Key inflammatory markers in bronchoalveolar lavage predict bronchiectasis progression in young children with CF.

INTRODUCTION: Inflammation appears early in cystic fibrosis (CF) pathogenesis, with specific elevated inflammatory markers in bronchoalveolar lavage fluid (BALF) correlating with structural lung disease. Our aim was to identify markers of airway inflammation able to predict bronchiectasis progression over two years with high sensitivity and specificity. METHODS: Children with CF with two chest computed tomography (CT) scans and bronchoscopies at a two-year interval were included (n= 10 at 1 and 3 years and n= 27 at 3 and 5 years). Chest CTs were scored for increase in bronchiectasis (Δ%Bx), using the PRAGMA-CF score. BALF collected with the first CT scan were analyzed for neutrophil% (n= 36), myeloperoxidase (MPO) (n= 25), neutrophil elastase (NE) (n= 26), and with a protein array for inflammatory and fibrotic markers (n= 26). RESULTS: MPO, neutrophil%, and inducible T-cell costimulator ligand (ICOSLG), but not clinical characteristics, correlated significantly with Δ%Bx. Evaluation of neutrophil%, NE, MPO, interleukin-8 (IL-8), ICOSLG, and hepatocyte growth factor (HGF), for predicting an increase of > 0.5% of Δ%Bx in two years, showed that IL-8 had the best sensitivity (82%) and specificity (73%). Neutrophil%, ICOSLG and HGF had sensitivities of 85, 82, and 82% and specificities of 59, 67 and 60%, respectively. The odds ratio for risk of >0.5% Δ%Bx was higher for IL-8 (12.4) than for neutrophil%, ICOSLG, and HGF (5.9, 5.3, and 6.7, respectively). Sensitivity and specificity were lower for NE and MPO). CONCLUSIONS: High levels of IL-8, neutrophil%, ICOSGL and HGF in BALF may be good predictors for progression of bronchiectasis in young children with CF.

Airway profile of bioactive lipids predicts early progression of lung disease in cystic fibrosis.

BACKGROUND: Previously, we showed that abnormal levels of bioactive lipids in bronchoalveolar lavage fluid (BALF) from infants with cystic fibrosis (CF) correlated with early structural lung damage. METHOD: To extend these studies, BALF bioactive lipid measurement by mass spectrometry and chest computed tomography (CT, combined with the sensitive PRAGMA-CF scoring method) were performed longitudinally at 2-year intervals in a new cohort of CF children (n = 21, aged 1-5 yrs). RESULTS: PRAGMA-CF, neutrophil elastase activity, and myeloperoxidase correlated with BALF lysolipids and isoprostanes, markers of oxidative stress, as well as prostaglandin E2 and combined ceramide precursors (Spearman's Rho > 0.5; P < 0.01 for all). Multiple protein agonists of inflammation and tissue remodeling, measured by Olink protein array, correlated positively (r = 0.44-0.79, p < 0.05) with PRAGMA-CF scores and bioactive lipid levels. Notably, levels of lysolipids, prostaglandin E2 and isoprostanes at first BALF predicted the evolution of PRAGMA-CF scores 2 years later. In wild-type differentiated primary bronchial epithelial cells, and in CFTR-inducible iCFBE cells, treatment with a lysolipid receptor agonist (VPC3114) enhanced shedding of pro-inflammatory and pro-fibrotic proteins. CONCLUSIONS: Together, our findings suggest that bioactive lipids in BALF correlate with and possibly predict structural lung disease in CF children, which supports their use as biomarkers of disease progression and treatment efficacy. Furthermore, our data suggest a causative role of airway lysolipids and oxidative stress in the progression of early CF lung disease, unveiling potential therapeutic targets.