ENaC Expression in Human COPD Airway and Lung Tissues

描述（由申请人提供）： 慢性阻塞性肺疾病（COPD）的一个主要表现是高分泌性粘液阻塞终末气道。在囊性纤维化肺（COPD的一种基因型）中，高活性的ENaC已被证明是气道脱水的基本机制，进而导致粘膜纤毛清除受损。然而，对ENaC通道在人COPD肺中的表达和调节知之甚少。气道粘液中蛋白酶和抗蛋白酶之间的平衡至关重要。已经证实，降低11-抗胰蛋白酶（一种非常重要的抗蛋白酶抑制剂）的活性可以抑制弹性蛋白酶（一种由中性粒细胞释放的引起肺气肿的酶）。基于我们以前和新的令人兴奋的初步结果，我们假设ENaC表达上调远端支气管肺泡上皮细胞介导的蛋白酶-抗蛋白酶失衡在COPD肺。我们的两个具体目标包括：1）定量研究COPD肺组织中ENaC亚基（1、2、3、4 ENaC）的表达模式和亚细胞定位; 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以对抗COPD的新靶点。公共卫生相关性：慢性阻塞性肺疾病（COPD）的特征是终末气道阻塞。盐转运蛋白ENaC在小鼠体内的过度表达导致COPD样肺。重要的是，抑制ENaC将显著改善他们的肺功能。然而，ENaC在人COPD肺中的表达尚未研究。我们将研究ENaC亚基表达及其与临床严重程度的关系。我们的研究结果将为ENaC在COPD肺组织中是否过度表达提供答案。(End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)