Airborne Particulates, Corneal Oxidative Stress and Infection

空气中的颗粒物、角膜氧化应激和感染

• 批准号: 10704266
• 负责人: LINDA D HAZLETT
• 金额: $ 39.44万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704266
• 关键词: 3-Dimensional; Acute; Affect; Air; Air Pollutants; Air Pollution; Airborne Particulate Matter; Animals; Antioxidants; Bacterial Infections; Biological; Cardiovascular system; Cell Culture Techniques; Cell Survival; Clinical; Conjunctivitis; Cornea; Cytoprotection; Data; Diameter; Disease; Disease Outcome; Emergency department visit; Epithelial Cells; Event; Exhibits; Exposure to; Eye; Genes; Goals; Health; Homeostasis; Human; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Interleukin-6; Irritants; Keratitis; Knowledge; Link; Lipid Peroxidation; Malondialdehyde; Messenger RNA; Mitochondria; Molecular; Moxifloxacin; Mucous Membrane; Mus; Oxidative Stress; PTGS2 gene; Pain; Particulate Matter; Pathway interactions; Perforation; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Reactive Inhibition; Reactive Oxygen Species; Reduced Glutathione; Regimen; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; TNF gene; Testing; Thinness; Work; antimicrobial; corneal epithelium; cytokine; economic outcome; exposed human population; eye dryness; improved; in vivo; inhibitor; insight; microbial; mouse model; novel; nuclear factor-erythroid 2; particle; pathogen; pollutant; protective effect; respiratory; response; therapeutic development

Summary Airborne particulate matter with a diameter of <10µm (PM10) is a major global airborne pollutant, with an irritant effect on mucous membranes, causing serious health (cardiovascular and respiratory) and economic outcomes. Pertinent to our studies, clinical evidence has shown that exposure to PM10 is linked to increased emergency room visits for keratitis and dry eye and conjunctivitis exacerbate the problem. Unfortunately, no studies have mechanistically investigated the effect of PM10 on the eye and the link/mechanisms leading to increased microbial infection. Therefore, the long-term goal of this study is to test the hypothesis that in the cornea, PM10 triggers reactive oxygen species (ROS), disrupts nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, leading to inflammation and that this in turn enhances the disease response to bacterial infection. A corollary to this is that inhibition of ROS by SKQ1, a novel mitochondrial targeted antioxidant, will reverse these changes. Preliminary in vivo data showed that airborne exposure of mice to PM10 vs ambient air results in disruption of the Nrf2 pathway, lower levels of reduced glutathione (GSH), and elevated mRNA levels of COX- 2, iNOS, IL-6 and TNF-α, decreased protein levels of Nrf2, and increased levels of malondialdehyde (MDA), the latter indicative of lipid peroxidation. We also showed that PM10 exposure exacerbates Pseudomonas aeruginosa (P. aeruginosa) infection in the mouse cornea with earlier perforation and corneal thinning compared with ambient air exposed mice. In vitro, human corneal epithelial cell cultures support these findings and show that PM10 adversely affects cell viability and that SKQ1 rescues it. Three aims are proposed: Specific Aim 1: Tests the hypothesis that PM10 exposure triggers ROS, disrupts the Nrf2 signaling pathway, decreases cytoprotective genes and leads to corneal inflammation; and that SKQ1, an antioxidant and inhibitor of ROS, reverses these effects. Specific Aim 2: Tests the hypothesis that PM10 exposure exacerbates bacterial keratitis and that SKQ1 alone or as an adjunct treatment to Moxifloxacin improves disease outcome. Specific Aim 3: Tests the hypothesis that PM10 exposure of human corneal epithelial cells parallels the mouse data in that it induces ROS, Nrf2 signaling, decreases cytoprotective genes and that SKQ1 reverses these effects.

概括 直径小于10µm（PM10）的空气寄生颗粒物是一种主要的全球空气污染物，具有刺激性 对粘膜的影响，导致严重的健康（心血管和呼吸系统）和经济 结果。与我们的研究相关，临床证据表明，暴露于PM10与增加有关 急诊室就角膜炎，干眼症和结膜炎加剧了问题。不幸的是，不 研究已经机械地研究了PM10对眼睛的影响以及导致的链接/机制 微生物感染增加。因此，这项研究的长期目标是检验以下假设。 Cornea，PM10触发活性氧（ROS），破坏了核因子红系2相关因子2（NRF2） 信号传导，导致感染，这又增强了疾病对细菌感染的反应。一个 推论的是，新型的线粒体靶向抗氧化剂SKQ1对ROS的抑制作用将逆转这些 更改。初步体内数据表明，在PM10与环境空气的空气传播导致 NRF2途径的破坏，降低谷胱甘肽（GSH）的较低水平以及mRNA水平升高 2，iNOS，IL-6和TNF-α，NRF2的蛋白质水平降低，丙二醛（MDA），升高 后者指示脂质过氧化。我们还表明，PM10暴露execerbates pseudomonas 铜绿（铜绿假单胞菌）在小鼠角膜中感染，较早的穿孔和角膜稀疏 与环境空气暴露的小鼠相比。在体外，人角膜上皮细胞培养物支持这些发现 并证明PM10不利影响细胞活力，并且SKQ1对此做出了反应。提出了三个目标： 特定目标1：检验以下假设：PM10暴露会触发ROS，破坏NRF2信号通路， 降低细胞保护基因并导致角膜注射；和SKQ1，一种抗氧化剂和抑制剂 ROS，逆转这些影响。 特定目的2：检验以下假设：PM10暴露会加剧细菌角膜炎，单独使用SKQ1 或作为莫西沙星的辅助治疗可改善疾病的预后。 特定目的3：检验以下假设：PM10人角膜上皮细胞与小鼠平行 数据诱导ROS，NRF2信号传导，降低细胞保护基因，而SKQ1逆转了这些基因 效果。