Reduced 15-lipoxygenase 2 and lipoxin A4/leukotriene B4 ratio in children with cystic fibrosis

Airway disease in cystic fibrosis (CF) is characterised by impaired mucociliary clearance, persistent bacterial infection and neutrophilic inflammation. Lipoxin A(4) (LXA(4)) initiates the active resolution of inflammation and promotes airway surface hydration in CF models. 15-Lipoxygenase (LO) plays a central role in the class switch of eicosanoid mediator biosynthesis from leukotrienes to lipoxins, initiating the active resolution of inflammation. We hypothesised that defective eicosanoid mediator class switching contributes to the failure to resolve inflammation in CF lung disease. Using bronchoalveolar lavage (BAL) samples from 46 children with CF and 19 paediatric controls we demonstrate that the ratio of LXA(4) to leukotriene B-4 (LTB4) is depressed in CF BAL (p<0.01), even in the absence of infection (p<0.001). Furthermore, 15-LO2 transcripts were significantly less abundant in CF BAL samples (p<0.05). In control BAL, there were positive relationships between 15-LO2 transcript abundance and LXA(4)/LTB4 ratio (p=0.01, r=0.66) and with percentage macrophage composition of the BAL fluid (p<0.001, r=0.82), which were absent in CF. Impoverished 15-LO2 expression and depression of the LXA(4)/LTB4 ratio are observed in paediatric CF BAL. These observations provide mechanistic insights into the failure to resolve inflammation in the CF lung.