Research ArticleCystic Fibrosis

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

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Science Translational Medicine  03 Apr 2019:
Vol. 11, Issue 486, eaav3488
DOI: 10.1126/scitranslmed.aav3488

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Early changes in cystic fibrosis

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene. The lung is one of the most affected organs. Mucus accumulation, inflammation, and infection are already evident early during development. Understanding early disease pathophysiology could help the development of preventive therapies. Here, Esther et al. analyzed bronchoalveolar lavage fluid (BALF) from toddlers with CF to understand the mechanisms initiating lung disease. Abnormal mucus accumulation was evident in CF BALF, associated with increased mucin and inflammatory marker expression. These abnormalities occurred despite low bacterial infection. The results suggest that mucolytic and anti-inflammatory treatments might be effective during the early stages in CF.

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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