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Airway remodelling in children with cystic fibrosis

¹ Department of Gene Therapy, National Heart and Lung Institute, Imperial College, London, UK
² Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth, UK
³ Department of Histopathology, Royal Brompton Hospital, London, UK
⁴ Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK

Correspondence to:
Dr Tom Hilliard, Department of Paediatric Respiratory Medicine, Royal Hospital for Children, Bristol BS2 8BJ, UK; tom.hilliard{at}ubht.nhs.uk

Background: The relationship between airway structural changes and inflammation is unclear in early cystic fibrosis (CF) lung disease. A study was undertaken to determine changes in airway remodelling in children with CF compared with appropriate disease and healthy controls.

Methods: Bronchoalveolar lavage and endobronchial biopsy were performed in a cross-sectional study of 43 children with CF (aged 0.3–16.8 years), 7 children with primary ciliary dyskinesia (PCD), 26 with chronic respiratory symptoms (CRS) investigated for recurrent infection and/or cough and 7 control children with no lower airway symptoms. Inflammatory cells, cytokines, proteases and matrix constituents were measured in bronchoalveolar lavage fluid (BALF). Reticular basement membrane (RBM) thickness was measured on biopsy specimens using light microscopy.

Results: Increased concentrations of elastin, glycosaminoglycans and collagen were found in BALF from children with CF compared with the CRS group and controls, each correlating positively with age, neutrophil count and proteases (elastase activity and matrix metalloproteinase-9 (MMP-9) concentration). There were significant negative correlations between certain of these and pulmonary function (forced expiratory volume in 1 s) in the CF group (elastin: r = –0.45, p<0.05; MMP-9:TIMP-1 ratio: r = –0.47, p<0.05). Median RBM thickness was greater in the CF group than in the controls (5.9 µm vs 4.0 µm, p<0.01) and correlated positively with levels of transforming growth factor-β₁ (TGF-β₁; r = 0.53, p = 0.01), although not with other inflammatory markers or pulmonary function.

Conclusions: This study provides evidence for two forms of airway remodelling in children with CF: (1) matrix breakdown, related to inflammation, proteolysis and impaired pulmonary function, and (2) RBM thickening, related to TGF-β₁ concentration but independent of other markers of inflammation.

Abbreviations: BALF, bronchoalveolar lavage fluid; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane regulator; CRS, chronic respiratory symptoms; FEV₁, forced expiratory volume in 1 s; IL, interleukin; MMP, matrix metalloproteinase; NE, neutrophil elastase; PCD, primary ciliary dyskinesia; RBM, reticular basement membrane; TGF-β₁, transforming growth factor-β₁; TIMP-1, tissue inhibitor of metalloproteinases-1

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