#NACFC2016 – Loss of Hydration in Airways Associated with Early CF in Preschoolers

In a talk presented today, Charles Esther Jr., MD, PhD, from UNC Chapel Hill, identified the loss of airway hydration as the first triggering factor in young children with cystic fibrosis (CF).

The talk, titled “Mucus Dehydration as the Initiating Defect in Early CF Airways Disease,” was presented at the 30^th Annual North American Cystic Fibrosis Conference Oct. 27-29 in Orlando, Florida.

Key ion channels, including the cystic fibrosis transmembrane conductance regulator (CFTR), control the hydration status of the airway epithelium. In cystic fibrosis, defective CFTR secretion results in a reduction in airway surface liquid volume, leading to poorly hydrated mucus and impaired mucus clearance. This phenomenon may be the initiating defect in CF airways disease.

Recent studies, however, suggest that proliferation of bacteria in CF patients’ airways and subsequent airway infection may actually occur before changes in hydration of the airway epithelium.

Now, a team of researchers investigated which factors are associated, from an early stage, to airway alterations in patients with CF. Researchers measured mucin protein (the main constituent of mucus) and performed a metabolomics profile of bronchoalveolar lavage fluid (BALF) retrieved from children with CF enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF).

Metabolic profiling is a strategy used by scientists to measure low-molecular-weight metabolites and their intermediates in biological samples, thereby reflecting how changes in metabolites correlate with specific physiological condition, in this case CF.

In total, researchers analyzed BALF samples from 40 preschool children with CF enrolled in AREST CF. Their median age was 3.5 years old. As controls, the team used 14 non-CF disease children (median age 3.2 years).

Researchers found an increase in airway mucus concentrations in preschool subjects with CF, when compared to non-CF disease controls. This increase was detected in patients without airway infections. The team found that a higher mucus concentration correlated with markers of inflammation (like interleukin [IL]-8) and the percentage of neutrophils (key cells of the immune system).

Additionally, researchers also detected metabolomics biomarkers for airway hypoxia (reduced oxygen conditions) and oxidative stress correlated with increased mucus concentration.

Structural changes such as bronchial wall thickening, an early marker of disease, and lung disease scores were also associated with elevated mucus concentrations and viscosity.

The results showed higher concentrations of mucus airways in preschool children with cystic fibrosis. This increase was associated with inflammatory markers, alterations in the airways, and early structural lung disease.

These changes were found to be independent of airways infection and correlated primarily with airway mucus dehydration. Therefore, the results suggest that airway dehydration is an important therapeutic target in young children with CF.