmia, inflammation and leukocyte infiltration. Our preliminary studies in mice show that TRPA1 inhibitors, when administered post-chlorine exposure, prevent the chlorine-induced decline of blood oxygenation, improve pulmonary function and mitigate inflammation. Here, we propose to test the efficacy of a 3rd generation TRPA1 inhibitor, found to block mouse, human and porcine TRPA1, in mouse and pig models of chlorine inhalation injury, with the goal to develop this compound as a future human countermeasure. The following aims are proposed: Aim 1: Screen potential therapeutic effects of a 3rd generation TRPA1 inhibitor in mouse models of Cl2 gas inhalation injury. Aim 2: Determine the pharmacokinetic and toxicological properties of TRPA1 inhibitor in pigs. Aim 3: Test the TRPA1 inhibitor in a pig model of chlorine gas inhalation injury