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Effects of alcohol-induced dysregulation of lung hyaluronic acid

酒精引起的肺透明质酸失调的影响

基本信息

批准号：
10389703
负责人：
Kathryn Marie Crotty
金额：
$ 4.6万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-07 至 2024-09-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10389703
关键词：
Adult Respiratory Distress Syndrome Affect Alveolar Alveolar Macrophages Antibodies Antioxidants Area Asthma Attenuated Bioenergetics Biogenesis Biology Bronchoalveolar Lavage Fluid CD44 Antigens CD44 gene COVID-19 pneumonia Carbohydrates Cells Cessation of life Chronic DNA copy number Data Electrophoresis Energy Metabolism Enzymes Ethanol Extracellular Matrix Fluorescence Fluorescence Microscopy Functional disorder Grant Heavy Drinking Hyaluronic Acid Hyaluronidase Immune Immune response Immunity Immunosorbents Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Injury Ligands Link Liver Lower respiratory tract structure Lung Lung diseases Measures Mediating Membrane Membrane Proteins Mesenchymal Stem Cells Metabolism Microbiology Mitochondria Mitochondrial DNA Modeling Modification Molecular Molecular Weight Morbidity - disease rate Mus Oxidation-Reduction Oxidative Stress PPAR alpha PPAR gamma Pathology Pathway interactions Pattern Phagocytes Phagocytosis Pharmacology Pioglitazone Play Pneumonia Polysaccharides Property Reactive Oxygen Species Respiratory Tract Infections Risk Role Signal Pathway Signal Transduction Structure of parenchyma of lung Techniques Testing Therapeutic Time Training alcohol effect alcohol exposure alcohol misuse alcohol use disorder chronic alcohol ingestion extracellular fluorophore immune function in vivo in vivo Model insight macrophage molecular dynamics novel novel therapeutics oxidant stress pathogen pneumocyte prevent problem drinker protein expression respiratory response restoration therapeutic target training opportunity translational model uptake wound

项目摘要

PROJECT SUMMARY/ABSTRACT Ethanol (EtOH) misuse is linked to over 5 million annual deaths globally, partly due to increased risk of developing respiratory infections and acute respiratory distress syndrome. Alveolar macrophages (AM), the first line of defense against pathogens in the lower respiratory tract, have impaired bioenergetic and phagocytic capabilities following chronic alcohol exposure. EtOH increases oxidative stress in the alveolar space and mitochondrial (MT)-derived oxidative stress in AM. Chronic oxidative stress disrupts redox signaling and induces molecular damage. Hyaluronic acid (HA) is an extracellular matrix polysaccharide produced in the alveolar space by pneumocytes and resident macrophages. Although evidence suggests that AM immunity and HA molecular weight/function are each negatively influenced by oxidative stress, their interactions have never been explored in the context of alcohol misuse. The objective of the proposed studies is to investigate the underlying mechanisms of EtOH-induced AM dysfunction due to intra- and extracellular oxidative stress. These studies will focus specifically on EtOH-induced redox imbalance and its effect on HA synthesis, degradation, and inflammatory signaling in the AM. Mechanistic studies will explore if perturbed HA synthesis, degradation, or signaling impact mitochondrial function and energy metabolism. Our overarching hypotheses is that EtOH-induced oxidative stress and altered MT function impair AM phagocytic capabilities by modulating HA dynamics. To test our hypothesis, we will use established murine in vitro and in vivo chronic EtOH consumption models to determine how HA modulates MT bioenergetics and AM phagocytosis and how EtOH-induced oxidative stress modulates HA dynamics. Aim 1 studies will focus on the effects of HA binding proteins and downstream signaling pathways on expression of key MT regulators, MT bioenergetics, and AM phagocytosis. Aim 2 studies will focus on how EtOH-induced lung redox imbalance results in HA disruptions in the AM. Lung HA concentrations will be correlated with AM oxidative stress. EtOH-induced lung oxidative stress and AM MT- derived oxidative stress will be targeted using pioglitazone, a peroxisome proliferator-activated receptor gamma ligand with antioxidant properties. The role of HA in EtOH-induced AM dysfunction is unexplored and significant in delineating this pathology. Novel pathways identified in these studies could shift scientific and therapeutic paradigms by identifying perturbed HA dynamics as a therapeutic target. This proposal will provide an invaluable training opportunity for the applicant and provide potential therapeutic strategies to target HA dynamics to prevent EtOH-induced impairments in AM phagocytosis and resultant pulmonary injury. These studies are not only important to investigate the mechanisms of impaired lung immunity due to alcohol misuse but may also provide valuable insights into HA derangements in several other pulmonary diseases including coronavirus disease 2019, pneumonia, and asthma.

项目总结/文摘