Tissue Hypoxia and Topical Oxygen Therapy in Ocular Mustard Gas Injury

眼芥子气损伤的组织缺氧和局部氧疗

• 批准号: 10630652
• 负责人: Jia Yin
• 金额: $ 24.63万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630652
• 关键词: Acceleration; Acute; Alkalies; Animals; Apoptosis; Atmosphere; Blindness; Bulla; Cataract; Cells; Chemical Injury; Chemical Weapons; Cornea; Corneal Neovascularization; Data; Defect; Edema; Emulsions; Enabling Factors; Engineering; Epithelial Cells; Equipment; Event; Exposure to; Eye; Eye Injuries; Eye diseases; Eyelid structure; Fibrosis; Fluorescein; Goals; Grant; HIF1A gene; Histologic; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Inflammation; Inflammatory; Injections; Injury; Knowledge; Leucocytic infiltrate; Mechlorethamine; Mediating; Mucous Membrane; Mus; Mustard Gas; Oxidative Stress; Oxygen; Oxygen Therapy Care; Pain; Penetration; Production; Proliferating; Research; Role; Signal Transduction; Skin Tissue; Stains; Structure of parenchyma of lung; Temperature; Testing; Therapeutic; Time; Tissues; Topical application; Training; Treatment Efficacy; Visual impairment; Work; chemical threat; corneal epithelium; cytokine; effective therapy; efficacy evaluation; exposed human population; healing; in vivo; limbal; mass casualty; mouse model; neovascularization; nerve supply; novel; portability; pressure; slit lamp imaging; stem cells; targeted treatment; transcription factor; weapons of mass destruction

Mustard gas (MG, most commonly sulfur mustard and nitrogen mustard) is a chemical weapon of mass destruction and a vesicating agent capable of penetrating mucous membranes. Ocular exposure to MG leads to eyelid edema, conjunctival injection and chemosis, corneal epithelial defect, opacification, and neovascularization (NV), limbal stem cell deficiency, and cataract formation, resulting in pain, visual impairment, and blindness. Despite numerous studies in human and animals, the underlying mechanisms of MG eye injury are not clear, and to date there is no targeted treatment. Hypoxia and inflammation are intertwining mechanisms mediating tissue damage after burn including chemical injuries. Tissue hypoxia is an important mechanism underlying skin and lung tissue damages after MG exposure. In our preliminary study, we found that ocular alkali burn leads to significant intraocular tissue hypoxia, resulting in the activation of hypoxia-inducible factor (HIF) signaling, oxidative stress, and inflammation in vivo. In addition, exposure of human corneal epithelial cells to nitrogen mustard promotes HIF signaling in vitro. However, the role of tissue hypoxia in ocular MG exposure in vivo has not been studied. We have engineered a perfluorodecalin-based supersaturated oxygen emulsion (SSOE) as a topical treatment to deliver high levels (over 4 times of atmospheric levels) of oxygen to the eye. In our preliminary work, we found that a single topical application of SSOE at time of acute alkali burn drastically reduces intraocular hypoxia and dampens HIF signaling, oxidative stress, and inflammation. SSOE accelerates corneal epithelial healing and ameliorates corneal opacification, cataract formation, and tissue fibrosis in vivo. Our overarching goal in this application is to identify the role of tissue hypoxia and inflammation in MG eye injury and to determine the efficacy of SSOE in treating MG-related ocular damages. We have established a novel mouse model of ocular nitrogen mustard exposure and plan to test the following aims: In Specific Aim 1, we hypothesize that tissue hypoxia occurs rapidly after MG exposure, and we will determine intraocular oxygen levels, HIF signaling, oxidative stress, and tissue inflammation after ocular nitrogen mustard exposure in vivo; In Specific Aim 2, we hypothesize that SSOE treatment will reverse tissue hypoxia and reduce inflammation after MG exposure, and will determine the efficacy of SSOE application in mitigating nitrogen mustard eye injury by assessing tissue hypoxia, oxidative stress, leukocyte infiltration, tissue fibrosis, corneal opacification/NV, and cataract formation in vivo. Successful completion of this proposal will not only fill in the knowledge gap in MG injury-related hypoxia research but provide first proof-of-concept data in demonstrating the therapeutic potential of SSOE as a novel topical treatment for acute MG exposure. Given that SSOE is formulated to be portable in a small canister and stable at room temperature, it can potentially be stockpiled and rapidly deployed in a mustard gas attack with mass casualty and provide countermeasure against chemical threats currently without any treatment options.

芥子气（MG，最常见的是硫芥子气和氮芥子气）是一种大规模化学武器