Hydrogen sulfide toxicity to the cornea

硫化氢对角膜的毒性

• 批准号: 10206388
• 负责人: Praveen K Balne
• 金额: $ 23.36万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206388
• 关键词: Acute; Anatomy; Animals; Anterior eyeball segment structure; Antidotes; Australia; Automobile Driving; Basic Science; Blindness; Brain Injuries; Bulla; Cardiac; Cause of Death; Cessation of life; Chemical Weapons; Chemicals; Clinical; Complex; Cornea; Corneal Injury; Data; Development; Diagnostic Imaging; Dose; Drops; Environmental Pollutants; Enzyme-Linked Immunosorbent Assay; Etiology; Exposure to; Eye; Eye Development; Eyelid structure; Fibroblasts; Fibrosis; Fill-It; Film; Fluorescein; Gases; Goals; Health Hazards; Heart; Histologic; Home; Human; Hydrogen Sulfide; Imaging Device; Immunofluorescence Immunologic; In Vitro; Industrialization; Inflammation; Inflammatory; Injury; Intervention; Intoxication; Ions; Iraq; Knowledge; Lacrimation; Lead; Lung; Membrane Potentials; Methods; Microscope; Mitochondria; Modeling; Molecular; Molecular Target; Neurologic; Ophthalmic examination and evaluation; Ophthalmologist; Oryctolagus cuniculus; Outcome; Oxidative Stress; Pathway interactions; Phase-Contrast Microscopy; Pre-Clinical Model; Process; Publishing; Quantitative Reverse Transcriptase PCR; Reactive Oxygen Species; Research; Research Personnel; Sewage; Sodium; Symptoms; TdT-Mediated dUTP Nick End Labeling Assay; Techniques; Terrorism; Testing; Time; Tissues; Toxic effect; Transmission Electron Microscopy; Ulcer; Western Blotting; World War I; acute toxicity; base; conjunctiva; cytochrome c oxidase; efficacious treatment; experience; human model; in vitro Model; in vivo; in vivo Model; irritation; medical countermeasure; mitochondrial membrane; new therapeutic target; novel; ocular surface; pre-clinical; prevent; respiratory; therapeutic target; tomography; tonometry

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.

摘要 硫化氢(H_2S)是一种有毒气体、化学武器、环境污染物，其中毒是有害的。 工业州第二常见的死亡原因。恐怖分子使用硫化氢伤害无辜人民 和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与普通化学品一起在 家居布景。在人类中，硫化氢中毒会导致神经系统、呼吸系统、心脏、眼部并发症，以及 死亡。在眼睛中，硫化氢暴露会导致角膜炎症和纤维化/混浊，从而导致视力丧失。 对导致角膜硫化氢中毒的机制缺乏了解，以及无法获得合适的人 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硫化氢毒性。这项提议的主要目标是确定分子 H_2S急性角膜毒性的机制及减轻H_2S毒性的新靶点 在角膜中采用体外和活体模型。我们的中心假设是，硫化氢与眼睛接触时， 与泪水反应，产生高度活性/毒性离子，损害线粒体功能 角膜基质成纤维细胞，并导致角膜氧化应激和纤维化/混浊，最终导致视力 损失。两个具体目标将检验这一点。AIM-1将确定剂量和时间依赖的硫化氢对角膜的毒性 在活体内使用兔子。目的2将阐明硫化氢急性毒性的分子和细胞机制。 角膜采用体外培养的人角膜基质成纤维细胞模型，体内采用兔角膜。 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。项目的成功完成将在实地产生重大影响，因为它填补了#年的空白。 硫化氢诱导干预的分子机制、途径及潜在的新靶点 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/治疗硫化氢暴露所致视力损失的对策。