Toxic Mechanisms of Vesicating Chemicals in the Eye

眼内起泡化学物质的毒性机制

• 批准号: 10676306
• 负责人: Patrick Michael McNutt
• 金额: $ 46.28万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676306
• 关键词: Accidents; Acute; Autopsy; Biological; Biological Assay; Biological Markers; Bulla; Cadaver; Cataract; Cell Death; Cessation of life; Chemical Injury; Chemicals; Clinical; Cornea; Corneal Injury; DNA; Development; Dose; Exposure to; Eye; Eye Injuries; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Histologic; Human; India; Industrialization; Inflammatory; Injury; Laboratories; Lesion; Liquid substance; Long-Term Effects; Longitudinal Studies; Measures; Methods; Modeling; Molecular; Molecular Target; Monitor; Mustard Gas; Optical Coherence Tomography; Organ Culture Techniques; Oryctolagus cuniculus; Outcome; Pathology; Pathway interactions; Penetration; Physiological; Poison; Population; Predisposition; Productivity; Prognosis; Property; Proteins; Proteome; Public Health; RNA; Recovery; Research Personnel; Risk; Risk Assessment; Route; Structure; Survivors; System; Therapeutic; Thick; Tissue-Specific Gene Expression; Tissues; Toxic effect; Toxicology; Translating; Vesicants; Vision; Visual impairment; Volatilization; absorption; adduct; chemical threat; chemokine; clinical examination; corneal epithelial wound healing; corneal epithelium; corneal regeneration; corneal scar; covalent bond; cytokine; cytotoxic; cytotoxicity; epithelium regeneration; experience; healing; in vivo; innovation; mass casualty; methyl isocyanate; neovascularization; programs; response; response to injury; small molecule; therapeutic target; transcriptome; transcriptomics; vapor; wound healing

PROJECT SUMMARY/ABSTRACT The cornea is highly susceptible to injury from chemotoxic vapors. Long-term prognosis after severe corneal injury is poor, involving impaired vision, progressive corneal decompensation and neovascularization. In particular, ocular injuries caused by the formation of chemical adducts between biological molecules and highly reactive organic toxic industrial materials (TIMs) remain poorly characterized. The ocular threat caused by organic TIMs was illustrated in Bhopal, India in 1984, when the accidental release of methyl isocyanate resulted in over 3,700 deaths and 500,000 casualties, with 4,000 survivors suffering permanently disabling ocular pathophysiologies such as corneal scars, opacities and cataracts. In this proposal we will characterize the dose- dependent, acute and long-term effects of diverse, highly reactive organic TIMs on corneal injury and recovery. The approach integrates in vivo methods developed to study corneal toxicities elicited by the archetypal vesicant sulfur mustard with ex vivo approaches pioneered to study the corneal effects of exposure to diverse chemotoxic agents. We will focus on TIMs that are widely availability in large quantities and thus pose a large-scale chemotoxic threat following accidental or purposeful release. In the first aim, we will integrate the ex vivo depth- of-injury exposure model with our well-described vapor cap exposure system to determine TIM vapor doses that produce mild and severe corneal lesions in isolated rabbit eyes. In the second aim, we will translate dose estimates to in vivo eyes in rabbits and study molecular, clinical and pathophysiological mechanisms of corneal injury over 8 weeks. In the final aim, we will compare and contrast (a) acute changes in gene expression in human and rabbit eyes exposed to superficial and penetrating doses of three TIMs and (b) study longitudinal changes in gene expression in vivo following exposure to penetrating doses of 3 TIMs. By studying the toxic effects of diverse reactive TIMs, we will develop a threat profile based on dose, tissue-specific cytotoxicities, pathophysiological progression and efficacy of available therapeutics. In addition to identifying toxicological mechanisms and expanding our understanding of chemotoxic injury in the cornea, these studies will inform risk assessments and exposure management plans for these highly toxic organic TIMs and related chemicals.

项目总结/摘要 角膜极易受到化学毒性蒸气的伤害。严重角膜炎后的长期预后 损伤程度较低，包括视力受损、进行性角膜失代偿和新生血管形成。在 特别是由生物分子之间的化学加合物的形成引起的眼损伤， 反应性有机有毒工业材料（TIM）的特性仍然很差。造成的视觉威胁 1984年在印度博帕尔展示了有机TIM，当时异氰酸甲酯的意外释放导致 超过3,700人死亡，50万人受伤，4,000名幸存者遭受永久性视力残疾 病理生理学，如角膜瘢痕、混浊和白内障。在本提案中，我们将描述剂量- 不同的高反应性有机TIM对角膜损伤和恢复的依赖性、急性和长期影响。 该方法整合了体内方法，用于研究原型水疱剂引起的角膜毒性 硫芥与体外方法率先研究暴露于各种化学毒性的角膜效应 剂.我们将重点关注广泛可用的大量TIM，从而构成大规模的 意外或有目的释放后的化学毒性威胁。在第一个目标中，我们将整合体外深度- 损伤暴露模型与我们描述良好的蒸汽帽暴露系统，以确定TIM蒸汽剂量， 在离体兔眼中产生轻度和重度角膜损伤。在第二个目标中，我们将把剂量 评估在体兔眼，研究角膜的分子，临床和病理生理机制， 8周以上的伤病。在最后的目标，我们将比较和对比（a）急性变化的基因表达， 暴露于三种TIM的表面和穿透剂量的人和兔眼睛，和（B）纵向研究 暴露于穿透剂量的3种TIM后体内基因表达的变化。通过研究有毒物质 不同反应性TIM的影响，我们将根据剂量，组织特异性细胞毒性， 病理生理学进展和可用治疗剂的功效。除了确定毒理学 机制和扩大我们对角膜化学毒性损伤的理解，这些研究将告知风险 这些剧毒有机TIM和相关化学品的评估和接触管理计划。

项目成果

Treatment of Sulfur Mustard Corneal Injury by Augmenting the DNA Damage Response (DDR): A Novel Approach.

通过增强 DNA 损伤反应 (DDR) 治疗硫芥角膜损伤：一种新方法。

• DOI: 10.1124/jpet.123.001686
• 发表时间: 2024
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: Shalwitz,Robert;Day,Tovah;Ruehlmann,AnnaKotsakis;Julio,Lindsay;Gordon,Shellaina;Vandeuren,Adrianna;Nelson,Marian;Lyman,Megan;Kelly,Kyle;Altvater,Amber;Ondeck,Celinia;O'Brien,Sean;Hamilton,Tracey;Hanson,RyanL;Wayman,Kayla;Mi
• 通讯作者: Mi