Mucus Dehydration and Evolution of CF Lung Disease

囊性纤维化是高加索人群中最常见的致死性遗传病。浩瀚无边 这些患者中的大多数死于以呼吸道分泌物浓厚为特征的肺部疾病， 呼吸道阻塞，以及慢性感染特有的细菌病原体。中国林木的自然历史 包括渐进性下降和急性间歇性恶化(称为恶化)。中的异常现象 盐和水通过呼吸道上皮的运输已被证明会导致衬里脱水。 在体外覆盖呼吸道表面的液体，据推测这种缺陷会导致粘液减少 肺泡灌洗液清除。我们的长期目标是确定呼吸道分泌物脱水的程度 有助于CF肺部疾病的演变，并制定维持粘液水合和 在生命早期就开始清理。我们将通过以下具体目标实现这一目标：(1)测试 假设慢性肺病的进展与粘液水合的变化有关；(2)测试 假设急性加重是由触发事件(即病毒)引起的地区性 粘液清除崩溃；以及(3)检验高渗盐水安全有效地引导 持续增加粘液纤毛清除率，减少CF患儿的呼吸道阻塞。在 首先，我们将直接测量呼吸道分泌物的水化程度，粘液水化的调节因素(例如： 核苷酸、细胞因子)和粘液脱水的后果(例如粘液流变学； 细菌群落)覆盖了各种肺部疾病的严重程度。在第二个目标中，我们将 用伽玛法前瞻性研究急性加重对体内粘液纤毛清除的影响 核素扫描；我们将直接测量可能改变粘液清除的粘液特性(即水合作用) 在病情恶化期间；我们将确定呼吸道病毒在引发急性呼吸道疾病中的作用 使用敏感的聚合酶链式反应技术，在第三个目标中，我们将确定高渗盐水， 通过解决这种水合缺陷，可以导致粘液纤毛清除和肺的持续改善 儿童(5-12岁)的功能，以及这种干预是否安全和耐受性好 患有CF3岁的婴儿。这些研究将直接影响我们对粘液清除的理解。 CF的进展和治疗，以及更广泛地说，它在健康和其他呼吸道疾病中的作用。

Cystic fibrosis (CF) is the most common lethal genetic disease in the Caucasian population. The vast majority of these patients die from lung disease that is characterized by thick airway secretions, progressive airways obstruction, and chronic infection with characteristic bacterial pathogens. The natural history of CF includes both a gradual decline and acute episodic deteriorations (termed exacerbations). Abnormalities in salt and water transport across the airway epithelium have been shown to cause dehydration of the lining fluid that covers airway surfaces in vitro, and it is postulated that this defect leads to reduced mucus clearance in the CF lung. Our long-term goal is to determine the extent that airway secretion dehydration contributes to the evolution of CF lung disease, and to develop strategies that maintain mucus hydration and clearance beginning early in life. We will pursue this goal through the following specific aims: (1) Test the hypothesis that CF lung disease progression is associated with changes in mucus hydration; (2) Test the hypothesis that acute exacerbations result from triggering events (i.e. viruses) that provoke a regional collapse of mucus clearance; and (3) Test the hypothesis that hypertonic saline safely and effectively leads to a sustained increase in mucociliary clearance and reduces airway obstruction in children with CF. In the first aim, we will directly measure the hydration of airway secretions, regulators of mucus hydration (e.g. nucleotides, cytokines), and the consequences of mucus dehydration (e.g. mucus rheology; evolution of bacterial communities) across a wide spectrum of lung disease severity. In the second aim, we will prospectively study the effect that acute exacerbations have on mucociliary clearance in vivo using gamma scintigraphy; we will directly measure mucus properties that may alter mucus clearance (i.e. hydration) during an exacerbation; and we will determine the role that respiratory viruses have on triggering acute exacerbations using sensitive PCR techniques, in the third aim, we will determine whether hypertonic saline, by addressing this hydration defect, can lead to sustained improvements in mucociliary clearance and lung function in children (age 5-12 years) with CF, and whether this intervention is safe and well tolerated in infants (age <3 years) with CF. These studies will directly impact our understanding of mucus clearance in the progression and treatment of CF, and more generally its role in health and other airways diseases.