ENaC Expression in Human COPD Airway and Lung Tissues

描述(由申请人提供)： 高分泌性黏液终末阻塞是慢性阻塞性肺疾病(COPD)的主要表现。在COPD的一种类型-囊性纤维化肺中，ENaC过度活跃已被证明是导致呼吸道脱水的基本机制，进而导致粘液纤毛清除功能受损。然而，对于ENaC通道在人COPD肺组织中的表达和调控却知之甚少。呼吸道粘液中的蛋白酶和抗蛋白酶之间的平衡是至关重要的。已经证实，11-抗胰蛋白酶活性的降低是一种非常重要的抗蛋白酶抑制剂，它可以抑制中性粒细胞释放的一种导致肺气肿的酶-弹性蛋白酶。根据我们先前和新的令人兴奋的初步结果，我们假设在COPD肺组织中，ENaC在远端支气管肺泡上皮细胞中的表达上调是由蛋白酶-抗蛋白酶失衡所介导的。我们的两个特异性目标包括：1)定量研究4个ENaC亚基(1、2、3和4ENaC)在COPD肺组织中的表达模式和亚细胞定位；2)研究蛋白水解酶/抗蛋白酶在COPD肺组织中的表达水平、活性及其与ENaC的相互作用。这些研究的结果可能为人类COPD患者ENaC表达、肺功能和临床病理的相关性提供概念验证，并发现呼吸道表面液体脱水是开发抗击COPD的新治疗策略的新靶点。公共卫生相关性：慢性阻塞性肺疾病(COPD)的特征是终末呼吸道阻塞。盐转运，即ENaC在小鼠体内的过度表达会导致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肺组织中的表达尚未见报道。我们将研究ENaC亚单位的表达及其与临床严重程度的关系。我们的结果肯定会为ENaC在人COPD肺组织中是否过度表达这一问题提供答案。(摘要结束)

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)