Treatment strategies for ocular toxicity from chloropicrin

氯化苦眼部毒性的治疗策略

• 批准号: 10206886
• 负责人: Neera Tewari-Singh
• 金额: $ 19.56万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206886
• 关键词: Acids; Acute; Antidotes; Antioxidants; Apoptotic; Biological Markers; Blindness; Burn injury; Cell Death; Cells; Chemical Agents; Chemical Exposure; Chemicals; Chronic; Complement; Cornea; Corneal Injury; Corneal edema; DNA Damage; Data; Defense Mechanisms; Disease; Emulsions; Enzymes; Epithelial Cells; Erythroid; Esters; Exposure to; Eye; Eye Injuries; Gases; Goals; Human; Hypoxia; Inbred BALB C Mice; Inflammation; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Lacrimation; Lead; Lesion; Lipid Peroxidation; Mediator of activation protein; Modeling; Mus; Nature; Necrosis; Nuclear; Occupational Exposure; Organ; Oryctolagus cuniculus; Outcome; Oxidative Stress; Oxygen; Oxygen Therapy Care; PTGS2 gene; Pathogenesis; Pathway interactions; Pesticides; Phase; Poison; Probability; Proteins; Reporting; Response Elements; Role; Signal Pathway; Soil; Stress; System; Terrorism; Testing; Therapeutic; Therapeutic Intervention; Tissue Preservation; Tissues; Topical application; Toxic effect; World War I; acute toxicity; biological adaptation to stress; corneal epithelium; cytokine; effective therapy; efficacy evaluation; efficacy testing; healing; heme oxygenase-1; improved; in vivo; irritation; mouse model; new therapeutic target; novel; novel strategies; novel therapeutic intervention; oleanane; pulmonary agents; soft tissue; targeted treatment; therapeutically effective; treatment strategy; wound; wound healing

Project Summary Chloropicrin (Trichloronitromethane, CP), currently used as a soil fumigant and pesticide, was employed during World War I as a tear gas and choking agent and remains a potential agent for chemical terrorism. Its exposure causes severe ocular injury, especially to the corneal tissue; however, mechanisms of its injury are not well-defined and effective targeted treatments are elusive. The major goal of this application is to identify a novel targeted therapeutic approach, which can effectively mitigate acute and long-term ocular injuries from CP exposure, with a potential to be further tested against ocular injuries from other toxic chemical exposures. Data from our studies in corneal epithelial cells and ex vivo rabbit cornea demonstrate increased levels of nuclear erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), a critical target enzyme downstream of Nrf2, suggesting that the Nrf2 pathway, a key antioxidant and cytoprotective system, could be activated following CP exposure. Under this application, we propose to further asses the role of the Nrf2 pathway under CP-induced ocular injury using Nrf2 knockout (KO) mice. Nrf2 activity triggers cellular protective mechanisms against oxidative stress and inflammatory responses and is reported as a key target of new approaches for treating various oxidative stress-related ocular diseases/injuries. Hence, employing Nrf2 activators may be a novel approach for the treatment of ocular injuries due to CP exposure. Chemical ocular injury causes hypoxia that leads to tissue damage; oxygen therapy is reported to improve tissue preservation and enhance wound healing to mitigate ocular chemical and thermal burns. Our preliminary data shows the therapeutic potential of supersaturated oxygen emulsion (SSOE) therapy in reversing CP-induced acute toxicity in HCE cells and ex vivo rabbit corneas. Our hypothesis is that the Nrf2 signaling pathway is a key mediator in protecting against CP-induced corneal injury; activation of the Nrf2 pathway can inhibit CP-induced oxidative stress and inflammation, and simultaneous treatment with SSOE can increase tissue oxygen levels to improve tissue preservation and enhance wound healing, leading to a novel and more effective treatment strategy against CP- induced acute and long-term ocular injury. To test this hypothesis, the proposed aims are: Aim 1. To develop a CP-induced ocular injury model in mice and determine if the Nrf2-ARE pathway is a key mediator in CP- induced ocular injury using wild type and Nrf2 KO mice. Aim 2. To evaluate the efficacy of Nrf2 activators and supersaturated oxygen emulsion alone, or in combination, to identify an effective therapeutic strategy against CP-induced ocular injury. We anticipate that the outcomes from the above aims will establish a useful mouse ocular injury model with CP and ascertain if the Nrf2 signaling pathway is a novel target for therapeutic intervention to counteract CP-induced ocular injury. Successful completion of this project will identify a novel therapeutic approach that can more effectively mitigate acute and chronic ocular injuries from CP and lead to a better understanding of the mechanisms of CP-induced ocular toxicity.

项目摘要 氯激素（三氯硝基甲烷，CP）目前用作土壤熏蒸和农药，在 第一次世界大战是催泪瓦斯和窒息的代理，仍然是化学恐怖主义的潜在特工。它是 暴露会导致严重的眼部损伤，尤其是对角膜组织；但是，其伤害的机制是 定义明确且有效的有针对性治疗难以捉摸。该应用程序的主要目的是确定 新型的靶向治疗方法，可以有效地减轻CP的急性和长期眼损伤 暴露，有可能进一步测试其他有毒化学暴露的眼部损伤。 我们在角膜上皮细胞和离体兔角膜研究中的研究表明， 核红细胞2相关因子2（NRF2）和血红素氧酶-1（HO-1），这是下游的关键靶酶 NRF2的of提示NRF2途径是一种关键的抗氧化剂和细胞保护系统，可以激活 CP暴露后。在此应用下，我们建议进一步评估NRF2途径的作用 使用NRF2敲除（KO）小鼠通过CP诱导的眼部损伤。 NRF2活性触发细胞保护机制 反对氧化应激和炎症反应，并报告是新方法的关键目标 治疗各种与氧化应激相关的眼部疾病/损伤。因此，使用NRF2激活剂可能是 由于CP暴露而导致的眼部损伤的新方法。化学眼损伤会导致缺氧 导致组织损伤；据报道氧疗法可改善组织保存并增强伤口 愈合以减轻眼部化学和热燃烧。我们的初步数据显示了 过饱和氧乳液（SSOE）治疗在逆转CP诱导的HCE细胞急性毒性和EX 体内兔角膜。我们的假设是NRF2信号传导途径是保护 CP引起的角膜损伤； NRF2途径的激活可以抑制CP诱导的氧化应激和 炎症和用SSOE同时治疗可以增加组织氧水平以改善组织 保存并增强伤口愈合，导致针对CP的新颖，更有效的治疗策略 诱发急性和长期眼损伤。为了检验这一假设，拟议的目的是：目标1。 CP诱导的小鼠眼损伤模型，并确定NRF2-ARE途径是否是CP-的关键介体 使用野生型和NRF2 KO小鼠诱导眼损伤。目标2。评估NRF2激活剂和 单独或组合过度饱和氧乳液，以确定有效的治疗策略 CP引起的眼部损伤。我们预计上述目标的结果将建立有用 带有CP的小鼠眼损伤模型，并确定NRF2信号通路是否是新的目标 治疗干预以抵消CP引起的眼部损伤。成功完成该项目 将确定一种新型的治疗方法，可以更有效地减轻急性和慢性眼 CP的伤害并可以更好地理解CP诱导的眼毒性的机制。