Mucus Dehydration and Evolution of CF Lung Disease

粘液脱水和 CF 肺病的演变

• 批准号: 7231813
• 负责人: SCOTT H DONALDSON
• 金额: $ 24.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231813
• 关键词: biological fluid transport; child (0-11); clinical research; cystic fibrosis; evolution; gel; human subject; human therapy evaluation; immune response; infant human (0-1 year); lung; mucus; opportunistic infections; patient oriented research; respiratory airway clearance; respiratory infections; respiratory therapy; saline

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.

囊性纤维化（CF）是白种人群体中最常见的致命遗传病。广阔的 这些患者大多数死于肺部疾病，其特征是气道分泌物粘稠、进行性加重 气道阻塞，以及特征性细菌病原体的慢性感染。 CF 的自然史 包括逐渐下降和急性发作性恶化（称为恶化）。异常情况 盐和水穿过气道上皮的运输已被证明会导致内壁脱水 体外覆盖气道表面的液体，推测这种缺陷会导致粘液减少 CF 肺的清除率。我们的长期目标是确定气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 清除从生命早期开始。我们将通过以下具体目标来实现这一目标： (1) 测试 假设 CF 肺部疾病进展与粘液水合作用的变化有关； (2) 测试 假设急性加重是由引发区域性炎症的触发事件（即病毒）引起的 粘液清除崩溃； (3)检验高渗盐水安全有效导致的假设 持续增加粘膜纤毛清除率并减少 CF 儿童的气道阻塞。在 第一个目标，我们将直接测量气道分泌物的水合作用，粘液水合作用的调节剂（例如， 核苷酸、细胞因子）以及粘液脱水的后果（例如粘液流变学； 细菌群落）涵盖广泛的肺部疾病严重程度。在第二个目标中，我们将 使用 γ 前瞻性研究急性加重对体内粘膜纤毛清除的影响 闪烁扫描；我们将直接测量可能改变粘液清除（即水合作用）的粘液特性 病情加重期间；我们将确定呼吸道病毒在引发急性呼吸道疾病中的作用 使用灵敏的 PCR 技术进行恶化，在第三个目标中，我们将确定高渗盐水是否， 通过解决这种水合缺陷，可以持续改善粘液纤毛清除和肺部功能 患有 CF 的儿童（5-12 岁）的功能，以及这种干预措施是否安全且耐受性良好 患有 CF 的婴儿（年龄 <3 岁）。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，以及更广泛的它在健康和其他气道疾病中的作用。