The pulmonary manifestations of cystic fibrosis (CF) reflect a failure of lung defense leading to chronic airways bacterial infection. Several key aspects of the pathogenesis of early CF lung disease must be understood for best treatment approaches and biomarker development, including the observations that there is minimal CF lung disease at birth and that disease onset/progression is highly heterogeneous. Based on assumptions that 1) the CF lung exhibits a vulnerability to disease producing """"""""outside"""""""" insults;2) the """"""""vulnerability defect"""""""" reflects localized loss of mucus clearance mechanisms due to airway surface dehydration, and 3) immobilized, relatively dehydrated mucus masses obstruct airways, stimulate inflammation, and serve as nidus for chronic bacterial infection, we hypothesize that the earliest CF lung disease will be characterized by quantifiable changes in airway mucin hydration/function, mucin stimulated macrophage activation, and airway hypoxia. This proposal will test the hypothesis in a unique CF cohort identified by newborn screening and studied at regular intervals with CT scans and bronchoscopy. Using samples obtained in the successful Australian AREST-CF program, we will develop a triad of novel measurement panels at U. North Carolina including: 1) biochemical and biophysical measurements of mucus hydration/function;2) novel markers of inflammation, focusing on macrophages and 3) microbiome and metabolomic analysis of the spectrum of bacteria and their metabolic environment. We will determine whether these panels can quantify the burden of CF lung disease as defined by chest CT cross- sectionally and longitudinally. In parallel, we will develop minimally invasive, exhaled breath condensate based methods to assess these biomarkers. Successful testing of these hypotheses will generate both novel insights into the pathogenesis of CF lung disease and novel biomarkers to follow disease progression/therapeutic interventions.

Public Health Relevance

Our goal is to understand the earliest changes in cystic fibrosis lung disease, a life shortening disease resulting in respiratory failure, by studying the mucus abnormalities, early inflammation, and the diverse bacteria and their metabolites in lung samples obtained by bronchoscopy. Working together with an existing program that studies CF infants from diagnosis onwards with bronchoscopy and CT scan, we can compare these changes in healthier vs. sicker parts of the lung in the same child and over time. We will also develop non-invasive methods to test for early disease using exhaled breath and these studies will advance our understanding of early changes before overt disease is visible.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-F (S1))
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Banks-Schlegel, Susan P
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Yu, Dongfang; Saini, Yogesh; Chen, Gang et al. (2018) Loss of ? Epithelial Sodium Channel Function in Meibomian Glands Produces Pseudohypoaldosteronism 1-Like Ocular Disease in Mice. Am J Pathol 188:95-110
Muhlebach, Marianne S; Zorn, Bryan T; Esther, Charles R et al. (2018) Initial acquisition and succession of the cystic fibrosis lung microbiome is associated with disease progression in infants and preschool children. PLoS Pathog 14:e1006798
Livraghi-Butrico, Alessandra; Wilkinson, Kristen J; Volmer, Allison S et al. (2018) Lung disease phenotypes caused by overexpression of combinations of ?-, ?-, and ?-subunits of the epithelial sodium channel in mouse airways. Am J Physiol Lung Cell Mol Physiol 314:L318-L331
Esther Jr, Charles R; Hill, David B; Button, Brian et al. (2017) Sialic acid-to-urea ratio as a measure of airway surface hydration. Am J Physiol Lung Cell Mol Physiol 312:L398-L404
Giddings, Olivia; Esther Jr, Charles R (2017) Mapping targetable inflammation and outcomes with cystic fibrosis biomarkers. Pediatr Pulmonol 52:S21-S28
Donoghue, Lauren J; Livraghi-Butrico, Alessandra; McFadden, Kathryn M et al. (2017) Identification of trans Protein QTL for Secreted Airway Mucins in Mice and a Causal Role for Bpifb1. Genetics 207:801-812
Muhlebach, Marianne S; Clancy, J P; Heltshe, Sonya L et al. (2016) Biomarkers for cystic fibrosis drug development. J Cyst Fibros 15:714-723
Esther Jr, Charles R; Turkovic, Lidija; Rosenow, Tim et al. (2016) Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis. Eur Respir J 48:1612-1621
Ehre, Camille; Ridley, Caroline; Thornton, David J (2014) Cystic fibrosis: an inherited disease affecting mucin-producing organs. Int J Biochem Cell Biol 52:136-45
Simpson, Shannon J; Mott, Lauren S; Esther Jr, Charles R et al. (2013) Novel end points for clinical trials in young children with cystic fibrosis. Expert Rev Respir Med 7:231-43