Cystic fibrosis (CF) is due to mutations in the CF transmembrane conductance regulator gene CFTR. CF is characterised by mucus dehydration, chronic bacterial infection and inflammation, and increased levels of cytosolic phospholipase A2a (cPLA2a) products in airways.We aimed to examine the role of cPLA2a in the modulation of mucus production and inflammation in CFTR-deficient mice and epithelial cells. Mucus production was assessed using histological analyses, immuno-histochemistry and MUC5AC ELISA. cPLA2a activation was measured using an enzymatic assay and lung inflammation determined by histological analyses and polymorphonuclear neutrophil counts in bronchoalveolar lavages.In lungs from Cftr -/-mice, lipopolysaccharide induced mucus overproduction and MUC5AC expression associated with an increased cPLA2a activity. Mucus overproduction was mimicked by instillation of the cPLA2a product arachidonic acid, and abolished by either a cPLA2a null mutation or pharmacological inhibition. An increased cPLA2a activity was observed in bronchial explants from CF patients. CFTR silencing induced cPLA2a activation and MUC5AC expression in bronchial human epithelial cells. This expression was enhanced by arachidonic acid and reduced by cPLA2a inhibition. However, inhibition of CFTR chloride transport function had no effect on MUC5AC expression. Reduction of CFTR expression increased cPLA2a activity. This led to an enhanced mucus production in airway epithelia independent of CFTR chloride transport function. cPLA2a represents a suitable new target for therapeutic intervention in CF.
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