Alcohol increases tight junction permeability & disrupts translocation of ZO-1

酒精会增加紧密连接的通透性

• 批准号: 8306369
• 负责人: Samantha Simet
• 金额: $ 5.39万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306369
• 关键词: Actins; Adult; Adult Respiratory Distress Syndrome; Alcohol consumption; Alcohols; Alveolar; Alveolar Cell; Apical; Asthma; Binding; Bronchitis; Cell Membrane Proteins; Cell Polarity; Cell membrane; Cells; Cytoplasm; Cytoskeleton; DNA Sequence Rearrangement; Data; Disease; Edema; Epithelial; Epithelial Cells; Epithelium; Floods; Fluid Balance; Gases; Inflammation; Inflammatory; Integral Membrane Protein; Ions; Lateral; Link; Liquid substance; Lung; Lung diseases; Malignant neoplasm of lung; Membrane Proteins; Mucociliary Clearance; Mus; Pathway interactions; Permeability; Pharmaceutical Preparations; Phenotype; Physiology; Play; Pneumonia; Population; Predisposition; Protein Isoforms; Protein Kinase; Protein Kinase C; Protein translocation; Proteins; Pulmonary Edema; Research Personnel; Risk; Surface; Testing; Tight Junctions; United States; Water; airway epithelium; alcohol consequences; alcohol effect; claudin-1 protein; feeding; improved; in vivo Model; innovation; junctional adhesion molecule; macromolecule; occludin; pathogen; relating to nervous system

DESCRIPTION (provided by applicant): Alcohol is the most commonly abused drug in the world. In the United States about half the adult population regularly consumes alcohol. It has been well established that alcohol has harmful effects on the lung. For example, heavy alcohol intake increases the risk for developing pulmonary diseases such as pneumonia, bronchitis and acute respiratory distress syndrome (ARDS). The first line of defense of the conducting airways is the airway epithelium, which contains tight junctions and expresses Zonula occluden-1 (ZO-1), and occludin. Claudin-1 is a transmembrane protein, which is important in regulating tight junction permeability claudin-1, . ZO-1 is a peripherally associated membrane protein, which links tight junction proteins to the actin cytoskeleton, other tight junction proteins (claudin and occludin) and is believed to be an important component in stabilizing tight junctions. Tight junctions are characteristically located at the apical-lateral borders in airway epithelium where they regulate cell polarity and act to selectively regulate the passage of water, ions, neutral molecules and inflammatory cells through the paracellular pathway. A number of studies have shown that alcohol disrupts tight junctions resulting in barrier "leak". In the lung this occurs in the parenchyma compartment resulting in pulmonary edema and alveolar edema. Tight junctions also play a key role in regulating the barrier function in the conducting airways. Airway "leak" is a cardinal feature of airway diseases such as bronchitis and asthma. Increased leak contributes to airway edema, which is a classic finding of these diseases. However, little is known about the effects of alcohol in the conducting airways. We have recently observed that alcohol impairs ZO-1 and claudin-1 translocation to the cell membrane and increases tight junction permeability resulting in "leakier" airway epithelial cells. Our data link this "leakiness" to alcohol-induced changes in airway protein kinase C (PKC) activation resulting in impaired protein translocation to the cell membrane. These findings led us to hypothesize that: Alcohol promotes airway leak linked to the delocalization of ZO-1 and claudin-1 through a PKC-dependent pathway in the airway epithelium. We propose to test this hypothesis with 3 specific aims: 1) Determine the functional consequences of alcohol on tight junctions in the epithelium of the conducting airways; 2) Define the mechanism through which alcohol impairs ZO-1 and translocation; 3) Establish the impact of alcohol-triggered ZO-1 and rearrangement in an in vivo model of alcohol-fed mice. Results for these studies will improve our understanding of the impact alcohol has on airway epithelial barrier functions, which are critical for the understanding and treatment of airway diseases common among alcohol abusers. claudin-1 claudin-1 )

描述（由申请人提供）：酒精是世界上最常见的滥用药物。在美国，大约一半的成年人经常饮酒。酒精对肺有害，这一点已得到公认。例如，大量饮酒会增加患肺炎、支气管炎和急性呼吸窘迫综合征等肺部疾病的风险。传导气道的第一道防线是气道上皮，其含有紧密连接并表达闭锁小带-1（ZO-1）和闭锁蛋白。claudin-1是一种跨膜蛋白，在调节紧密连接通透性中起重要作用。ZO-1是一种外周相关的膜蛋白，其将紧密连接蛋白与肌动蛋白细胞骨架、其他紧密连接蛋白（claudin和occludin）连接，并且被认为是稳定紧密连接的重要组分。紧密连接特征性地位于气道上皮中的顶侧边界，在那里它们调节细胞极性并用于选择性地调节水、离子、中性分子和炎性细胞通过细胞旁途径的通道。许多研究表明，酒精破坏紧密连接，导致屏障“泄漏”。在肺中，这发生在实质隔室中，导致肺水肿和肺泡水肿。紧密连接也在调节传导气道中的屏障功能中起关键作用。气道“渗漏”是支气管炎和哮喘等气道疾病的主要特征。增加的泄漏有助于气道水肿，这是这些疾病的典型发现。然而，很少有人知道酒精在传导气道的影响。我们最近观察到，酒精损害ZO-1和claudin-1易位到细胞膜，并增加紧密连接的通透性，导致“泄漏”气道上皮细胞。我们的数据将这种“泄漏”与酒精诱导的气道蛋白激酶C（PKC）激活的变化联系起来，导致蛋白质转运至细胞膜受损。这些发现使我们假设：酒精促进气道渗漏与ZO-1和claudin-1通过气道上皮中的PKC依赖性途径的离域有关。我们提出用3个具体目标来检验这一假设：1）确定酒精对传导气道上皮细胞紧密连接的功能后果; 2）定义酒精损害ZO-1和易位的机制; 3）在酒精喂养的小鼠体内模型中建立酒精触发的ZO-1和重排的影响。这些研究的结果将提高我们对酒精对气道上皮屏障功能的影响的理解，这对于理解和治疗酒精滥用者中常见的气道疾病至关重要。claudin-1 claudin-1）