Hydrogen sulfide toxicity to the cornea

摘要 硫化氢（H_2S）是一种有毒气体、化学武器、环境污染物，其中毒是一种危害人类健康的化学物质。 是工业国家第二常见的死亡原因恐怖分子使用H2S伤害无辜人民 并造成大规模伤亡是一个迫在眉睫的威胁，因为它可以很容易地准备与常见的化学品在一个 家庭环境在人类中，H2S中毒引起神经、呼吸、心脏、眼部并发症， 死亡在眼睛中，H2S暴露引起角膜炎症和纤维化/混浊，导致视力丧失。 缺乏对角膜中H2S毒性的机理理解，以及缺乏合适的人类 体外和动物体内临床前模型是缺乏安全有效的治疗方法的主要因素， 最大限度地减少和减轻角膜中的H2S毒性。这项提案的主要目标是确定分子 H2S诱导的急性角膜毒性的机制，并确定减轻H2S毒性的新治疗靶点 在角膜中使用体外和体内模型。我们的中心假设是H2S，在接触眼睛时， 与泪液反应并产生高活性/有毒离子，损害了线粒体的功能， 角膜基质成纤维细胞，并导致角膜中的氧化应激和纤维化/混浊，最终导致视力 损失两个具体目标将检验这一点。Aim-1将定义H2S对角膜的剂量和时间依赖性毒性 in vivo体内using运用rabbits兔子.目的2阐明H2S急性毒性的分子和细胞机制， 角膜使用人角膜基质成纤维细胞的体外模型和使用兔角膜的体内模型。 将使用各种临床眼科检查和成像工具、细胞和分子技术来完成 这些目标。该项目的成功完成将在实地产生重大影响，因为它填补了 H2S诱导的细胞凋亡的分子机制和途径以及潜在的新靶点 角膜损伤和失明。该项目的长期目标是开发一种有效和安全的医疗 预防/治疗H2S暴露所致视力丧失的对策。

ABSTRACT Hydrogen sulfide (H2S) is a toxic gas, chemical weapon, environmental pollutant, and its intoxication is the second most common cause of death in industrial states. The use of H2S by terrorists to harm innocent people and cause mass causalities is an imminent threat as it can be prepared easily with common chemicals in a home setting. In humans, H2S intoxication causes neurological, respiratory, cardiac, ocular complications, and death. In the eye, H2S exposure causes corneal inflammation and fibrosis/opacity that leads to vision loss. The lack of mechanistic understanding driving H2S toxicity in the cornea and unavailability of suitable human in vitro and animal in vivo preclinical models are primary factors for lack of safe and efficacious therapies to minimize and mitigate H2S toxicity in the cornea. The main goal of this proposal is to determine the molecular mechanisms of H2S induced acute corneal toxicity and identify novel therapeutic targets to mitigate H2S toxicity in the cornea using in vitro and in vivo models. Our central hypothesis is that H2S, on contact to the eye, reacts with tears and generates highly reactive/toxic ions, compromises the mitochondrial function of the corneal stromal fibroblasts, and causes oxidative stress and fibrosis/opacity in the cornea and finally, vision loss. Two specific aims will test this. Aim-1 will define the dose- and time-dependent H2S toxicity to the cornea in vivo using rabbits. Aim 2 will delineate molecular and cellular mechanisms of H2S-induced acute toxicity to the cornea using the in vitro model of human corneal stromal fibroblasts and in vivo using rabbit corneas. Various clinical eye exam and imaging tools, cellular and molecular techniques will be used to accomplish these aims. The successful completion of the project will have a significant impact in the field as it fills gaps in the molecular mechanisms and pathways and potential novel targets for the intervention of H2S induced corneal damage and blindness. The long-range goal of this project is to develop an effective and safe medical countermeasure to prevent/treat vision loss from H2S exposure.