ALCOHOLISM & LUNG INJURY--CIRRHOSIS & GLUTATHIONE DEF

酗酒

• 批准号: 6166254
• 负责人: I MARC MOSS
• 金额: $ 11.93万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6166254
• 关键词: adult respiratory distress syndrome; alcoholic liver cirrhosis; alcoholism /alcohol abuse; clinical research; diagnostic respiratory lavage; epidemiology; glutathione; human subject; metabolism disorder; pathologic process; pulmonary surfactants; respiratory infections

The acute respiratory distress syndrome (ARDS) is a severe form of acute edematous lung injury that afflicts approximately 150,000 individuals per year in the United States. Despite three decades of research concerning ARDS, there are presently no effective therapies and the mortality from this syndrome remains unacceptably high at 40-60 percent. The ability of the lung to neutralize the harmful effects of oxygen radicals has been postulated to be a critical step in preventing the development and decreasing the severity of ARDS. Initially, we hypothesized that the presence of pre-existing co-morbid conditions, which independently reduce the anti-oxidant capacity of the lung, will result in an increased incidence and severity of ARDS in critically ill patients. We have previously reported that chronic alcohol abuse, without hepatic dysfunction, decreases pulmonary glutathione concentrations and alters surfactant function in both animals and humans, and increases the incidence and severity of ARDS in critically ill patients. Based on the profound effects of chronic hepatic dysfunction on systemic glutathione homeostasis, we hypothesize that cirrhosis secondary to chronic alcohol abuse will lead to a dramatic reduction in pulmonary glutathione reserve with subsequent impairment of surfactant function, thereby markedly increasing the risk of critically ill cirrhotic patients to develop ARDS. In this first part of this proposal, we will determine lung lavage glutathione concentrations and surfactant properties in control subjects and patients with clinically stable cirrhosis. In the second part of the proposal, we will examine how cirrhosis alters the pulmonary response to sepsis. Finally, we will further explore the epidemiological association between cirrhosis and ARDS using a large national database. The results of these studies will create a strong foundation of evidence supporting the potential use of glutathione replacement therapy to decrease lung injury in patients with cirrhosis secondary to alcohol abuse.

急性呼吸窘迫综合征（ARDS）是一种严重的急性水肿肺损伤，在美国每年约有15万名患者。 尽管有关ARDS的研究进行了三十年的研究，但目前尚无有效的疗法，该综合征的死亡率仍然是40-60％的不可接受的。 假定肺中和氧自由基的有害作用的能力已被认为是防止发育和降低ARDS的严重程度的关键步骤。 最初，我们假设存在于独立降低肺部抗氧化能力的合并合并状况将导致重症患者的发病率和严重程度增加。 我们以前曾报道过，慢性酒精滥用没有肝功能障碍，可以降低肺谷胱甘肽浓度，并改变动物和人类的表面活性剂功能，并增加严重患者ARDS的发病率和严重性。 基于慢性肝功能障碍对全身性谷胱甘肽稳态的深远影响，我们假设继发于慢性酒精滥用的肝硬化将导致肺谷胱甘肽储量的大幅度降低，并随后表达功能的影响，从而显着增加表面症患者的风险，从而增加了患有严重的病人的风险。 在该提案的第一部分中，我们将在对照受试者和患有临床稳定肝硬化的患者中确定肺厕所谷胱甘肽浓度和表面活性剂特性。 在提案的第二部分中，我们将研究肝硬化如何改变对败血症的肺反应。 最后，我们将使用大型国家数据库进一步探讨肝硬化与ARDS之间的流行病学关联。 这些研究的结果将为支持谷胱甘肽替代疗法的潜在使用，以减少继发于酒精滥用的肝硬化患者的肺损伤的强大基础。