Cystic fibrosis (CF) is the most common lethal genetic disease in the Caucasian population. The vastmajority of these patients die from lung disease that is characterized by thick airway secretions, progressiveairways obstruction, and chronic infection with characteristic bacterial pathogens. The natural history of CFincludes both a gradual decline and acute episodic deteriorations (termed exacerbations). Abnormalities insalt and water transport across the airway epithelium have been shown to cause dehydration of the liningfluid that covers airway surfaces in vitro, and it is postulated that this defect leads to reduced mucusclearance in the CF lung. Our long-term goal is to determine the extent that airway secretion dehydrationcontributes to the evolution of CF lung disease, and to develop strategies that maintain mucus hydration andclearance beginning early in life. We will pursue this goal through the following specific aims: (1) Test thehypothesis that CF lung disease progression is associated with changes in mucus hydration; (2) Test thehypothesis that acute exacerbations result from triggering events (i.e. viruses) that provoke a regionalcollapse of mucus clearance; and (3) Test the hypothesis that hypertonic saline safely and effectively leadsto a sustained increase in mucociliary clearance and reduces airway obstruction in children with CF. In thefirst 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 ofbacterial communities) across a wide spectrum of lung disease severity. In the second aim, we willprospectively study the effect that acute exacerbations have on mucociliary clearance in vivo using gammascintigraphy; 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 acuteexacerbations 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 lungfunction in children (age 5-12 years) with CF, and whether this intervention is safe and well tolerated ininfants (age <3 years) with CF. These studies will directly impact our understanding of mucus clearance inthe progression and treatment of CF, and more generally its role in health and other airways diseases.
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