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

• 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
• 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

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.

摘要 不受控制的炎症是哮喘和COPD病理生理学的核心， 长期接触臭氧有证据表明，这些病理是由于无法充分 解决肺损伤的急性炎症反应。这表明，促进解决 抑制炎症将比抑制持续的不受限制的炎症更有益。我们的研究是 重点是巨噬细胞，它在启动和解决炎症反应中起着关键作用， 组织损伤这种活性是由不同的亚群介导的，这些亚群被广泛分类为促炎性M1和 促消退M2巨噬细胞。炎症的有效解决取决于代谢重编程， 巨噬细胞从M1表型转变为M2表型，这涉及从糖酵解转变为氧化 磷酸化作为能量来源。我们发现，这种重编程在慢性炎症后被抑制， 臭氧暴露我们研究的目的是分析抑制巨噬细胞的机制， 重新编程在最近的研究中，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，在促进M1至M2巨噬细胞中同样重要 在肺部重新编程。臭氧暴露后，巨噬细胞FXR活性下调。这是 与促炎性M1巨噬细胞活性增加和促消退性M2活性降低相关 巨噬细胞我们还发现，调节促炎转录因子NFκB的microRNA在细胞内表达。 在臭氧暴露后巨噬细胞中的失调。因此，NFκB的活化延长 信号传导导致TNFα、IL-1β和细胞毒性活性氮物质的产生增加。我们 假设这些介质抑制FXR活性，阻止核受体的激活 NR 4A 1，巨噬细胞M1至M2代谢重编程的关键诱导剂。为了验证这个假设，我们将（1） 确定慢性臭氧暴露后的持续性炎症和肺部疾病的发展是否 由于促消退M2巨噬细胞的发育缺陷，并评估这是否由 M1巨噬细胞中NFκB的持久激活;（2）分析FXR及其靶点NR 4A 1在M1巨噬细胞中的作用。 慢性臭氧暴露后肺中出现促消退M2巨噬细胞;以及（3） 确定NFκB的长期激活是否是由于臭氧诱导的调节NFκB的microRNA的改变。 这些研究的结果将为慢性臭氧毒性提供新的机理见解，并可能导致 开发新的方法来阻止慢性肺病的发展。