ENaC Expression in Human COPD Airway and Lung Tissues

ENaC 在人 COPD 气道和肺组织中的表达

基本信息

批准号：
7701068
负责人：
HONG-LONG JI
金额：
$ 7.05万
依托单位：
UNIVERSITY OF TEXAS HLTH CTR AT TYLER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-11 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7701068
关键词：
Animal Model Cells Chronic Obstructive Airway Disease Clinical Confocal Microscopy Cystic Fibrosis Data Dehydration Distal Elastases Enzymes Epithelial Cells Equilibrium Gel Genotype Grant Human Immunoprecipitation Inflammatory Liquid substance Location Lung Measures Mediating Messenger RNA Molecular Mucins Mucociliary Clearance Mucous body substance Mus Pathogenesis Pattern Peptide Hydrolases Play Prevention Protease Inhibitor Protein C Inhibitor Proteins Pulmonary Emphysema Regulation Research Respiratory physiology Reverse Transcriptase Polymerase Chain Reaction Role Severities Sodium Chloride Specimen Structure of parenchyma of lung Surface Symptoms Time Transgenic Mice Water Western Blotting abstracting airway epithelium base combat epithelial Na+ channel improved inhibitor/antagonist interest matriptase mouse model neutrophil novel novel therapeutics overexpression protein expression public health relevance

项目摘要

DESCRIPTION (provided by applicant): Terminal airway occlusion by hypersecretive mucus is a major manifestation in chronic obstructive pulmonary disease (COPD). In the cystic fibrosis lung, a genotype of COPD, hyperactive ENaC has already been proved to be a fundamental mechanism for dehydration of airway, in turn, causes impaired mucociliary clearance. However, little is known about the expression and regulation of ENaC channels in human COPD lung. The balance between protease and antiprotease in the airway mucus is crucial. It has been confirmed that reduction of the activity of 11-antitrypsin, a very important antiprotease inhibitor to inhibit elastase, an emphysema-causing enzyme released by neutrophils. Based on our previous and new exciting preliminary results, we hypothesize that ENaC expression is up-regulated in distal bronchoalveolar epithelial cells mediated by a protease-antiprotease imbalance in COPD lungs. Our two Specific Aims include: 1) to quantitatively investigate the expression patterns and subcellular locations of four ENaC subunits (1, 2, 3, and 4 ENaC) in the lung specimens collected from COPD; 2) to investigate the expression levels and enzymatic activities of protease/antiprotease and their interactions with ENaC in the lung tissues in COPD. Results of these studies may provide a proof-of-concept for the correlation of ENaC expression, lung function, and clinicopathology in human COPD and discover dehydration of airway surface fluid as a novel target for developing new therapeutic strategies to combat COPD. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is characterized by terminal airway occlusion. Over expression of a salt transport, namely, ENaC in mice results in COPD-like lung. Importantly, inhibition of ENaC will significantly improve their lung function. However, ENaC expression in human COPD lung has not been studied. We will examine ENaC subunit expression and their association with clinical severity. Our results will definitely provide answers to the question if ENaC is over expressed or not in human COPD lung. (End of Abstract)

描述（由申请人提供）：过度分泌粘液导致的终末气道阻塞是慢性阻塞性肺病（COPD）的主要表现。在囊性纤维化肺（COPD 的一种基因型）中，过度活跃的 ENaC 已被证明是气道脱水的基本机制，进而导致粘液纤毛清除功能受损。然而，人们对 ENaC 通道在人类 COPD 肺中的表达和调控知之甚少。气道粘液中蛋白酶和抗蛋白酶之间的平衡至关重要。已证实，11-抗胰蛋白酶的活性降低，11-抗胰蛋白酶是一种非常重要的抗蛋白酶抑制剂，可抑制弹性蛋白酶，而弹性蛋白酶是中性粒细胞释放的一种引起肺气肿的酶。基于我们之前和新的令人兴奋的初步结果，我们假设 COPD 肺中蛋白酶-抗蛋白酶失衡介导的远端支气管肺泡上皮细胞中 ENaC 表达上调。我们的两个具体目标包括：1）定量研究从 COPD 采集的肺标本中四个 ENaC 亚基（1、2、3 和 4 ENaC）的表达模式和亚细胞位置； 2)研究COPD肺组织中蛋白酶/抗蛋白酶的表达水平和酶活性及其与ENaC的相互作用。这些研究的结果可能为人类 COPD 中 ENaC 表达、肺功能和临床病理学的相关性提供概念验证，并发现气道表面液体脱水作为开发新的治疗策略来对抗 COPD 的新目标。公共卫生相关性：慢性阻塞性肺病 (COPD) 的特点是终末气道阻塞。盐转运（即 ENaC）在小鼠中的过度表达会导致 COPD 样肺。重要的是，抑制 ENaC 将显着改善他们的肺功能。然而，尚未研究人 COPD 肺中的 ENaC 表达。我们将检查 ENaC 亚基表达及其与临床严重程度的关联。我们的结果肯定会回答 ENaC 在人类 COPD 肺中是否过度表达的问题。（摘要完）