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：
10581572
负责人：
SRINIVASA T. Reddy
金额：
$ 47.23万
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/10581572
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 Cells Cholates Chronic Chronic Disease Chronic Obstructive Pulmonary Disease Circulation Development Diabetes Mellitus Diesel Exhaust Disease Disease model Eicosanoids Environmental Exposure Environmental Pollutants Enzymes Epithelium 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 Macrophage Malignant Neoplasms Mediating Mediator 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 chronic inflammatory disease dietary experimental study fighting gut inflammation immunoregulation improved in vivo intestinal barrier intestinal epithelium lipid mediator lipid metabolism lipid transport lipoxin A4 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.

抽象的炎症是对伤害，感染和环境暴露的必要生物学反应，并且精心策划的生理过程，如果不受组织地产生不良的毒性。未解决的炎症会导致环境暴露加剧慢性疾病的发展。分子炎症解决的机制和参与者尚不清楚。在此应用程序中，我们将检查我们假设的两种新型途径在炎症的解决中起着关键作用。 1 先前报道的柴油排气颗粒提取物和相关的多环芳族烃会抑制鼠巨噬细胞中的Cox2依赖性类花生素合成。虽然通常认为Cox2是炎症，COX2巨噬细胞特异性敲除（COX2MKO）小鼠喂养时会出现肠道炎症高脂饮食。因此，巨噬细胞COX2似乎对慢性炎症提供了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的丧失小鼠原发性巨噬细胞中的肿瘤病受损，COX2调节了吞噬作用的产生依赖性脂质炎症介质不仅影响继发性吞噬作用，还会诱导组织修复肠上皮器官中的表型。根据特定的目标1，基于已发表和最新的初步结果，我们将检验以下假设：巨噬细胞cox2依赖性类固醇起着至关重要的作用在慢性炎症性疾病中，环境污染物加剧了。 2。我们的实验室开创了形成模仿抗氧化剂和抗炎特性的两亲性肽的发展载脂蛋白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炎）会加剧。我们证明4F会减弱环境超铁颗粒（UFP）介导的氧化应激，脂质代谢，动脉粥样硬化和肠炎。 4F在所有这些疾病中的保护作用的常见机制模型是将炎症的脂质介质的净平衡倾斜到抗炎状态，循环和组织。在初步结果中，我们证明了apoa-i模拟肽增强透脑脂质转运（倾斜）离体和体内。在特定目标2下，我们将检验以下假设。倾斜是炎症解决方案的关键调解人，在慢性发展中起着重要作用环境暴露加剧了炎症性疾病。成功完成提出的研究在这项新的R01应用中，不仅会提高我们对生物学和分子机制的理解环境暴露对炎症解决的影响的基础空气污染加剧了我们针对慢性炎症疾病的斗争中的治疗策略。