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：
10686267
负责人：
Kathryn Marie Crotty
金额：
$ 4.77万
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/10686267
关键词：
Acute Respiratory Distress Syndrome Affect Alcoholic Liver Diseases Alveolar Alveolar Macrophages Anti-Inflammatory Agents 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 Enzyme-Linked Immunosorbent Assay Ethanol Extracellular Matrix Fluorescence Fluorescence Microscopy Functional disorder Grant Heavy Drinking Hyaluronic Acid Hyaluronidase Immune Immune response Immunity Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Investigation Ligands Link Lower respiratory tract structure Lung Lung diseases Macrophage Measures Mediating Membrane Proteins Mesenchymal Stem Cells Metabolism Microbiology Mitochondria Mitochondrial DNA Modeling Modification Molecular Molecular Weight Morbidity - disease rate Mus Oxidation-Reduction Oxidative Stress Oxidative Stress Induction PPAR gamma Pathology Pathway interactions Patients Pattern Phagocytes Phagocytosis Pioglitazone 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 cell motility chronic alcohol ingestion chronic respiratory disease extracellular fluorophore immune function in vivo in vivo Model insight lung injury molecular dynamics mortality novel novel therapeutics oxidant stress pathogen pharmacologic pneumocyte prevent protein expression recruit response restoration therapeutic target training opportunity translational model uptake wound healing

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.

项目概要/摘要乙醇 (EtOH) 滥用与全球每年超过 500 万人死亡有关，部分原因是酒精中毒风险增加出现呼吸道感染和急性呼吸窘迫综合征。肺泡巨噬细胞 (AM) 下呼吸道抵抗病原体的第一道防线，生物能和吞噬细胞受损长期接触酒精后的能力。乙醇会增加肺泡腔的氧化应激， AM 中线粒体 (MT) 衍生的氧化应激。慢性氧化应激会破坏氧化还原信号并引起分子损伤。透明质酸（HA）是一种细胞外基质多糖，产生于肺泡腔由肺泡细胞和常驻巨噬细胞组成。尽管有证据表明 AM 免疫和 HA 分子量/功能均受到氧化应激的负面影响，它们的相互作用从未在酒精滥用的背景下进行过探索。拟议研究的目的是调查由于细胞内和细胞外氧化应激，EtOH 诱导的 AM 功能障碍的潜在机制。这些研究将特别关注乙醇引起的氧化还原失衡及其对 HA 合成的影响， AM 中的降解和炎症信号传导。机制研究将探讨 HA 合成是否受到干扰，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 诱导的氧化应激和改变的 MT 功能通过以下方式损害 AM 吞噬能力：调节 HA 动态。为了检验我们的假设，我们将使用已建立的小鼠体外和体内慢性乙醇消耗量确定 HA 如何调节 MT 生物能学和 AM 吞噬作用以及 EtOH 如何诱导的模型氧化应激调节 HA 动力学。目标 1 研究将重点关注 HA 结合蛋白和关键 MT 调节因子、MT 生物能学和 AM 吞噬作用表达的下游信号通路。目标 2 研究将重点关注 EtOH 引起的肺氧化还原失衡如何导致 AM 中的 HA 破坏。肺 HA 浓度与 AM 氧化应激相关。 EtOH 诱导的肺氧化应激和 AM MT- 使用吡格列酮（一种过氧化物酶体增殖物激活受体）来靶向衍生的氧化应激具有抗氧化特性的γ配体。 HA 在 EtOH 诱导的 AM 功能障碍中的作用尚未被探索，并且对描述这种病理学具有重要意义。这些研究中发现的新途径可能会改变科学和通过将受干扰的 HA 动态确定为治疗目标来制定治疗范式。该提案将提供为申请人提供宝贵的培训机会，并提供针对 HA 的潜在治疗策略动力学以防止 EtOH 引起的 AM 吞噬作用损伤和由此产生的肺损伤。这些研究不仅对于调查因滥用酒精而导致肺部免疫力受损的机制很重要但也可能为其他几种肺部疾病中的 HA 紊乱提供有价值的见解，包括 2019 年冠状病毒病、肺炎和哮喘。