Treatment strategies for ocular toxicity from chloropicrin

项目摘要 化学威胁因素，如发泡芥剂硫芥剂(SM)和氮芥剂(NM)导致 眼睛和皮肤组织中与炎症和水泡有关的临床和组织病理学毒性变化。 皮肤变色剂和其他一些化学试剂，如氯苦(CP)和氯，会引起严重的急性和 长期的眼睛损伤，并且仍然是战争和恐怖活动的潜在动因。CP，用作杀虫剂， 据报道，与发泡剂等其他有毒化学物质混合可增强其对眼睛和皮肤的毒性作用。 CP和芥末发泡剂都会造成类似的严重眼部损伤，特别是对角膜；然而， 他们的伤害机制，特别是来自CP的伤害，没有明确的定义和有效的靶向治疗 难以捉摸。在我们目前资助的NIH-CCRP项目下正在进行的研究中，我们已经在体内建立了一个 CP致小鼠眼损伤模型的建立及Nrf2通路在CP诱导的眼损伤中的作用 用Nrf2基因敲除(KO)小鼠进行损伤。与芥末等突出化学威胁造成的化学伤害类似 发泡剂和CP是辐射毒性的主要原因之一，涉及炎症，最 在细胞快速增殖的组织中表现突出。此外，各种器官的急性损伤，包括纤维化和 骨髓抑制以及感染和长期健康影响在这两种情况下都被观察到 辐射和化学物质暴露。这份增刊建议与萨哈博士合作，资助PI 在NIH RNCP U01拨款下，加强对化学CP和NM所致眼部损伤的了解 已经在辐射损伤模型中显示出希望的途径，并验证这些途径是否可能 辐射和化学损伤的治疗靶点。根据萨哈博士实验室的结果表明 趋化因子受体2(CCR2)信号在辐射诱导的炎症中起重要作用 假设CCR2信号可调节化学诱导的眼部炎症和损伤 在辐射引起的炎症中观察到。我们建议与萨哈博士的实验室合作研究这一问题 假设和将：1)从他的实验室获得CCR2 KO小鼠，并将设计拟议的研究 基于他实验室的辐射；2)我们将与Dr共享化学暴露的眼组织样本。 萨哈的实验室，并获得他的协助进行趋化因子和T细胞分析，并确定另一个 炎性细胞。以下目标在NIH-CCRP R21资助下扩大目标1的范围是 建议。具体目的：探讨CCR2受体在CP和NM诱导的急性和长时间脑损伤中的作用。 小鼠眼部炎症和损伤。这一合作努力预计将确定 可用于对抗化学或辐射引起的广谱炎症和组织损伤 在突发公共卫生事件中暴露和援助不可知的医疗反应能力

Project Summary Chemical threat agents like vesicating mustard agents sulfur mustard (SM) and nitrogen mustard (NM) cause clinical and histopathological toxic changes related to inflammation and vesication in both eye and skin tissues. Vesicating agents and some other chemical agents like chloropicrin (CP) and chlorine, cause severe acute and long-term ocular injuries, and remain potential agents of warfare and terror activities. CP, used as a pesticide, is reported to be mixed with other toxic chemicals like vesicants to enhance their ocular and skin toxic effects. Both CP and mustard vesicants cause severe comparable ocular injury, especially to the cornea; however, mechanisms of their injury, especially from CP, are not well-defined and effective targeted treatments are elusive. In our ongoing studies under the current funded NIH-CCRP project, we have established an in vivo mouse ocular injury model with CP and are further defining the role of Nrf2 pathway in CP-induced ocular injury using Nrf2 knockout (KO) mice. Similar to chemical injuries from prominent chemical threats like mustard vesicants and CP, one of the leading causes of radiation induced toxicity involves inflammation and is most prominent in tissues with rapid proliferating cells. Also, acute injuries to various organs including fibrosis and bone marrow suppression as well as infections and long-term health effects are observed following both radiation and chemical exposures. This supplement proposes a collaborative effort with Dr. Saha, funded PI under the NIH RNCP U01 grant, to enhance understanding of the chemical CP and NM induced ocular injury pathways that have shown promise in radiation injury model, and validate if these could be potential therapeutic targets across radiation and chemical injury. Based on results from Dr. Saha’s lab which indicate that chemokine receptor 2 (CCR2) signaling plays an important role in radiation induced inflammation, we hypothesize that CCR2 signaling could regulate chemical induced ocular inflammation and injury as observed in radiation-induced inflammation. We propose to work together with Dr. Saha’s lab to study this hypothesis and will: 1) Obtain the CCR2 KO mice from his lab and the proposed studies will be designed based on radiation in his laboratory; 2) We will share the chemical exposed ocular tissue samples with Dr. Saha’s lab and obtain his assistance for the chemokine and T cell analysis ,and to determine the other inflammatory cells. The below aim expanding the scope of the aim 1 under the funded NIH-CCRP R21 grant is proposed. Specific Aim: Determine the role of CCR2 receptor in CP- and NM-induced acute and long- term ocular inflammation and injury in mice. This collaborative effort is anticipated to identify targets that can be manipulated to counteract broad spectrum inflammation and tissue injury from chemical or radiation exposures and aid in agnostic medical response capabilities during public health emergencies