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 破坏和能够穿透粘膜的起泡剂。眼睛暴露于 MG 导联 眼睑水肿、结膜充血和球结膜水肿、角膜上皮缺损、混浊和 新生血管形成 (NV)、角膜缘干细胞缺乏和白内障形成，导致疼痛、视力下降 损伤和失明。尽管对人类和动物进行了大量研究，但其潜在机制 MG眼损伤尚不明确，且迄今为止尚无针对性的治疗方法。缺氧和炎症是 介导烧伤后组织损伤（包括化学损伤）的交织机制。组织缺氧是 MG 暴露后皮肤和肺组织损伤的重要机制。在我们的初步研究中， 我们发现眼部碱烧伤导致眼内组织显着缺氧，导致眼内组织的激活 缺氧诱导因子（HIF）信号传导、氧化应激和体内炎症。此外，曝光的 人角膜上皮细胞对氮芥的体外促进 HIF 信号传导。然而，组织的作用 尚未研究体内眼部 MG 暴露的缺氧情况。我们设计了一种基于全氟萘烷的 过饱和氧乳剂 (SSOE) 作为局部治疗，可提供高浓度（超过 4 倍） 大气水平）眼睛的氧气。在我们的前期工作中，我们发现单一局部应用 急性碱烧伤时的 SSOE 可显着减少眼内缺氧并抑制 HIF 信号传导、氧化 压力和炎症。 SSOE 加速角膜上皮愈合并改善角膜混浊， 白内障形成和体内组织纤维化。我们在此应用程序中的首要目标是确定 组织缺氧和炎症在 MG 眼损伤中的作用，并确定 SSOE 在治疗中的疗效 治疗 MG 相关的眼部损伤。我们建立了一种新型眼氮芥小鼠模型 暴露并计划测试以下目标：在具体目标 1 中，我们假设发生组织缺氧 MG 暴露后，我们将迅速测定眼内氧水平、HIF 信号、氧化应激和 体内眼氮芥暴露后组织炎症；在具体目标 2 中，我们假设 SSOE 治疗将逆转 MG 暴露后的组织缺氧并减少炎症，并将确定 通过评估组织缺氧，应用 SSOE 来减轻氮芥眼损伤的功效， 体内氧化应激、白细胞浸润、组织纤维化、角膜混浊/NV和白内障形成。 该提案的成功完成不仅将填补MG损伤相关缺氧的知识空白 研究，但提供了第一个概念验证数据来证明 SSOE 作为一种新型药物的治疗潜力 急性 MG 暴露的局部治疗。鉴于 SSOE 的配方适合装在小罐中携带，并且 它在室温下稳定，可以储存并在芥子气攻击中快速部署 大规模伤亡并提供针对化学威胁的对策，目前没有任何治疗选择。