Alcohol abuse and alveolar epithelial barrier function

酒精滥用与肺泡上皮屏障功能

• 批准号: 6897816
• 负责人: I MARC MOSS
• 金额: $ 34.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897816
• 关键词: adult respiratory distress syndrome; alcoholism /alcohol abuse; blood tests; bronchoscopy; capillary bed; clinical research; clinical trials; diagnostic respiratory lavage; diethylenetriaminepentaacetate; disease /disorder proneness /risk; enzyme linked immunosorbent assay; glutathione; human subject; lung injury; oxidative stress; respiratory epithelium; respiratory function; vascular endothelium permeability

DESCRIPTION (provided by applicant): Alcohol is one of the most commonly abused drugs in the world. In the intensive care unit (ICU), patients with a history of alcohol abuse are common, and their rates of mortality and morbidity are significantly higher when compared to patients with no prior history of alcohol abuse. Though ICU patients are a heterogeneous group, Acute Respiratory Distress Syndrome (ARDS), a devastating form of acute lung injury, is one of the more frequent diagnoses among these critically ill patients. Our group has pioneered the clinical research concerning the association between alcohol abuse and ARDS. We have determined that chronic alcohol abuse significantly increases the risk of developing ARDS. This association is a common phenomenon as 50% of all ARDS patients had a prior history of alcohol abuse in our patient population. Though defined by the development of hypoxemia and diffuse bilateral infiltrates on chest radiograph in the absence of left atrial hypertension, ARDS is characterized by diffuse alveolar damage, increased pulmonary alveolar capillary permeability, and the subsequent accumulation of extravascular lung water. Using animal models of chronic alcohol abuse, we have determined that chronic ethanol ingestion alone produces oxidative stress and glutathione depletion within the alveolar space and impairs alveolar-capillary barrier function. We hypothesize that alterations in alveolar capillary barrier function that are associated with decreased pulmonary glutathione concentrations will be present in humans with a history of chronic alcohol abuse. Similarly, we expect that a prior history of chronic alcohol abuse will be associated with enhanced defects in the alveolar capillary permeability in critically ill patients with ARDS. In addition, we hypothesize that oral glutathione replacement therapy will correct these deficiencies in alveolar capillary barrier function, thereby establishing a causal relationship between glutathione deficiency and alveolar capillary permeability in individuals with a history of chronic alcohol abuse. More importantly, this work will identify glutathione replacement therapy as a prophylactic therapy for the many alcoholic patients who may be at risk for the development of ARDS, and establish the important precedent for the potential use of glutathione replacement therapy for alcohol-associated ARDS patients

描述（由申请人提供）：酒精是世界上最常见的滥用药物之一。在重症监护室（ICU）中，与没有先前的酒精滥用史的患者相比，患有酗酒病史的患者很普遍，死亡率和发病率显着更高。尽管ICU患者是一个异质组，但急性呼吸遇险综合征（ARDS）是急性肺损伤的毁灭性形式，是这些重症患者中最频繁的诊断之一。我们的小组开创了有关酗酒与ARDS之间关联的临床研究。我们已经确定，慢性酒精滥用大大增加了发展ARD的风险。这种关联是一种普遍现象，因为所有ARDS患者中有50％在我们的患者人群中有先前的酗酒史。尽管在没有左心高血压的情况下，低氧血症和弥漫性双侧浸润的发展为胸部X光片的发展而定义，但ARDS的特征是弥漫性肺泡损伤，肺肺泡毛细管渗透率增加，以及随后的肺间肺肺水的积累。使用慢性酒精滥用的动物模型，我们确定单独摄入慢性乙醇会在肺泡空间内产生氧化应激和谷胱甘肽耗竭，并损害肺泡毛细血管屏障功能。我们假设，与慢性酒精滥用病史有关，肺泡毛细血管屏障功能的改变与肺谷胱甘肽浓度降低有关。同样，我们预计先前的慢性酒精滥用病史将与患有ARDS的重症患者的肺泡毛细血管渗透性增加有关。此外，我们假设口服谷胱甘肽替换疗法将纠正这些缺陷的肺泡毛细管屏障功能，从而在患有慢性酒精滥用史的个体中建立了谷胱甘肽缺乏症与肺泡毛细管渗透率之间的因果关系。更重要的是，这项工作将确定谷胱甘肽的替代疗法是一种预防治疗，用于许多可能有可能发育ARDS的酒精患者，并确定潜在使用谷胱甘肽替代疗法的酒精相关ARDS患者的重要先例