Cystic Fibrosis (CF) is characterised by impaired muco-ciliary clearance, persistent neutrophilic inflammation and bacterial infection. Normal resolution of inflammation involves an active switch in mediators that predominate in exudates. Early in inflammation, Leukotriene B4 (LTB4) plays a role in neutrophil activation. Resolution and return to tissue homeostasis are signalled by the trans-cellular synthesis of Lipoxin A4 (LXA4) by the action of Lipoxygenase enzymes (LO) expressed in cells such as neutrophils and airway epithelial cells.
The aims of this study were to quantify LXA4 production in the airways of children with CF and characterise LXA4 synthesis by airway epithelial cells in CF.
LXA4 and LTB4 were measured in paediatric BAL samples by ELISA. We quantified the capacity of Non CF (NuLi-1) and CF (CuFi-1 Homozygous ΔF508) cells cultured as differentiated bronchial epithelia to synthesize LXA4 by the action of 15-LO on 5(S),6(R)-DiHETE, (a precursor of LXA4). Expression of 15-LO was measured by Western Blot.
Relative production of LXA4 is significantly depressed in paediatric CF patients versus controls when compared to LTB4. The ability of CuFi-1 cells to convert 5(S), 6(R)-DiHETE to LXA4 was reduced as compared with NuLi-1 cells. The expression of 15-LO2 was reduced in CuFi-1 compared with Nuli-1 cells.
The ratio of LXA4 to LTB4 in the airway of young children with CF is depressed. Our results indicate that the contribution of airway epithelial cells to Lipoxin A4 synthesis is reduced in CF. This may contribute to the persistence of acute inflammation and consequent lung damage in CF.