Causes of Lung Barrier Dysfunction in a Translational Model of Chronic Alcohol Ingestion

慢性酒精摄入转化模型中肺屏障功能障碍的原因

• 批准号: 10231208
• 负责人: Lauren Ann Jeffers
• 金额: $ 4.6万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-21 至 2022-08-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231208
• 关键词: Acute; Acute Lung Injury; Address; Adenovirus Vector; Admission activity; Adult Respiratory Distress Syndrome; Affect; Alcohol abuse; Alcoholism; Alcohols; Alveolar; Alveolus; Bacterial Pneumonia; Binding; Biological Assay; Blood Pressure; Blood Vessels; Blood capillaries; Cells; Chronic; Clinical; Clinical Management; Clinical Research; Critical Illness; Development; Diffusion; Disease; Dyes; Epithelial; Epithelial Cells; Evans blue stain; Extravasation; Family; Floods; Fluid Balance; Foundations; Functional disorder; Future; Gases; Goals; Homeostasis; Human; Immune; Impairment; In Vitro; Incidence; Inflammatory; Injections; Intensive Care Units; Intercellular Fluid; Lead; Life; Liquid substance; Lung; Measures; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Oxygen; Pathology; Patient risk; Patients; Peptides; Permeability; Phenotype; Pneumonia; Proteins; Public Health; Pulmonary Edema; Rattus; Recording of previous events; Rehydrations; Risk; Risk Factors; Role; Severities; Sodium; Syndrome; Testing; Tight Junctions; Trachea; Water; Work; alcohol effect; alcohol response; alveolar epithelium; chronic alcohol ingestion; claudin 4; cytokine; evidence base; improved; in vivo; inflammatory lung disease; interstitial; lung injury; mortality; novel; novel strategies; novel therapeutics; peptidomimetics; pressure; prevent; problem drinker; response; solute; translational model

SUMMARY Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung disease due to significant airspace (alveolar) flooding, also known as pulmonary edema. Chronic alcohol abuse significantly increases the severity and risk of developing ARDS. In the normal lung, sodium-driven fluid clearance and epithelial barrier integrity maintain the airspace fluid balance. The alveoli, where gas exchange occurs, is surrounded by a fluid- filled interstitium and capillaries. In response to chronic alcohol use, fluid in the airspace increases due to paracellular leak from the interstitium and capillary blood vessels, rendering the lung more susceptible to developing ARDS. Patients with a history of chronic alcohol abuse resolve increased extravascular lung fluid slower. Alcohol abuse is also a significant risk factor for critical illnesses, such as pneumonia, that require rehydration or blood pressure stabilization, treatments that increase pressure from fluid in the interstitium surrounding the alveoli. I will first use a novel approach to measure fluid pressure-induced leak in the alcoholic lung and define the mechanisms that cause differential permeability by measuring the effect of increased fluid pressure on pulmonary edema in alcoholic lung syndrome at baseline and in pneumonia. To accomplish this, I will measure the threshold at which alveolar flooding occurs in normal and alcohol-fed mice at baseline and in response to bacterial pneumonia; at the same intravascular injection volume, we hypothesize that lungs from alcohol-fed mice are more susceptible to alveolar flooding than a healthy lung. Identifying a lowered leak threshold could impact the clinical management of patients with a history of alcohol abuse. In addition to leak threshold, the molecular mechanisms behind alcoholic lung syndrome need to be further investigated. Tight junction (TJ) proteins regulate paracellular solute passage and prevent fluid leakage into the airspace. Chronic alcohol abuse impairs the alveolar epithelial barrier by increasing paracellular diffusion and changing the protein composition of claudins, a family of TJ proteins that regulate fluid and solute homeostasis. Specifically, alcohol decreases the barrier-protective TJ protein Claudin-4 and increases the barrier-disruptive TJ protein Claudin-5 in cultured alveolar epithelial cells. In the second aim, I will measure the effect of altered Claudin-4 and/or Claudin-5 expression on lung permeability in vivo. I will manipulate levels of Claudin-4 and Claudin-5 in the lower airway and measure changes in baseline lung permeability using a modified Evans Blue permeability assay. In this project, I hypothesize that chronic alcoholism decreases Claudin-4 and increases Claudin-5 which impair alveolar epithelial barrier function and increases the sensitivity of the lung to develop alveolar flooding. A long-term goal for this translational project is to provide a foundation to inform future clinical studies by evaluating novel therapeutically viable targets to improve lung barrier function at the molecular level. By understanding how clinical parameters such as fluid pressure influence lung barrier function in response to alcohol, we hope to provide a novel evidence-based approach that can be applied to the treatment of ARDS.

概括 急性呼吸窘迫综合征（ARDS）是一种危及生命的炎症性肺部疾病，由于严重的呼吸窘迫综合征 空腔（肺泡）充盈，也称为肺水肿。长期酗酒会显着增加 发生 ARDS 的严重程度和风险。在正常肺中，钠驱动的液体清除和上皮屏障 完整性维持气腔流体平衡。发生气体交换的肺泡被液体包围 充盈的间质和毛细血管。由于长期饮酒，空气中的液体会增加，因为 间质和毛细血管的细胞旁渗漏，使肺部更容易受到 发展为ARDS。有慢性酗酒史的患者可解决血管外肺液增多的问题 慢点。酗酒也是严重疾病的一个重要危险因素，例如肺炎，需要 补液或稳定血压，增加间质液体压力的治疗 肺泡周围。我将首先使用一种新颖的方法来测量酒精中流体压力引起的泄漏 肺并通过测量液体增加的影响来定义导致渗透性差异的机制 基线时酒精性肺综合征和肺炎中肺水肿的压力。为了实现这一目标，我 将测量正常小鼠和酒精喂养小鼠在基线和实验中发生肺泡溢流的阈值 对细菌性肺炎的反应；在相同的血管内注射量下，我们假设肺 与健康的肺部相比，酒精喂养的小鼠更容易受到肺泡溢流的影响。识别降低的泄漏 阈值可能会影响有酗酒史患者的临床管理。除了漏气之外 阈值，酒精性肺综合征背后的分子机制需要进一步研究。紧的 连接 (TJ) 蛋白调节细胞旁溶质通道并防止液体渗漏到空气空间中。慢性的 酒精滥用通过增加细胞旁扩散和改变蛋白质来损害肺泡上皮屏障 Claudins 的组成，这是调节液体和溶质稳态的 TJ 蛋白家族。具体来说，酒精 减少屏障保护性 TJ 蛋白 Claudin-4 并增加屏障破坏性 TJ 蛋白 Claudin-5 在培养的肺泡上皮细胞中。在第二个目标中，我将测量改变的 Claudin-4 和/或 Claudin-5 表达对体内肺通透性的影响。我将操纵较低层中 Claudin-4 和 Claudin-5 的水平 气道并使用改良的伊文思蓝渗透性测定测量基线肺渗透性的变化。在 在这个项目中，我假设慢性酒精中毒会减少 Claudin-4 并增加 Claudin-5，从而 损害肺泡上皮屏障功能并增加肺发育肺泡的敏感性 洪水。该转化项目的长期目标是为未来的临床研究提供基础 通过评估新的治疗可行的靶标，以在分子水平上改善肺屏障功能。经过 了解流体压力等临床参数如何影响肺屏障功能 酒精，我们希望提供一种新的循证方法，可应用于 ARDS 的治疗。