Targeted Therapeutic Approaches to Counteract Toxicity from Phosgene Oxime Skin Exposure

抵消光气肟皮肤暴露毒性的靶向治疗方法

• 批准号: 10013129
• 负责人: Neera Tewari-Singh
• 金额: $ 47.44万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013129
• 关键词: Acute; Allergic Reaction; Anaphylaxis; Antidotes; Biological Markers; Blood; C57BL/6 Mouse; Cardiovascular system; Cell Degranulation; Cessation of life; Chemical Agents; Chemical Warfare Agents; Chemical Weapons; Congestive; Cutaneous; Data; Dermal; Development; Dose; Drops; Edema; Epinephrine; Erythema; Event; FDA approved; Goals; Grant; Hair; Heart Rate; Histamine; Histamine Release; Human; Inbred HRS Mice; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Injury; Mediator of activation protein; Military Personnel; Modeling; Molecular Target; Morbidity - disease rate; Mus; Nature; Necrosis; Organ; Outcome; Oximes; Pathway interactions; Pharmaceutical Preparations; Phosgene; Positioning Attribute; Property; Pruritus; Publishing; Scheme; Shock; Skin; Skin Tissue; Skin injury; Symptoms; Temperature; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Tryptase; Unconscious State; Urticaria; Vesicants; World War II; absorption; base; cardiovascular injury; cytokine; effective therapy; efficacy testing; interest; mast cell; mortality; mouse model; new therapeutic target; novel; optimal treatments; respiratory; response; skin irritation; systemic toxicity; targeted treatment; treatment strategy

Project Summary Abstract Stockpiled during World War II, Phosgene Oxime (CX; dichloroform oxime) is a potent chemical weapon that poses a threat of exposure; both, alone and with other chemical agents. It is an urticant or nettle agent grouped with vesicating agents due to similar damaging properties; although, it causes more severe damage than other vesicants due to its highly reactive nature. Even though it is the most notorious vesicant with special military and terrorist interests, it is one of the least studied chemical warfare agents with no specific antidote available. Information on its effect on human dermal tissue and absorption is limited, and its mechanism of action is unknown. To overcome these limitations, our completed and ongoing studies are directed towards the development of a relevant cutaneous CX exposure mouse injury model to elucidate the mechanisms of skin damage by CX and examine systemic toxic effects of CX to identify novel therapeutic targets. The results from our completed studies demonstrate that mast cells could be important players in CX-induced toxicity. The toxicity response and skin urticaria from CX resembles anaphylactic reaction and urticaria from allergic reactions, which involves an inflammatory response mainly due to mast cell activation. Data from our published and completed studies in SKH-1 hairless mice show that CX cutaneous exposure causes mast cell degranulation and release of mediators including histamine and tryptase, pro-inflammatory cytokines, and an inflammatory response in the skin tissue associated with edema, erythema, necrosis, urticaria and blanching. CX cutaneous exposure in mice also caused vasculature dilation and blood congestion in multiple organs resulting in systemic toxicity, and decrease in breath and heart rate, temperature drop and mortality. These symptoms were similar to anaphylaxis (potentially lethal multisystem allergic reaction with acute respiratory and cardiovascular compromise leading to unconsciousness, shock and mortality), which is a result of sudden systemic release of mediators from mast cells. Based on our published and recently obtained data under the current R21 grant, we hypothesize that mast cell activation and associated release of mediators are the major events following CX cutaneous exposure which cause inflammatory pathway activation as well as lethal allergic reaction, and that these would be novel targets for therapeutic intervention to mitigate CX-induced skin morbidity and mortality. To test this hypothesis, the specific aims proposed are: 1. To further establish mast cells as key players and molecular targets in CX toxicity by employing mast cell deficient mice; and 2. To test the efficacy of FDA approved therapies that can counteract CX-induced morbidity and mortality from cutaneous exposure in mice, mainly by targeting mast cell activation and release of histamine. We believe that outcomes from above aims will help establish that mast cell activation and mediators like histamine are novel targets for therapeutic intervention, and identify an FDA approved targeted therapeutic strategy that can target these to counteract toxicity from CX cutaneous exposure.

项目概要 摘要 光气肟（CX；二氯仿肟）是一种强效化学武器，在第二次世界大战期间储存。 造成暴露威胁；单独或与其他化学试剂一起使用。它是一种荨麻剂或荨麻剂 由于具有类似的破坏特性，与发泡剂一起使用；虽然，它造成的损害比其他方法更严重 由于其高反应性而成为起泡剂。尽管它是最臭名昭著的特殊军事起泡剂 和恐怖分子利益，它是研究最少的化学战剂之一，没有具体的解毒剂。 关于其对人体真皮组织的影响和吸收的信息有限，其作用机制为 未知。为了克服这些限制，我们已完成和正在进行的研究旨在 开发相关皮肤 CX 暴露小鼠损伤模型以阐明皮肤损伤机制 CX 损伤并检查 CX 的全身毒性作用以确定新的治疗靶点。结果来自 我们完成的研究表明，肥大细胞可能是 CX 诱导毒性的重要参与者。这 CX 的毒性反应和皮肤荨麻疹类似于过敏反应和过敏性荨麻疹 反应，其中涉及主要由肥大细胞激活引起的炎症反应。数据来自我们发布的 在 SKH-1 无毛小鼠中完成的研究表明，CX 皮肤暴露会导致肥大细胞 脱粒和释放介质，包括组胺和类胰蛋白酶、促炎细胞因子和 皮肤组织的炎症反应与水肿、红斑、坏死、荨麻疹和变白有关。 小鼠皮肤暴露 CX 还会导致多个器官的血管扩张和血液充血 导致全身毒性、呼吸和心率下降、体温下降和死亡率。这些 症状与过敏反应相似（可能致命的多系统过敏反应，伴有急性呼吸道疾病） 和心血管损害导致意识不清、休克和死亡），这是突然发生的结果 肥大细胞全身释放介质。根据我们发布和最近获得的数据 目前的 R21 资助，我们假设肥大细胞激活和相关的介质释放是 CX 皮肤暴露后导致炎症通路激活的主要事件为 以及致命的过敏反应，这些将成为治疗干预的新目标 减轻 CX 引起的皮肤发病率和死亡率。为了检验这一假设，提出的具体目标是： 1. 利用肥大细胞进一步确立肥大细胞作为CX毒性的关键参与者和分子靶点 缺陷小鼠； 2. 测试 FDA 批准的可抵消 CX 引起的发病率的疗法的功效 小鼠皮肤暴露引起的死亡和死亡率，主要是通过靶向肥大细胞激活和释放 组胺。我们相信，上述目标的结果将有助于确定肥大细胞的激活和 组胺等介质是治疗干预的新靶标，并确定了 FDA 批准的 靶向治疗策略可以针对这些因素来抵消 CX 皮肤暴露的毒性。