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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.

摘要