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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.

总结