Treatment strategies for ocular toxicity from chloropicrin

氯化苦眼部毒性的治疗策略

• 批准号: 10853300
• 负责人: Neera Tewari-Singh
• 金额: $ 15.7万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10853300
• 关键词: Acute; Bone Marrow Suppression; Bulla; Cell Proliferation; Cells; Chemical Agents; Chemical Exposure; Chemical Injury; Chemicals; Chlorine; Clinical; Cornea; Eye; Eye Injuries; Fibrosis; Funding; Grant; Health; Infection; Inflammation; Inflammatory; Injury; Knockout Mice; Laboratories; Mechlorethamine; Medical; Modeling; Mus; Mustard; Mustard Agent; Mustard Gas; Organ; Pathway interactions; Pesticides; Pilot Projects; Play; Poison; Radiation; Radiation Injuries; Radiation exposure; Reporting; Role; Signal Transduction; Skin; Skin Tissue; T-Lymphocyte; Therapeutic; Tissue Sample; Tissues; Toxic effect; United States National Institutes of Health; Vesicants; Work; chemical threat; chemokine; chemokine receptor; design; effective therapy; efficacy study; in vivo; monocyte chemoattractant protein 1 receptor; public health emergency; pulmonary agents; response; retinal toxicity; therapeutic target; tissue injury; treatment strategy

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

项目摘要 化学威胁剂，如起泡芥子气剂硫芥子气（SM）和氮芥子气（NM）， 与眼睛和皮肤组织中的炎症和水疱相关的临床和组织病理学毒性变化。 起疱剂和一些其他化学剂，如氯化苦（CP）和氯，引起严重的急性和 长期的眼部损伤，仍然是战争和恐怖活动的潜在因素。CP，用作杀虫剂， 据报道，它与其他有毒化学品如起泡剂混合，以增强其对眼睛和皮肤的毒性作用。 CP和芥子类起疱剂都能引起严重的眼部损伤，尤其是角膜损伤;然而， 它们的损伤机制，特别是来自CP的损伤机制，还没有很好的定义，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，我们已经建立了一个体内 CP小鼠眼损伤模型，并进一步确定Nrf 2途径在CP诱导的眼损伤中的作用。 使用Nrf 2敲除（KO）小鼠的损伤。类似于芥子气等突出的化学威胁造成的化学伤害 作为辐射诱导毒性的主要原因之一， 在具有快速增殖细胞的组织中突出。此外，对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的健康影响都被观察到， 辐射和化学暴露。本补充建议与Saha博士合作，资助PI 根据NIH RNCP U 01基金，加强对化学CP和NM诱导的眼损伤的理解 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有潜力 治疗靶点跨越辐射和化学损伤。根据萨哈博士实验室的结果， 趋化因子受体2（CCR 2）信号在辐射诱导的炎症中起重要作用， 假设CCR 2信号传导可以调节化学诱导眼部炎症和损伤， 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点 假设和将：1）从他的实验室获得CCR 2 KO小鼠，并设计拟定的研究 2）我们将与Dr. 萨哈的实验室，并获得他的协助，为趋化因子和T细胞的分析，并确定其他 炎症细胞以下目标扩大了NIH-CCRP R21资助下目标1的范围， 提出了具体目的：确定CCR 2受体在CP和NM诱导的急性和长期免疫应答中的作用。 术语小鼠眼部炎症和损伤。预计这一合作努力将确定目标， 可以被操纵来对抗广谱炎症和化学或辐射引起的组织损伤 在突发公共卫生事件期间，

项目成果

Ocular injury progression and cornea histopathology from chloropicrin vapor exposure: Relevant clinical biomarkers in mice.

• DOI: 10.1016/j.exer.2023.109440
• 发表时间: 2023-03
• 期刊: Experimental eye research
• 影响因子: 3.4
• 作者: Okoyeocha OM. Ebenezar;A. Roney;D. Goswami;J. M. Petrash;D. Sledge;A. Komáromy;K. Liby;N. Tewari-Singh