Novel Approaches for Improving Inflammation Resolution Following Chronic Exposure to Air Pollutants

改善长期接触空气污染物后炎症消退的新方法

基本信息

批准号：
10348421
负责人：
SRINIVASA T. Reddy
金额：
$ 48.86万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2022-03-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10348421
关键词：
Acute Affect Air Pollutants Air Pollution Alzheimer&apos s Disease Anti-Inflammatory Agents Antioxidants Apolipoprotein A-I Arachidonic Acids Aromatic Polycyclic Hydrocarbons Atherosclerosis Attenuated Biological Biology Blood Circulation Cells Cholates Chronic Chronic Disease Chronic Obstructive Pulmonary Disease Development Diabetes Mellitus Diesel Exhaust Disease Disease model Eicosanoids Environmental Exposure Environmental Pollutants Enzymes Epithelial Equilibrium Exposure to Fatty acid glycerol esters High Fat Diet Homeostasis Impairment Infection Inflammation Inflammation Mediators Inflammatory Intestines Knock-out Knockout Mice Knowledge Laboratories Lesion Lipids Malignant Neoplasms Mediating Mediator of activation protein Molecular Mus Myelogenous Obesity Organoids Oxidative Stress PTGS2 gene Parkinson Disease Pathway interactions Phenotype Physiological Processes Play Production Property Prostaglandins Public Health Publishing Recovery Reporting Research Resolution Role Small Intestines Testing Tissues Toxic Environmental Substances Toxic effect Work analog base chronic inflammatory disease dietary experimental study fight against gut inflammation immunoregulation improved in vivo intestinal barrier intestinal epithelium lipid mediator lipid metabolism lipid transport lipoxin A4 macrophage novel novel strategies novel therapeutic intervention novel therapeutics particle peptide L peptidomimetics repaired response to injury tissue repair ultrafine particle

项目摘要

Abstract Inflammation is a necessary biological response to injury, infection, and environmental exposures, and a well- orchestrated physiological process, which if unchecked produces undesirable toxicity. Unresolved inflammation contributes to the development of chronic diseases exacerbated by environmental exposures. The molecular mechanisms and players of resolution of inflammation are not well understood. In this application, we will examine two novel pathways that we hypothesize to play a critical role in the resolution of inflammation. 1. We previously reported that diesel exhaust particle extracts and associated polycyclic aromatic hydrocarbons inhibit COX2-dependent eicosanoid synthesis in murine macrophages. While COX2 is commonly thought to be pro- inflammatory, Cox2 macrophage-specific knock-out (Cox2MKO) mice develop intestinal inflammation when fed a high fat diet. Macrophage COX2 thus appears to provide an inhibitory molecular check on chronic inflammation mediated by dietary and environmental exposures. In preliminary experiments, we show that loss of COX2 impaired efferocytosis in mouse primary macrophages and COX2 modulated the production of efferocytosis- dependent lipid inflammatory mediators that not only affect secondary efferocytosis but also induce a tissue repair phenotype in intestinal epithelial organoids. Under specific aim 1, based on published and recent preliminary results, we will test the hypothesis that macrophage COX2-dependent eicosanoids play a critical role in chronic inflammatory diseases exacerbated by environmental pollutants. 2. Our laboratory pioneered the development of amphipathic peptides that mimic the antioxidant and anti-inflammatory properties of apolipoprotein A-I (apoA-I). ApoA-I mimetic peptides (4F) inhibit the development of inflammatory diseases that are exacerbated by dietary and environmental exposures including atherosclerosis and intestinal inflammation. We demonstrated that 4F attenuates ambient ultrafine particle (UFP)-mediated oxidative stress, lipid metabolism, atherosclerosis and intestinal inflammation. A common mechanism of protective action of 4F in all these disease models is by tilting the net balance of lipid mediators of inflammation to an anti-inflammatory state, in the circulation and tissues. In preliminary results, we demonstrated that apoA-I mimetic peptides enhance transintestinal lipid transport (TILT) ex vivo and in vivo. Under specific aim 2, we will test the hypothesis that TILT is a key mediator of resolution of inflammation and plays an important role in the development of chronic inflammatory diseases exacerbated by environmental exposures. Successful completion of the studies proposed in this new R01 application will not only advance our understanding of the biology and molecular mechanisms underlying the effects of environmental exposures on the resolution of inflammation but also provide novel therapeutic strategies in our fight against chronic inflammatory diseases exacerbated by air pollution.

抽象的炎症是对损伤、感染和环境暴露的必要生物反应，也是一种良好的生物反应。精心策划的生理过程，如果不加以控制，会产生不良的毒性。未解决的炎症有助于因环境暴露而加剧的慢性疾病的发展。分子炎症消退的机制和参与者尚不清楚。在这个应用程序中，我们将研究我们假设在炎症消退中发挥关键作用的两条新途径。 1.我们先前报道柴油机尾气颗粒提取物和相关的多环芳烃抑制小鼠巨噬细胞中 COX2 依赖性类二十烷酸合成。虽然 COX2 通常被认为是亲炎症性 Cox2 巨噬细胞特异性敲除 (Cox2MKO) 小鼠在进食时会出现肠道炎症高脂肪饮食。因此，巨噬细胞 COX2 似乎可以对慢性炎症提供抑制性分子检查由饮食和环境暴露介导。在初步实验中，我们表明 COX2 的损失小鼠原代巨噬细胞的胞吞作用受损，COX2 调节胞吞作用的产生依赖的脂质炎症介质不仅影响继发性胞吞作用，而且还诱导组织肠上皮类器官的修复表型。根据具体目标 1，基于已发表的和最近的初步结果，我们将检验巨噬细胞 COX2 依赖性类二十烷酸发挥关键作用的假设环境污染物加剧的慢性炎症性疾病。 2. 我们实验室首创开发模拟抗氧化和抗炎特性的两亲性肽载脂蛋白 A-I (apoA-I)。 ApoA-I 模拟肽 (4F) 抑制炎症性疾病的发展饮食和环境暴露（包括动脉粥样硬化和肠道炎症）会加剧这种情况。我们证明 4F 可以减弱环境超细颗粒 (UFP) 介导的氧化应激、脂质代谢、动脉粥样硬化和肠道炎症。 4F 在所有这些疾病中的共同保护作用机制模型是通过将炎症的脂质介质的净平衡倾斜到抗炎状态，在循环和组织。初步结果表明，apoA-I 模拟肽可增强体外和体内的跨肠脂质转运（TILT）。在具体目标 2 下，我们将检验以下假设： TILT 是炎症消退的关键介质，在慢性炎症的发展中发挥着重要作用。环境暴露会加剧炎症性疾病。成功完成拟议的研究在这个新的 R01 应用中，不仅将增进我们对生物学和分子机制的理解揭示环境暴露对炎症消退的影响，同时也提供了新的对抗因空气污染而加剧的慢性炎症性疾病的治疗策略。