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.

项目概要/摘要 角膜非常容易受到化学毒性蒸气的伤害。严重角膜损伤后的长期预后 损伤程度较轻，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，由于生物分子与高度化学物质之间形成化学加合物而造成的眼部损伤 反应性有机有毒工业材料（TIM）的特征仍然很少。造成的眼部威胁 有机 TIM 于 1984 年在印度博帕尔进行了说明，当时异氰酸甲酯的意外释放导致 超过 3,700 人死亡和 500,000 人伤亡，其中 4,000 名幸存者患有永久性眼部残疾 病理生理学，例如角膜疤痕、混浊和白内障。在本提案中，我们将描述剂量- 多种高反应性有机 TIM 对角膜损伤和恢复的依赖性、急性和长期影响。 该方法整合了为研究原型起泡剂引起的角膜毒性而开发的体内方法 硫芥采用离体方法率先研究暴露于多种化学毒性物质对角膜的影响 代理。我们将重点关注可大量广泛使用并因此构成大规模应用的 TIM 意外或故意释放后的化学毒性威胁。在第一个目标中，我们将整合离体深度- 使用我们完善描述的蒸气帽暴露系统建立损伤暴露模型，以确定 TIM 蒸气剂量， 在离体兔眼中产生轻度和严重的角膜损伤。在第二个目标中，我们将翻译剂量 对兔子体内眼睛进行评估并研究角膜的分子、临床和病理生理机制 受伤超过 8 周。在最终目标中，我们将比较和对比（a）基因表达的急剧变化 人类和兔子的眼睛暴露于表面和穿透剂量的三种 TIM 和 (b) 研究纵向 暴露于渗透剂量的 3 个 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疗法的功效。除了毒理学鉴定 机制并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 针对这些剧毒有机 TIM 和相关化学品的评估和暴露管理计划。

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