CYSTIC-FIBROSIS GENE MUTATION (DELTA-F-508) IS ASSOCIATED WITH AN INTRINSIC ABNORMALITY IN CA2-INDUCED ARACHIDONIC-ACID RELEASE BY EPITHELIAL-CELLS()

The mechanism(s) of chronic airway inflammation in cystic fibrosis (CF ) remains poorly understood, We studied Ca2+-induced release of arachi donic acid (AA), a precursor of proinflamatory lipid mediators, in epi thelial cell lines with the Delta F-508 mutation in CF transmembrane c onductance regulator (CFTR) gene and in those lacking this mutation or cells in which this mutation was corrected by a functional CFTR gene transfer, We found that: (i) the mutant cells manifested an abnormally high Ca2+-induced AA release as compared to controls, (ii) AA release appeared to be catalyzed by a phospholipase A(2) (PLA(2)) but not by phospholipase C followed by diacylglycerol lipase, and (iii) either co rrection of the CFTR-mutation or inhibition of PLA(2) activity rectifi ed this AA release abnormality, Taken together, our results suggest th at CFTR mutation is associated with an intrinsic abnormality in AA rel ease by epithelial cells carrying the Delta F-508 mutation and suggest that the mechanism of chronic airway inflammation in CF, at least in part, involves this abnormality, These results also partly explain the effectiveness of high-dose ibuprofen therapy in arresting the progres sion of destructive lung disease in CF. Furthermore, they raise the po ssibility that correction of abnormal AA release by inhibiting PLA(2) activity may improve the therapeutic benefits of ibuprofen.