The role of polyunsaturated fatty acid and eicosanoid biosynthesis in the pathogenesis of cystic fibrosis
The primary cause of morbidity and mortality in cystic fibrosis is progressive pulmonary disease, an important component of which is a hyperactive inflammatory response, the mechanisms of which are not completely understood. Previous studies have highlighted alterations in polyunsaturated fatty acid and eicosanoid metabolism in cystic fibrosis airway epithelial cells leading to increased arachidonic acid and its metabolites, the pro-inflammatory leukotrienes and prostaglandins. This work tests the hypothesis that these underlying metabolic abnormalities play an important role in the excessive inflammatory response. Using airway epithelial cell culture models of cystic fibrosis, we demonstrate that there is increased release of AA in response to stimulation in CF cells. Additionally, we show that enzymes of fatty acid and eicosanoid metabolism, including Δ6-desaturase, cytosolic phospholipase A2, cyclooxygenase-2, microsomal PGE2 synthase, and 5-lipoxygenase, are upregulated in cystic fibrosis cells compared to wild-type counterparts. These increases are exaggerated when the cells are stimulated with products of Pseudomonas aeruginosa culture, leading to increased production of PGE2 and LTB4 and the pro-inflammatory cytokines IL-6 and IL-8. Inhibition of the LTB4 synthesis pathway at any of multiple points results in blunting of both cyclooxygenase-2 expression and IL-6 and IL-8 production, while inhibition of cyclooxygenase-2 itself results in only minor suppression of cytokine production. Similar results are seen with docosahexaenoic acid, an anti-inflammatory n-3 fatty acid. Taken together, these results indicate that fatty acid and eicosanoid metabolic abnormalities that are intrinsic to epithelial cells in cystic fibrosis, particularly the LTB4 synthesis pathway, may play an important role in the hyperactive inflammatory response characteristic of this disease.