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：
10614953
负责人：
Kathryn Marie Crotty
金额：
$ 4.68万
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/10614953
关键词：
Acute 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 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 lung injury 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

Acute 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 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 lung injury 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

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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.

项目摘要/摘要乙醇（ETOH）滥用与全球500万人死亡有关，部分是由于增加的风险发展呼吸道感染和急性呼吸窘迫综合征。肺泡巨噬细胞（AM），在下呼吸道中针对病原体的第一道防线，生物能和吞噬性受损慢性酒精暴露后的能力。 ETOH增加肺泡空间中的氧化应激和线粒体（MT）衍生的氧化应激。慢性氧化应激破坏了氧化还原信号传导和诱导分子损伤。透明质酸（HA）是在中产生的细胞外基质多糖肺细胞和常驻巨噬细胞的肺泡空间。尽管有证据表明是免疫力和HA分子量/功能/功能都受氧化应激的负面影响，它们的相互作用具有在滥用酒精的背景下从未探索过。拟议研究的目的是调查由于细胞内和细胞外氧化应激引起的ETOH诱导的AM功能障碍的基本机制。这些研究将专门集中于EtOH诱导的氧化还原不平衡及其对HA合成的影响， AM中的降解和炎症信号传导。机械研究将探索是否扰动HA合成，降解或信号传导影响线粒体功能和能量代谢。我们的总体假设 EtOH诱导的氧化应激和MT功能的改变会损害AM吞噬能力调节HA动力学。为了检验我们的假设，我们将在体外和体内使用已建立的鼠类消耗量确定HA如何调节MT生物能学和AM吞噬作用以及EtOH诱导的模型氧化应力调节HA动力学。 AIM 1研究将侧重于HA结合蛋白和关键MT调节剂，MT生物能学和AM吞噬作用的下游信号通路。 AIM 2研究将重点介绍ETOH诱导的肺氧化还原不平衡如何导致AM中的HA中断。肺 HA浓度将与AM氧化应激相关。 EtOH诱导的肺氧化应激和mt- 衍生的氧化应激将使用Pioglitazone（一种过氧化物酶体增殖物激活受体）靶向具有抗氧化特性的伽马配体。 HA在ETOH诱导的AM功能障碍中的作用未开发，并且对描述这种病理意义很重要。这些研究中确定的新途径可能会改变科学和通过识别扰动的HA动力学作为治疗靶标，治疗范例。该建议将提供申请人的宝贵培训机会，并提供潜在的治疗策略来针对HA 动力学以防止ETOH诱导的AM吞噬作用和导致肺损伤的损伤。这些研究不仅很重要，对于因酒精滥用而导致的肺免疫力受损机制很重要但也可能会提供有关其他几种肺部疾病中HA危险的宝贵见解 2019年冠状病毒病，肺炎和哮喘。