Effects of alcohol-induced dysregulation of lung hyaluronic acid

项目总结/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 出现呼吸道感染和急性呼吸窘迫综合征。肺泡巨噬细胞（AM）， 下呼吸道中抵抗病原体的第一道防线，具有受损的生物能和吞噬细胞 慢性酒精暴露后的能力。EtOH增加肺泡空间中的氧化应激， 线粒体（MT）来源的氧化应激在AM。慢性氧化应激破坏氧化还原信号传导， 引发分子损伤。透明质酸（HA）是一种细胞外基质多糖， 肺泡腔被肺泡细胞和驻留的巨噬细胞覆盖。尽管有证据表明AM免疫力 和HA分子量/功能各自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研究。拟议研究的目的是调查 乙醇诱导的AM功能障碍的潜在机制，由于内部和细胞外的氧化应激。 这些研究将特别关注EtOH诱导的氧化还原失衡及其对HA合成的影响， 降解和AM中的炎症信号。机制研究将探索是否干扰HA合成， 降解或信号传导影响线粒体功能和能量代谢。我们首要的假设是 EtOH诱导的氧化应激和MT功能改变通过以下方式损害AM吞噬能力： 调节HA动力学。 为了验证我们的假设，我们将使用已建立的小鼠体外和体内慢性乙醇消耗 模型来确定HA如何调节MT生物能量学和AM吞噬作用以及EtOH诱导的 氧化应激调节HA动力学。目的1研究将集中在HA结合蛋白的作用， 下游信号通路对关键MT调节因子表达、MT生物能量学和AM吞噬作用的影响。 目的2研究将集中于乙醇诱导的肺氧化还原失衡如何导致AM中HA破坏。肺 HA浓度将与AM氧化应激相关。EtOH诱导的肺氧化应激和AM MT- 吡格列酮是一种过氧化物酶体增殖物激活受体， 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研究， 对描述这种病理学有重要意义。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动力学确定为治疗靶点来确定治疗范式。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诱导的AM吞噬功能受损和由此产生的肺损伤。这些 研究不仅对研究酒精滥用导致肺免疫力受损的机制很重要， 但也可能提供有价值的见解HA紊乱在几个其他肺部疾病， 2019年冠状病毒病、肺炎和哮喘。

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.