Advanced TRPA1 Inhibitor for the Treatment of Chlorine Inhalation Injury

用于治疗氯吸入损伤的先进 TRPA1 抑制剂

• 批准号: 10002221
• 负责人: Satyanarayana Achanta
• 金额: $ 76.98万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002221
• 关键词: Acrolein; Acute; Acute Lung Injury; Airway Resistance; American; Animal Model; Antidotes; Arrhythmia; Blood; Blood specimen; Bronchiolitis Obliterans; Cardiovascular system; Cell Count; Cell Culture Techniques; Chemical Weapons; Chemicals; Chlorine; Clinical Trials; Conflict (Psychology); Development; Dose; Drug Kinetics; Edema; Family suidae; Frequencies; Future; Gases; Generations; Goals; Histopathology; Human; In Vitro; Industrial Accidents; Infiltration; Inflammation; Inhalation; Injury; Intramuscular; Investigational Therapies; Ion Channel; Irritants; Leukocytes; Lung; Lung Inflammation; Measures; Modeling; Morbidity - disease rate; Mus; Nervous system structure; Neurologic Effect; Oral; Organ; Oxygen; Pain; Partial Pressure; Physiological; Plasma; Preparation; Process; Property; Proteins; Protocols documentation; Recovery; Respiratory System; Riots; Rodent; Route; Skin injury; Supine Position; Terrorism; Testing; Therapeutic Effect; Therapeutic Studies; Time; Tissues; Toxicology; Transportation; Treatment Efficacy; United States; Vasodilation; Ventilator; Vesicants; Weight; White Blood Cell Count procedure; World War I; animal rule; appropriate dose; base; chlorine gas; cytokine; effective therapy; efficacy testing; improved; in vivo; indexing; inhibitor/antagonist; injured; liquid chromatography mass spectrometry; lung injury; medical countermeasure; methacholine; mortality; mouse model; nerve supply; pressure; prevent; primary endpoint; pulmonary function; receptor; respiratory; response; sensor; severe injury; standard of care; symptom treatment; therapeutic evaluation; weapons

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

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