Airborne Particulates, Corneal Oxidative Stress and Infection

空气中的颗粒物、角膜氧化应激和感染

基本信息

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
项目类别：
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

项目摘要

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<10微米的空气颗粒物（PM10）是全球主要的空气污染物，具有刺激性对粘膜的影响，造成严重的健康（心血管和呼吸系统）和经济损失与我们的研究相关，临床证据表明，接触 PM10 与结果增加有关。不幸的是，因角膜炎、干眼症和结膜炎而去急诊室却加剧了这个问题。研究机械地调查了 PM10 对眼睛的影响以及导致因此，本研究的长期目标是检验以下假设：角膜，PM10 触发活性氧 (ROS)，破坏核因子红细胞 2 相关因子 2 (Nrf2) 信号传导，导致炎症，进而增强对细菌感染的疾病反应。由此推论，SKQ1（一种新型线粒体靶向抗氧化剂）对 ROS 的抑制将逆转这些初步体内数据表明，与环境空气相比，小鼠在空气中暴露于 PM10 会导致变化。 Nrf2 通路破坏、还原型谷胱甘肽 (GSH) 水平降低以及 COX-mRNA 水平升高 2、iNOS、IL-6 和 TNF-α，Nrf2 蛋白水平降低，丙二醛 (MDA) 水平升高，后者是脂质过氧化的指标，我们还发现 PM10 暴露会使假单胞菌恶化。小鼠角膜中的铜绿假单胞菌（P. aeruginosa）感染导致早期穿孔和角膜变薄与体外暴露于环境空气的小鼠相比，人角膜上皮细胞培养物支持了这些发现。并表明 PM10 对细胞活力有不利影响，而 SKQ1 可以拯救它，提出了三个目标：具体目标 1：测试 PM10 暴露触发 ROS、破坏 Nrf2 信号通路的假设，减少细胞保护基因并导致角膜炎症；SKQ1，一种抗氧化剂和抑制剂 ROS 可以逆转这些影响。具体目标 2：检验 PM10 暴露会加重细菌性角膜炎以及单独使用 SKQ1 的假设或作为莫西沙星的辅助治疗可改善疾病结果。具体目标 3：检验人角膜上皮细胞 PM10 暴露与小鼠相似的假设数据显示，它会诱导 ROS、Nrf2 信号传导，减少细胞保护基因，而 SKQ1 可以逆转这些影响。