Altered Eicosanoid Metabolism in the Cystic Fibrosis Mouse Small Intestine

Objectives: Imbalances in essential fatty acid levels have been reported in cystic fibrosis (CF), which may relate to elevated proinflammatory eicosanoid generation. The aim of this work was to better define eicosanoid metabolism in the CF intestine.

Materials And Methods: We used the small intestine of the cystic fibrosis transmembrane conductance regulator knockout mouse (CF mouse) to measure eicosanoid metabolic gene expression by quantitative reverse transcription polymerase chain reaction and Western blot, and eicosanoid levels by enzyme immunoassay, as compared with wild-type (WT) littermates.

Results: In the CF small intestine, expression of the secretory phospholipase A2 Pla2g5 mRNA was upregulated to 980% of WT levels. The following were downregulated: leukotriene C4 synthase Ltc4s (mRNA 55% of WT); omega-hydroxylase cytochrome P450s Cyp2c40 (mRNA 54% of WT), and Cyp4a10 (mRNA 4% of WT); and the major prostaglandin degradative enzymes prostaglandin dehydrogenase Hpgd (mRNA 27% of WT) and leukotriene B4 12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase Ltb4dh (mRNA 64% and protein 30% of WT). The prostaglandins PGE2 and PGF2alpha were increased to 400% to 600% of WT levels in the CF mouse intestine, and the hydroxyeicosatetraenoic acids (HETEs) 12-, 15-, and 20-HETE were decreased to 3% to 20% of WT levels.

Conclusions: There are changes in eicosanoid metabolic gene expression that are accompanied by significant changes in specific eicosanoid levels. These changes are expected to play important roles in the pathophysiology of CF in the intestine.