Targeted Therapeutic Approaches to Counteract Toxicity from Phosgene Oxime Skin Exposure

项目摘要摘要 在第二次世界大战期间储存的光气酮(CX；二氯仿)是一种强大的化学武器， 构成暴露的威胁；单独或与其他化学制剂一起。它是一种止痒或止痒的药剂 与发泡剂由于类似的破坏性质；尽管它造成的损害比其他 发泡剂由于其高活性的性质。尽管它是最臭名昭著的特种部队发泡剂 和恐怖主义利益，它是研究最少的化学战剂之一，没有具体的解毒剂可用。 关于其对人体皮肤组织和吸收的影响的信息有限，其作用机制是 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 环氧氯丙烷致小鼠皮肤损伤模型的建立 并检测CX的全身毒性作用，以确定新的治疗靶点。结果来自于 我们已完成的研究表明，肥大细胞可能在环磷酰胺诱导的毒性中发挥重要作用。这个 CX的毒性反应和皮肤过敏反应类似于过敏反应，而皮肤过敏类似于过敏性荨麻疹 反应，主要是由于肥大细胞的激活而引起的炎症反应。来自我们发布的数据 在SKH-1无毛小鼠身上完成的研究表明，Cx皮肤暴露会导致肥大细胞 脱颗粒和释放介体，包括组胺和类胰蛋白酶，促炎细胞因子和 皮肤组织中的炎症反应与浮肿、红斑、坏死、荨麻疹和发白有关。 环磷酰胺皮肤暴露还可引起多器官血管扩张和充血。 导致全身毒性，呼吸和心率下降，体温下降和死亡率。这些 症状类似于过敏反应(急性呼吸道的潜在致命性多系统过敏反应 和心血管损害导致昏迷、休克和死亡)，这是突然的 肥大细胞全身释放介质。基于我们发布的和最近获得的以下数据 目前的R21授权，我们假设主细胞激活和相关的介质释放是 CX皮肤暴露后导致炎症途径激活的主要事件为 以及致命性过敏反应，这些将是治疗干预的新靶点 减轻CX引起的皮肤发病率和死亡率。为了验证这一假设，提出的具体目标是： 1.通过利用肥大细胞进一步确立肥大细胞在CX毒性中的关键作用和分子靶点 2.测试FDA批准的可对抗环磷酰胺引起的发病率的治疗方法的有效性 和小鼠皮肤暴露的死亡率，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建立肥大细胞激活和 像组胺这样的介质是治疗干预的新靶点，并确定了FDA批准的 有针对性的治疗策略，可以针对这些，以抵消CX皮肤暴露的毒性。

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.