ETHANOL PROMOTES LUNG ENDOTHELIAL:NEUTROPHIL INTERACTIONS

乙醇促进肺内皮细胞：中性粒细胞的相互作用

基本信息

批准号：
6724380
负责人：
Lou Ann S Brown
金额：
$ 19.51万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-01 至 2007-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Investigators in this Center Application have identified chronic alcohol abuse as a co-morbid variable that significantly increases the incidence and severity of the Acute Respiratory Distress Syndrome (ARDS). The overall theme of this Center application postulates that chronic ethanol ingestion enhances the risk of alveolar flooding in response to inflammatory mediators and activated neutrophils. This suggests a "two-hit" model wherein chronic ethanol ingestion constitutes the first hit but does not generate pulmonary dysfunction. However, the first hit does predispose the lung to an enhanced response to the inflammatory mediators and activated neutrophils produced during sepsis. We postulate that one mechanism by which chronic ethanol ingestion predisposes the lung to endothelial barrier dysfunction involves ethanol-induced decreases in the availability of the antioxidant glutathione (GSH), particularly the mitochondrial pool in pulmonary microvascular endothelial cells (MVEC). When GSH availability decreases, the reactive oxygen species (ROS) generated during normal respiration and ethanol detoxification becomes amplified. With chronic exposure to ROS, the MVEC is altered and the basal expression of adhesion molecules are upregulated. During sepsis, the adhesion of the activated neutrophils and the microenvironment is potentiated. The ethanol-induced GSH depletion then amplifies the ROS produced resulting in mitochondrial dysfunction and decreased ATP generation. With limited ATP availability, the MVEC are more susceptible to cytotoxin- and neutrophil-induced apoptosis and necrosis. When MVEC death is enhanced, barrier dysfunction and neutrophil migration is potentiated. Furthermore, we propose that GSH precursors will attenuate this enhanced endothelial:neutrophil interaction and result in decreased sepsis-induced acute lung injury. Using a rat model of chronic ethanol ingestion, three Specific Aims will explore this hypothesis to determine: 1) if chronic ethanol ingestion potentiates inflammatory mediator-induced oxidative stress in MVEC, 2) if ethanol-induced chronic ROS up regulates MVEC adhesion factor expression and neutrophil transmigration during sepsis and 3) if intervention with GSH precursors will attenuate ethanol potentiation of adhesion factor expression and neutrophil transmigration during sepsis. This proposal will improve our understanding of the relationship between alcohol and lung injury and potentially identify strategies for ARDS prevention and treatment.

描述（申请人提供）：该中心申请中的调查人员已经确定慢性酒精滥用是一种合并的变量，可显着增加急性呼吸窘迫综合征（ARDS）的发病率和严重程度。该中心应用的总体主题假设慢性乙醇摄入会增加肺泡洪水的风险，以响应炎症介质和激活的中性粒细胞。这表明了一个“两击”模型，其中慢性乙醇摄入构成第一个命中，但不会引起肺部功能障碍。然而，第一个命中确实使肺易于对炎症介质的反应增强，并在败血症期间产生的中性粒细胞激活。我们假设慢性乙醇摄入的一种机制使肺易于肺部屏障功能障碍涉及乙醇诱导的抗氧化剂谷胱甘肽（GSH）的可用性降低，尤其是肺部微血管内皮细胞（MVEC）中的线粒体池。当GSH的可用性降低时，在正常呼吸和乙醇排毒过程中产生的活性氧（ROS）被放大。随着慢性暴露于ROS，MVEC会改变，并上调粘附分子的基础表达。在败血症期间，激活的嗜中性粒细胞的粘附和微环境的粘附增强。然后，乙醇诱导的GSH耗竭会扩增产生的ROS，从而导致线粒体功能障碍并减少ATP的产生。 ATP的可用性有限，MVEC更容易受到细胞毒素和中性粒细胞诱导的细胞凋亡和坏死的影响。当MVEC 死亡增强，屏障功能障碍和中性粒细胞迁移受到增强。此外，我们提出GSH前体将减轻这种增强的内皮：中性粒细胞相互作用，并导致败血症诱导的急性肺损伤减少。 Using a rat model of chronic ethanol ingestion, three Specific Aims will explore this hypothesis to determine: 1) if chronic ethanol ingestion potentiates inflammatory mediator-induced oxidative stress in MVEC, 2) if ethanol-induced chronic ROS up regulates MVEC adhesion factor expression and neutrophil transmigration during sepsis and 3) if intervention with GSH precursors will attenuate ethanol败血症期间的粘附因子表达和中性粒细胞传播的增强。该提案将提高我们对酒精与肺损伤之间关系的理解，并有可能确定预防和治疗的ARDS策略。