| First Author | Dif F | Year | 2010 |
| Journal | Eur Respir J | Volume | 36 |
| Issue | 5 | Pages | 1120-30 |
| PubMed ID | 20413542 | Mgi Jnum | J:323249 |
| Mgi Id | MGI:7262757 | Doi | 10.1183/09031936.00183409 |
| Citation | Dif F, et al. (2010) Critical role of cytosolic phospholipase A2{alpha} in bronchial mucus hypersecretion in CFTR-deficient mice. Eur Respir J 36(5):1120-30 |
| abstractText | 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 A2alpha (cPLA2alpha) products in airways. We aimed to examine the role of cPLA2alpha 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. cPLA2alpha 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 cPLA2alpha activity. Mucus overproduction was mimicked by instillation of the cPLA2alpha product arachidonic acid, and abolished by either a cPLA2alpha null mutation or pharmacological inhibition. An increased cPLA2alpha activity was observed in bronchial explants from CF patients. CFTR silencing induced cPLA2alpha activation and MUC5AC expression in bronchial human epithelial cells. This expression was enhanced by arachidonic acid and reduced by cPLA2alpha inhibition. However, inhibition of CFTR chloride transport function had no effect on MUC5AC expression. Reduction of CFTR expression increased cPLA2alpha activity. This led to an enhanced mucus production in airway epithelia independent of CFTR chloride transport function. cPLA2alpha represents a suitable new target for therapeutic intervention in CF. |
