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.

芥末气（mg，最常见的是硫芥末酱和氮芥末）是质量的化学武器 破坏和能够穿透粘膜的囊泡剂。眼部暴露于MG铅 在眼睑水肿，结膜注射和化学，角膜上皮缺陷，不透明和 新生血管化（NV），边缘干细胞缺乏症和白内障形成，导致疼痛，视觉 损害和失明。尽管在人类和动物中进行了许多研究，但 MG眼损伤还不清楚，至今还没有针对性的治疗。缺氧和炎症是 燃烧后介导组织损伤的交织机制，包括化学损伤。组织缺氧是 毫克暴露后皮肤和肺组织损害的重要机制。在我们的初步研究中 我们发现眼碱燃烧会导致眼内组织缺氧，导致激活 缺氧诱导因子（HIF）信号传导，氧化应激和体内炎症。另外，暴露 人的角膜上皮细胞至氮芥末可在体外促进HIF信号传导。但是，组织的作用 尚未研究眼部MG暴露体内的缺氧。我们已经设计了一个基于全氟的 过饱和氧乳液（SSOE）作为局部处理，可提供高水平（超过4倍 大气水平）眼睛的氧气。在我们的初步工作中，我们发现 急性碱燃烧时的SSOE大大降低了眼内缺氧并抑制HIF信号传导，氧化 压力和炎症。 SSOE加速了角膜上皮愈合并改善角膜的厌恶， 白内障形成和体内组织纤维化。我们在此应用程序中的总体目标是确定 组织缺氧和炎症在MG眼损伤中的作用，并确定SSOE在 治疗与MG相关的眼部损伤。我们已经建立了一种新型的眼氮芥末模型 暴露并计划测试以下目标：在特定的目标1中，我们假设发生组织缺氧 MG暴露后迅速，我们将确定眼内氧气水平，HIF信号传导，氧化应激和 眼部氮芥菜在体内暴露后的组织炎症；在特定目标2中，我们假设 SSOE治疗将逆转组织缺氧并减少毫克暴露后的炎症，并确定 通过评估组织缺氧，SSOE应用在减轻氮芥末损伤方面的功效， 体内氧化应激，白细胞浸润，组织纤维化，角膜糊状/NV和白内障形成。 该提案的成功完成不仅会填补与MG伤害相关的缺氧的知识差距 研究但提供了概念验证数据，以证明SSOE作为一种新颖的治疗潜力 急性MG暴露的局部治疗。鉴于SSOE被配制为在小罐中便携 在室温下稳定，它可能会被储存并迅速部署在芥末气攻击中 大规模伤亡，并为目前没有任何治疗选择的化学威胁提供对策。