Mucus Dehydration and Evolution of CF Lung Disease

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

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