Advanced TRPA1 Inhibitor for the Treatment of Chlorine Inhalation Injury

摘要 氯气曾被用作恐怖分子的武器，用于战争，并在 交通或工业事故。尽管它有毁灭性的影响，但还没有任何基于机制的治疗方法 发展起来的。在本应用中，我们假设暴露后靶向TRPA1离子通道将 改善氯的急性肺、心血管和神经影响，导致 发病率和恢复率的提高。TRPA1是一种化学刺激性受体，可引起疼痛、浮肿、血管扩张、 心律失常、炎症和白细胞浸润。我们在小鼠身上的初步研究表明，TRPA1 氯气暴露后给药时，抑制剂可防止氯气引起的血液下降 氧合，改善肺功能，减轻炎症。 在这里，我们建议测试第三代TRPA1抑制剂的有效性，发现它可以阻断小鼠、人 以及猪的TRPA1，在小鼠和猪的氯气吸入损伤模型中，目的是开发这种 作为未来人类的一种对策。提出了以下目标：目标1：屏幕电位 第三代TRPA1抑制剂对小鼠Cl2气体吸入性损伤的治疗作用目标2： 测定TRPA1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的应用

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