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慢性阻塞性肺病的病理生理学的核心，可在以下情况下发展：有证据表明，这些病症是由于无法充分接触臭氧造成的。解决肺损伤的急性炎症反应，这表明促进了肺损伤的解决。我们的研究表明，抑制炎症比抑制持续性不受抑制的炎症更有益。重点关注巨噬细胞，巨噬细胞在引发和解决炎症反应方面发挥着关键作用这种活性是由大致分为促炎性 M1 和 M1 的不同子集介导的。炎症的有效消退取决于 M2 巨噬细胞的代谢重编程。巨噬细胞从 M1 表型转变为 M2 表型，这涉及从糖酵解到氧化的转变我们发现这种重编程在慢性过程中受到抑制。我们研究的目的是分析抑制巨噬细胞的机制。在最近的研究中，我们发现了法尼醇 X 受体 (FXR)，这是胆汁中重要的核受体。酸代谢，具有抗炎活性，对于促进 M1 巨噬细胞向 M2 巨噬细胞的促进同样重要暴露于臭氧后，肺中的巨噬细胞 FXR 活性下调。与促炎性 M1 巨噬细胞活性增加和促消解 M2 活性降低相关我们还发现调节促炎转录因子 NFκB 的 microRNA 是巨噬细胞。臭氧暴露后巨噬细胞失调，导致 NFκB 长期激活。信号传导导致 TNFα、IL-1β 和细胞毒性活性氮的产生增加。认为这些介质会抑制 FXR 活性，从而阻止核受体的激活 NR4A1，巨噬细胞 M1 至 M2 代谢重编程的关键诱导物，为了检验这一假设，我们将 (1)。确定慢性臭氧暴露后的持续炎症和肺部疾病的发展是否是由于促分辨率 M2 巨噬细胞发育缺陷，并评估这是否是由 (2)分析FXR及其靶标NR4A1在M1巨噬细胞中的长期激活作用；长期接触臭氧后，肺部促分解 M2 巨噬细胞的发育；以及 (3) 确定 NFκB 的长期激活是否是由于臭氧诱导调节 NFκB 的 microRNA 发生变化。这些研究的结果将为慢性臭氧毒性提供新的机制见解，并可能导致开发阻止慢性肺病发展的新方法。