Toxic Mechanisms of Vesicating Chemicals in the Eye

项目摘要/摘要 眼角膜极易受到化学毒气的伤害。重度角膜病变的远期预后 损伤程度较重，包括视力受损、进行性角膜失代偿和新生血管。在……里面 特别是，由于生物分子之间形成化学加合物而引起的眼部损伤 反应性有机有毒工业材料(TIMs)仍然没有得到很好的表征。对眼睛的威胁是由 1984年在印度博帕尔展示了有机TIMs，当时意外释放了甲基异氰酸酯 在超过3700人死亡和50万人伤亡中，4000名幸存者永久性致残眼睛 病理生理学，如角膜疤痕、浑浊和白内障。在这份提案中，我们将描述剂量- 不同的、高活性有机TIMs对角膜损伤和恢复的依赖、急性和长期影响。 该方法集成了体内研究原型发泡剂引起的角膜毒性的方法。 硫磺芥末与体外方法率先用于研究接触不同化学毒物对角膜的影响 探员们。我们将重点关注大批量广泛可用的TIMs，从而形成大规模的 意外或故意释放后的化学毒性威胁。在第一个目标中，我们将整合体外深度- 使用我们描述良好的蒸汽帽暴露系统来确定TIM蒸汽剂量的伤害暴露模型 在隔离的兔眼上造成轻度和严重的角膜损伤。在第二个目标中，我们将转换剂量 兔在体眼的评估及角膜分子、临床和病理生理机制的研究 受伤时间超过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 人和兔眼暴露于三种TIMs的表面剂量和穿透剂量以及(B)纵向研究 3TIMs透入剂量后体内基因表达的变化。通过研究有毒物质 不同的反应性TIMs的影响，我们将开发一个基于剂量，组织特异性细胞毒性， 现有治疗药物的病理生理进展和疗效。除了确定毒物学 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 对这些剧毒有机TIMs和相关化学品的评估和暴露管理计划。

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.