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Sci Transl Med. 2019 Apr 3;11(486). pii: eaav3488. doi: 10.1126/scitranslmed.aav3488.

Mucus accumulation in the lungs precedes structural changes and infection in children with cystic fibrosis.

Author information

1
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. charles_esther@med.unc.edu.
2
Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
3
Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
4
Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
5
Telethon Kids Institute, University of Western Australia, Perth 6009, Australia.
6
Departments of Mathematics, Biomedical Engineering, and Applied Physical Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
7
Parion Sciences, Durham, NC 27713, USA.
8
Department of Research, Mount Sinai Medical Center, Miami Beach, FL 33140, USA.
9
Murdoch Children's Research Institute, University of Melbourne, Parkville 3052, Australia.
10
Division of Paediatrics and Child Health, University of Western Australia, Perth 6009, Australia.
11
Princess Margaret Hospital for Children, Perth 6009, Australia.

Abstract

Although destructive airway disease is evident in young children with cystic fibrosis (CF), little is known about the nature of the early CF lung environment triggering the disease. To elucidate early CF pulmonary pathophysiology, we performed mucus, inflammation, metabolomic, and microbiome analyses on bronchoalveolar lavage fluid (BALF) from 46 preschool children with CF enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program and 16 non-CF disease controls. Total airway mucins were elevated in CF compared to non-CF BALF irrespective of infection, and higher densities of mucus flakes containing mucin 5B and mucin 5AC were observed in samples from CF patients. Total mucins and mucus flakes correlated with inflammation, hypoxia, and oxidative stress. Many CF BALFs appeared sterile by culture and molecular analyses, whereas other samples exhibiting bacterial taxa associated with the oral cavity. Children without computed tomography-defined structural lung disease exhibited elevated BALF mucus flakes and neutrophils, but little/no bacterial infection. Although CF mucus flakes appeared "permanent" because they did not dissolve in dilute BALF matrix, they could be solubilized by a previously unidentified reducing agent (P2062), but not N-acetylcysteine or deoxyribonuclease. These findings indicate that early CF lung disease is characterized by an increased mucus burden and inflammatory markers without infection or structural lung disease and suggest that mucolytic and anti-inflammatory agents should be explored as preventive therapy.

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