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: 10023172
• 负责人: Lauren Ann Jeffers
• 金额: $ 4.55万
• 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/10023172
• 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; Epithelium; 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）是一种威胁生命的炎症性肺部疾病 空域（牙槽）洪水，也称为肺水肿。慢性酒精滥用大大增加了 严重性和发展ARD的风险。在正常的肺中，钠驱动的流体间隙和上皮屏障 完整性保持空域流体平衡。发生气体交换的肺泡被流体包围 填充的间质和毛细血管。为了响应慢性酒精的使用，由于 间质和毛细血管血管的细胞细胞泄漏，使肺更容易受到 发展ARDS。有慢性酒精滥用病史的患者可以增加血管外肺液 慢点。酗酒也是重大疾病的重要危险因素，例如肺炎，需要 补液或血压稳定，增加了间质体液压力的处理 周围的肺泡。我将首先使用一种新颖的方法来测量液体压力诱导的酒精泄漏 通过测量液体增加的效果，肺并定义引起差异渗透率的机制 基线和肺炎时酒精肺综合征中肺水肿的压力。为此，我 将测量在基线和在基线和酒精喂养的小鼠中以及在基线和在 对细菌性肺炎的反应；在相同的血管内注射体积，我们假设 与健康的肺相比，酒精喂养的小鼠更容易受到肺泡洪水的影响。确定降低的泄漏 阈值可能会影响滥用酒精病史的患者的临床管理。除了泄漏 阈值，需要进一步研究酒精肺综合征背后的分子机制。紧的 连接（TJ）蛋白调节细胞细胞溶质通道并防止流体泄漏到空域中。慢性的 酒精滥用通过增加细胞细胞扩散并改变蛋白质来损害肺泡上皮屏障 Claudins的组成，Claudins是一个调节液体和溶质稳态的TJ蛋白质家族。特别是酒精 降低屏障保护TJ蛋白Claudin-4并增加屏障干扰性TJ蛋白Claudin-5 在培养的肺泡上皮细胞中。在第二个目标中，我将衡量改变Claudin-4和/或改变的影响 Claudin-5在体内肺通透性的表达。我将操纵claudin-4和claudin-5的水平 使用改良的Evans蓝色渗透率测定法测量基线肺通透性的变化。在 这个项目，我假设慢性酒精中毒降低了Claudin-4并增加了Claudin-5 损害肺泡上皮屏障功能，并增加肺部发展肺泡的敏感性 洪水。该翻译项目的长期目标是为未来的临床研究提供基础 通过评估新型的治疗靶标，以改善分子水平的肺屏障功能。经过 了解临床参数（例如流体压力）如何影响肺屏障功能 酒精，我们希望提供一种新型的基于证据的方法，可用于治疗ARDS。