Abstract

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.