Development of chronic bronchitis and emphysema in β-epithelial Na+ channel-overexpressing mice
Development of chronic bronchitis and emphysema in β-epithelial Na+ channel-overexpressing mice
复制标题
DOI：
10.1164/rccm.200708-1233oc
复制
发表时间：
2008-04-01
影响因子：
24.7
通讯作者：
Boucher, Richard C.
中科院分区：
文献类型：
--
作者：
Mall, Marcus A.;Harkema, Jack R.;Boucher, Richard C.
理由：慢性阻塞性肺疾病是全球死亡的主要原因，但其发病机制尚不清楚。既往研究表明，气道表面β-上皮Na+通道脱水（β ENaC）-过表达小鼠引起慢性肺病，新生儿肺部死亡率高，成年存活者慢性支气管炎。目的：本研究的目的是确定起始病变，并研究气道表面脱水引起的肺病的自然进展。方法：在不同年龄的β ENaC过表达小鼠中研究了肺形态、基因表达、支气管肺泡灌洗和肺力学。β ENaC过表达小鼠的粘液阻塞起源于出生后最初几天的气管，并与缺氧、气道上皮坏死、与死在存活的β ENaC过表达小鼠中，粘液阻塞延伸到肺中，并伴有杯状细胞化生、粘蛋白表达增加和气道炎症，伴有肿瘤坏死因子-α和巨噬细胞、IL-13和嗜酸性粒细胞的短暂围产期增加，以及肺中角质形成细胞衍生的细胞因子（KC）、中性粒细胞和几丁质酶的持续增加。β ENaC过表达小鼠肺气肿肺体积增加，远端空域扩大，增加肺compliance.Conclusions：我们的研究表明，气道表面脱水足以启动持续嗜酸性粒细胞气道炎症慢性气道粘液阻塞，并导致短暂的嗜酸性粒细胞气道炎症和肺气肿。这些结果表明，气道表面水化不足可能在不同病因的慢性阻塞性肺疾病的发病机制中发挥关键作用，并可作为新疗法的靶点。
Rationale: Chronic obstructive pulmonary disease is a leading cause of death worldwide, but its pathogenesis is not well understood. Previous studies have shown that airway surface dehydration in beta-epithelial Na+ channel (beta ENaC)-overexpressing mice caused a chronic lung disease with high neonatal pulmonary mortality and chronic bronchitis in adult survivors.Objectives: The aim of this study was to identify the initiating lesions and investigate the natural progression of lung disease caused by airway surface dehydration.Methods: Lung morphology, gene expression, bronchoalveolar lavage, and lung mechanics were studied at different ages in beta ENaC-overexpressing mice.Measurements and Main Results: Mucus obstruction in beta ENaC-overexpressing mice originated in the trachea in the first days of life and was associated with hypoxia, airway epithelial necrosis, and death. In surviving beta ENaC-overexpressing mice, mucus obstruction extended into the lungs and was accompanied by goblet cell metaplasia, increased mucin expression, and airway inflammation with transient perinatal increases in tumor necrosis factor-a and macrophages, IL-13 and eosinophils, and persistent increases in keratinocyte-derived cytokine (KC), neutrophils, and chitinases in the lung. beta ENaC-overexpressing mice also developed emphysema with increased lung volumes, distal airspace enlargement, and increased lung compliance.Conclusions: Our studies demonstrate that airway surface dehydration is sufficient to initiate persistent neutrophilic airway inflammation with chronic airways mucus obstruction and to cause transient eosinophilic airway inflammation and emphysema. These results suggest that deficient airway surface hydration may play a critical role in the pathogenesis of chronic obstructive pulmonary diseases of different etiologies and serve as a target for novel therapies.