Phosgene Oxime Cutaneous Toxicity and Mechanisms to Identify Therapeutic Targets

光气肟皮肤毒性和识别治疗靶点的机制

• 批准号: 9420148
• 负责人: Neera Tewari-Singh
• 金额: $ 21.38万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9420148
• 关键词: Acute; Address; Allergic; Animal Model; Antidotes; Apoptotic; Biological Markers; Blood; Blood Pressure; Bone Marrow; Cell Death; Cell Degranulation; Cessation of life; Chemical Agents; Chemical Warfare Agents; Chemical Weapons; Clinical; Congestive; Cutaneous; DNA Damage; Data; Dermal; Development; Dilatation - action; Edema; Erythema; Exposure to; Eye; Genes; Goals; Heart; Histamine Release; Human; Hypoxia; Inbred HRS Mice; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Intervention; Kidney; Lesion; Liver; Lung; Measures; Membrane; Military Personnel; Modeling; Molecular; Morbidity - disease rate; Mucous body substance; Mus; Mustard; Nature; Necrosis; Neutrophil Infiltration; Organ; Outcome; Oximes; Oxygen; PTGS2 gene; Pain; Pathologic; Pathway interactions; Penetration; Peripheral; Peroxidases; Phosgene; Phosphorylation; Property; Pruritus; Publishing; Reaction Time; Rodent; Scheme; Signal Transduction Pathway; Skin; Skin Tissue; Skin injury; Spleen; TNF gene; TP53 gene; Testing; Therapeutic Intervention; Time; Time Study; Tissues; Toxic effect; Urticaria; Vesicants; World War II; absorption; base; cyclooxygenase 2; cytokine; design; drug development; effective therapy; efficacy study; falls; in vivo; insight; interest; mast cell; mortality; new therapeutic target; novel; response; screening; skin irritation; systemic toxicity; theories; therapeutic candidate; therapeutic target; therapy development; vapor

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. Well defined animal models of exposure to CX are thus essential to study its skin toxicity and for the development of effective treatments. Thus, the ultimate goal of this proposal is to develop a relevant cutaneous CX exposure mouse injury model to elucidate mechanisms of skin damage by CX and examine its systemic toxic effects with the objective of identifying novel targets for therapeutic intervention and drug development. Our preliminary data show that cutaneous CX vapor exposure (4 min) on to the SKH-1 hairless mouse skin causes edema, erythema, blanching, urticaria and necrosis within 30 min with sustained effects till 8 h post- exposure. The rapid onset of these clinical lesions from cutaneous CX exposure were associated with: a) an increase in apoptotic cell death and p53 phosphorylation indicating a DNA damaging response, b) an inflammatory response associated with i) mast cell degranulation and increase in pro-inflammatory cytokine tumor necrosis factor-α and cyclooxygenase-2, and ii) neutrophil infiltration and an increase myeloperoxidase levels. These results suggest that CX possesses alkylating and nucleophilic properties resembling mustard vesicants that can cause DNA damage and an inflammatory response. The skin urticaria from CX resembles urticaria from frequently caused allergic and non-allergic reactions involving an inflammatorily response mainly via histamine release from mast cells. Additionally, the CX-exposure effects were accompanied with dilatation of peripheral vessels with a robust surge in RBCs in vessels of all the major internal organs, which could cause sudden blood pressure fall, hypoxia and death. Based on these findings, our hypothesis is that CX activates inflammatory and p53-DNA damaging pathways that are potential major contributors of CX-induced skin toxic lesions, and that it causes vasculature dilation and blood congestion in multiple organs resulting in systemic toxicity and mortality. Specific aims proposed to test this hypothesis are: 1) Characterize and establish CX- induced in vivo rodent skin injury model following its cutaneous exposure, and identify associated mechanism/s of action; and 2) examine systemic toxic effects and related mortality from CX cutaneous exposure. We anticipate that our studies would establish skin and systemic injury biomarkers of acute CX exposure that can be employed for screening therapies for the rescue of skin injuries and mortality by CX.

在第二次世界大战期间储存的光气肟（CX;二氯仿肟）是一种强大的化学武器， 单独使用或与其他化学制剂一起使用，都有暴露的危险。它是一种瘙痒或荨麻剂分组 与起泡剂由于类似的损害性质;虽然，它导致更严重的损害比其他 由于其高度反应性的性质。尽管它是最臭名昭著的具有特殊军事用途的发泡剂， 和恐怖分子的利益，它是研究最少的化学战剂之一，没有具体的解毒剂。 关于其对人体皮肤组织和吸收的影响的信息有限，其作用机制是 未知因此，明确定义的暴露于CX的动物模型对于研究其皮肤毒性和 开发有效的治疗方法。因此，本建议的最终目标是开发相关皮肤 目的：建立CX染毒小鼠皮肤损伤模型，探讨CX对小鼠皮肤的损伤机制， 毒性作用，目的是确定治疗干预和药物开发的新靶点。 我们的初步数据表明，皮肤CX蒸汽暴露（4分钟）的SKH-1无毛小鼠皮肤 在30分钟内引起水肿、红斑、发白、荨麻疹和坏死，并持续影响至注射后8小时。 exposure.这些临床病变的快速发作与皮肤CX暴露相关：a） 凋亡性细胞死亡和p53磷酸化的增加表明DNA损伤应答，B）和 与i）肥大细胞脱颗粒和促炎细胞因子增加相关炎性反应 肿瘤坏死因子-α和环氧合酶-2，和ii）中性粒细胞浸润和髓过氧化物酶增加 程度.这些结果表明，CX具有类似芥子气的烷基化和亲核性质 可导致DNA损伤和炎症反应的水疱剂。CX的皮肤荨麻疹类似于 荨麻疹由经常引起的过敏和非过敏反应引起，主要涉及炎症反应 通过肥大细胞释放组胺。此外，CX暴露效应伴有扩张 外周血管中的红细胞在所有主要内脏器官的血管中强烈激增，这可能导致 突然血压下降缺氧和死亡基于这些发现，我们的假设是，CX激活 炎症和p53-DNA损伤途径是CX诱导的皮肤毒性的潜在主要贡献者 病变，并导致多个器官的血管扩张和血液充血，导致全身性 毒性和死亡率。具体的目标提出来测试这一假设是：1）表征和建立CX- 在皮肤暴露后诱导体内啮齿动物皮肤损伤模型，并确定相关机制 检查CX皮肤暴露的全身毒性作用和相关死亡率。我们 我们的研究将建立急性CX暴露的皮肤和全身损伤生物标志物 其可用于筛选治疗以挽救CX引起的皮肤损伤和死亡。