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.
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