Harnessing Inflammatory Macrophages to Thwart Lung Disease Caused by Chronic Ozone Exposure

利用炎症巨噬细胞预防慢性臭氧暴露引起的肺部疾病

基本信息

批准号：
10573170
负责人：
Debra L Laskin
金额：
$ 55.17万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10573170
关键词：
Acute Acute Lung Injury Air Pollutants Anti-Inflammatory Agents Area Asthma Bile Acids Cells Child Chronic Chronic Disease Chronic Obstructive Pulmonary Disease Chronic lung disease Classification Development Disease Elderly Energy-Generating Resources Exposure to Functional disorder Genes Glycolysis Goals Health Impairment Individual Inflammation Inflammatory Inflammatory Response Inhalation Interleukin-1 beta Ligands Link Lipids Lung Lung diseases Macrophage Macrophage Activation Mediating Mediator Metabolic MicroRNAs NR4A1 gene Nitric Oxide Nuclear Receptors Oxidative Phosphorylation Ozone Pathogenesis Pathogenicity Pathology Phenotype Play Predisposition Process Production Public Health Pulmonary Emphysema Pulmonary Inflammation Reactive Nitrogen Species Repression Resolution Role Runaway Signal Transduction Smog TNF gene Testing Tissues Toxic effect bile acid metabolism blood glucose regulation constriction cytotoxic insight irritation lung development lung injury metropolitan novel novel strategies ozone exposure prevent pulmonary function receptor response tissue injury transcription factor

项目摘要

ABSTRACT Uncontrolled inflammation is central to the pathophysiology of asthma and COPD which can develop following chronic exposure to ozone. Evidence suggests that these pathologies are due to an inability to adequately resolve the acute inflammatory response to lung injury. This suggests that promoting the resolution of inflammation will be more beneficial than suppressing persistent unrestrained inflammation. Our studies are focused on macrophages which play a key role in both initiating and resolving inflammatory responses to tissue injury. This activity is mediated by distinct subsets broadly classified as proinflammatory M1 and proresolution M2 macrophages. Effective resolution of inflammation depends on metabolic reprogramming of macrophages from an M1 phenotype to an M2 phenotype, which involves a switch from glycolysis to oxidative phosphorylation as a source of energy. We discovered that this reprogramming is suppressed following chronic ozone exposure. The goal of our studies is to analyze mechanisms underlying suppression of macrophage reprogramming. In recent studies we identified farnesoid-X receptor (FXR), a nuclear receptor important in bile acid metabolism, with anti-inflammatory activity, as important in promoting M1 to M2 macrophage reprogramming in the lung. Following ozone exposure, macrophage FXR activity is downregulated. This is associated with increased activity of proinflammatory M1 macrophages and reduced activity of proresolving M2 macrophages. We also found that microRNAs that regulate the proinflammatory transcription factor NFκB are dysregulated in macrophages after ozone exposure. As a consequence, there is protracted activation of NFκB signaling resulting in increased production of TNFα, IL-1β, and cytotoxic reactive nitrogen species. We hypothesize that these mediators suppress FXR activity which prevents activation of the nuclear receptor NR4A1, a key inducer of macrophage M1 to M2 metabolic reprogramming. To test this hypothesis, we will (1) Determine if persistent inflammation following chronic ozone exposure and the development of lung disease is due to defective development of proresolution M2 macrophages, and assess whether this is caused by protracted activation of NFκB in M1 macrophages; (2) Analyze the role of FXR and its target NR4A1, in the development of proresolution M2 macrophages in the lung following chronic ozone exposure; and (3) Determine if protracted activation of NFκB is due to ozone-induced alterations in microRNAs regulating NFκB. Results of these studies will provide new mechanistic insights into chronic ozone toxicity and may lead to the development of new approaches for thwarting the development of chronic lung disease.

抽象的不受控制的炎症是哮喘和COPD的病理生理的核心，这可以发展为以下长期暴露于臭氧。证据表明，这些病理是由于无法充分的解决对肺损伤的急性炎症反应。这表明促进解决方案炎症将比抑制持续不受约束的注射更有益。我们的研究是专注于巨噬细胞在发起和解决对组织损伤。该活动是由广泛归类为促炎M1的不同子集介导的预处理M2巨噬细胞。炎症的有效分辨率取决于代谢重编程从M1表型到M2表型的巨噬细胞，涉及从糖酵解转变为氧化磷酸化作为能源的来源。我们发现慢性后，这种重编程被抑制臭氧暴露。我们研究的目的是分析巨噬细胞抑制的基础机制重新编程。在最近的研究中，我们确定了Farneoid-X受体（FXR），这是胆汁中重要的核接收器具有抗炎活性的酸性代谢，对将M1促进M2巨噬细胞同样重要在肺中重新编程。臭氧暴露后，巨噬细胞FXR活性下调。这是与促炎性M1巨噬细胞的活性增加以及预处理M2的活性降低有关巨噬细胞。我们还发现调节促炎转录因子NFκB的microRNA是臭氧暴露后巨噬细胞失调。结果，NFκB的持久激活信号导致TNFα，IL-1β和细胞毒性反应性氮种的产生增加。我们假设这些介体抑制了防止核接收器激活的FXR活性 NR4A1，巨噬细胞M1至M2代谢重编程的关键诱导剂。为了检验这一假设，我们将（1）确定在慢性臭氧暴露后持续注射和肺部疾病的发展是由于预算M2巨噬细胞的发展有缺陷，并评估这是否是由 M1巨噬细胞中NFκB的长期激活；（2）分析FXR及其目标NR4A1的作用慢性臭氧暴露后，肺中预溶液中M2巨噬细胞的发展；（3）确定NFκB的受保护激活是否是由于臭氧诱导的MicroRNAS调节NFκB的改变引起的。这些研究的结果将为慢性臭氧毒性提供新的机械见解，并可能导致开发新方法来挫败慢性肺部疾病的发展。