Hydrogen sulfide toxicity to the cornea

硫化氢对角膜的毒性

基本信息

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
项目类别：
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

项目摘要

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.

抽象的硫化氢（H2S）是一种有毒气体、化学武器、环境污染物，其中毒危害是工业国家第二大常见死因。恐怖分子利用硫化氢伤害无辜人民并造成大规模人员伤亡是一个迫在眉睫的威胁，因为它可以很容易地用普通化学品在家庭设置。对于人类来说，硫化氢中毒会导致神经、呼吸、心脏、眼部并发症，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。对角膜中 H2S 毒性的机制缺乏了解，并且缺乏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原因最大限度地减少和减轻 H2S 对角膜的毒性。该提案的主要目标是确定分子 H2S 诱发急性角膜毒性的机制并确定减轻 H2S 毒性的新治疗靶点使用体外和体内模型在角膜中进行研究。我们的中心假设是 H2S 在接触到眼睛后，与眼泪发生反应并产生高活性/有毒离子，损害线粒体的功能角膜基质成纤维细胞，导致角膜氧化应激和纤维化/混浊，最终影响视力损失。有两个具体目标将对此进行测试。 Aim-1 将定义 H2S 对角膜的剂量和时间依赖性毒性使用兔子进行体内实验。目标 2 将描述 H2S 引起的急性毒性的分子和细胞机制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填补该领域的空白，产生重大影响。干预H2S诱导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、安全的医疗预防/治疗 H2S 暴露引起的视力丧失的对策。