Electroyte Transport in Small Airways

小气道中的电解质运输

• 批准号: 7075534
• 负责人: PAUL M QUINTON
• 金额: $ 37.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7075534
• 关键词: clinical research; electrolyte balance; electrophysiology; gene expression; human subject; immunocytochemistry; intracellular; ion transport; lung; membrane potentials; perfusion; polymerase chain reaction; respiratory epithelium; respiratory function; secretion; single cell analysis; swine

DESCRIPTION (provided by applicant): Lung disease in cystic fibrosis (CF) arises from obstruction and destruction of small airways (bronchioles). A fluid layer over the inner bronchiolar epithelial surface is normally the first line of airway defense against inhaled pathogens. Since fluid transport in CF is defective and bronchioles invariably become infected in CF, it is evident that proper fluid transport is essential to respiratory health. Despite the importance of this conclusion, small airways have largely evaded studies of their native fluid transport components because it is very difficult to obtain intact bronchiolar epithelium without destroying it. Recently, we successfully applied techniques to small airways that we developed much earlier for microperfusing single sweat duct tubules. We propose here to determine the properties of fluid transport in freshly isolated native, intact epithelia of bronchioles. In contrast to the common notion that the same cells both secrete and absorb, we now have evidence that this epithelium is made up of distinct secretory and absorptive cells. This proposal will define the previously undetermined basic fluid transport properties of small airway epithelia and test the novel hypothesis that in small airways some cells secrete while others absorb fluid. Three specific aims will use a combination of electrophysiological, RT-PCR gene expression assays, and immunocytochemistry to: 1.) optimize conditions and systems to preserve and examine bronchioles, 2.) determine basic absorptive and secretory properties of small airway epithelia, and 3.) show that there are functionally and structurally separate zones of absorptive and secretory cells in small airway epithelia. Lay Abstract: The genetic disease of cystic fibrosis (CF) is a rare form of obstructive lung disease in which the very small airways or bronchioles become so damaged and plugged with mucus that the patient dies. Normal bronchioles are hollow with a thin layer of fluid that coats their inner surfaces and helps remove inhaled debris, bacteria, and viruses. The basic problem in CF is abnormal fluid formation, which tells us that problems in the CF lung start in this fluid layer. Studies of small airways in their natural state are difficult, and very few have been attempted. We have applied a micro-method we used on small sweat gland tubes to study small intact bronchiole tubes. We propose to test a new finding that cells that secrete fluid are different from those that absorb fluid as opposed to the common idea that the same cells do both. This work may fundamentally change how we think about how normal bronchioles handle fluid and how bronchioles in CF and other forms of inflammatory lung diseases are destroyed. Correctly understanding this fundamental structure/function is critical to developing effective therapies.

描述（由申请人提供）：囊性纤维化中的肺疾病（CF）是由于小气道（支气管）的阻塞和破坏而引起的。内支支气管上皮表面上的流体层通常是针对吸入病原体的第一线防御。由于CF中的流体转运有缺陷，细支气管始终被CF感染，因此很明显，适当的液体转运对于呼吸健康至关重要。尽管这一结论是重要的，但小型气道在很大程度上避免了对本机流体转运组件的研究，因为很难在不破坏它的情况下获得完整的细支气管上皮。最近，我们成功地将技术应用于小型气道，这些呼吸道为微孔填充单汗管小管而开发了很多。我们在这里建议确定新鲜分离的天然，完整的细支气管上皮的流体转运的特性。与普遍的观念相同的观念（同一细胞都会分泌和吸收），我们现在有证据表明该上皮由不同的分泌和吸收性细胞组成。该提案将定义小气道上皮的先前未定的基本流体转运特性，并检验新的假设，即在小气道中，有些细胞会分泌而有些则吸收流体。 Three specific aims will use a combination of electrophysiological, RT-PCR gene expression assays, and immunocytochemistry to: 1.) optimize conditions and systems to preserve and examine bronchioles, 2.) determine basic absorptive and secretory properties of small airway epithelia, and 3.) show that there are functionally and structurally separate zones of absorptive and secretory cells in small airway epithelia.摘要：囊性纤维化的遗传疾病（CF）是一种罕见的阻塞性肺部疾病，其中很小的气道或细支气管变得如此受损，并被粘液堵塞，以至于患者死亡。正常的细支气管是空心的，含有薄薄的液体，可覆盖其内表面，并有助于去除吸入的碎屑，细菌和病毒。 CF中的基本问题是流体形成异常，它告诉我们CF肺中的问题在此流体层开始。对自然状态的小气道的研究很困难，很少尝试。我们已经在小汗腺上使用了微方法研究小型支气管管。我们建议测试一种新发现，即分泌流体的细胞与吸收液体的细胞不同，而不是相同细胞同时使用的常见观念。这项工作可能从根本上改变了我们如何看待正常支气管的处理液以及CF和其他形式的炎症性肺部疾病中的细支气管的方式。正确理解这种基本结构/功能对于开发有效的疗法至关重要。