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.

ADAM17, Amphiregulin, EGFR, Lysolipid receptor, Lysophosphatidic acid, Oxidative stress,
Journal of Cystic Fibrosis
Department of Pediatrics

Horati, H. (Hamed), Janssens, H.M, Margaroli, C. (Camilla), Veltman, M, Stolarczyk, M, Kilgore, M.B. (Matthew B.), … Scholte, B.J. (2020). Airway profile of bioactive lipids predicts early progression of lung disease in cystic fibrosis. Journal of Cystic Fibrosis. doi:10.1016/j.jcf.2020.01.010