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。MG电极导线的眼部暴露 眼睑水肿、结膜充血和球结膜水肿、角膜上皮缺损、混浊， 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、视觉障碍、视网膜病变和视网膜脱离。 损伤和失明。尽管在人类和动物中进行了大量研究，但其潜在机制仍然存在。 MG的眼部损伤尚不明确，且至今尚无针对性的治疗方法。缺氧和炎症是 缠绕机制介导烧伤后的组织损伤，包括化学损伤。组织缺氧是一种 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明显缺氧，从而激活 缺氧诱导因子（HIF）信号传导、氧化应激和体内炎症。此外， 人角膜上皮细胞对氮芥的作用促进HIF信号转导。然而，组织的作用 尚未研究体内眼MG暴露中的缺氧。我们设计了一种全氟萘烷 过饱和氧乳剂（SSOE）作为局部治疗，以提供高水平（超过4倍于 大气水平）的氧气。在我们的初步工作中，我们发现， 急性碱烧伤时的SSOE显著减少眼内缺氧，抑制HIF信号传导，氧化应激， 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MG眼损伤中的疗效。 治疗MG相关的眼部损伤。我们建立了一种新的小鼠眼部氮芥模型 暴露，并计划测试以下目标：在具体目标1中，我们假设组织缺氧发生 MG暴露后迅速，我们将确定眼内氧水平，HIF信号，氧化应激， 体内眼部氮芥暴露后的组织炎症;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， 氧化应激、白细胞浸润、组织纤维化、角膜混浊/NV和体内白内障形成。 成功完成本提案不仅将填补MG损伤相关缺氧方面的知识空白 研究，但提供了第一个概念验证数据，证明SSOE作为一种新的治疗潜力。 局部治疗急性MG暴露。鉴于SSOE的配方是便携式的小罐， 它在室温下稳定，可以储存并在芥子气袭击中迅速部署， 大规模伤亡，并针对目前没有任何治疗方案的化学威胁提供对策。