A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr ^−/− mice

Abstract

A deficiency in essential fatty acid metabolism has been reported in plasma from patients with cystic fibrosis (CF). However, its etiology and role in the expression of disease is unknown. The objective of this study was to determine whether alterations in fatty acid metabolism are specific to CF-regulated organs and whether they play a role in the expression of disease. A membrane lipid imbalance was found in ileum, pancreas, and lung from cftr ؊͞؊ mice characterized by an increase in phospholipid-bound arachidonic acid and a decrease in phospholipid-bound docosahexaenoic acid (DHA). This lipid imbalance was observed in organs pathologically affected by CF including lung, pancreas, and ileum and was not secondary to impaired intestinal absorption or hepatic biosynthesis of DHA. As proof of concept, oral administration of DHA to cftr ؊͞؊ mice corrected this lipid imbalance and reversed the observed pathological manifestations. These results strongly suggest that certain phenotypic manifestations of CF may result from remediable alterations in phospholipid-bound arachidonic acid and DHA levels.docosahexaenoic acid ͉ arachidonic acid ͉ fish oil ͉ pancreas ͉ lung C ystic fibrosis (CF) is the most prevalent lethal autosomal recessive disorder in the Caucasian population, affecting 1 in 2,500 newborns (1). Patients with CF express a typical phenotype characterized by pancreatic insufficiency, ileal hypertrophy, and recurrent pulmonary infections that ultimately lead to pulmonary failure and death. In 1989, the gene whose mutation results in CF was identified and cloned (2, 3). The product of the gene, the CF transmembrane conductance regulator (CFTR), was characterized as an ATP-gated chloride channel that is regulated by cAMP-dependent protein kinase phosphorylation (4).Despite the significant advances made in CF research in recent years, the mechanism by which a mutation in the CFTR gene leads to the manifestations of this disease remains unclear. Although a decrease in apical membrane CFTR-dependent chloride conductance might explain some of the pathological manifestations observed in CF, e.g., viscous secretions, it explains neither the increased inflammation in the lung nor the membrane-recycling defects observed in CF (5-7).Arachidonic acid (AA), an agonist of inflammatory pathways and a stimulant of mucus secretion, is elevated in the phospholipid fraction from bronchial alveolar lavage fluid in CF patients (5). However, the increased inflammation and elevated AA levels observed in CF have long been thought to be secondary to infection (8). This conclusion has been challenged recently by Heeckeren et al. (9), who demonstrated that instillation of agarose beads coated with Pseudomonas into the lungs of cftr Ϫ͞Ϫ mice resulted in increased inflammation and mortality compared with that observed in wild-type mice. These findings suggest that the lungs of cftr Ϫ͞Ϫ mice are primed for inflammation and that the increase in AA and inflammation observed in cftr Ϫ͞Ϫ mice may be a primary event and not secondary to infect...

Antibiotic and Anti-Inflammatory Therapies for Cystic Fibrosis

“…There is an increase in arachidonic acid and a decrease in docosahexaenoic acid (DHA) in cftr 2/2 mice (Freedman et al 1999). Investigators have shown that oral administration of DHA to cftr 2/2 mice corrected the lipid imbalance and reversed the observed pathological manifestations (Freedman et al 2002;Beharry et al 2007).…”

Influence of Pancreatic Status and Sex on Polyunsaturated Fatty Acid Profiles in Cystic Fibrosis

“…These alterations were first reported to be related to essential fatty acid deficiency (EFAD) (9 ) or defective essential fatty acid metabolism (10 ). More recently, an imbalance between arachidonic acid (AA) and docosahexaenoic acid (DHA), rather than a deficiency in PUFAs, was described in an animal model of CF (11 ) and in patients (12 ). However, it emerges from previous studies that PUFA status is quite variable in CF and discrepancies can result from a variety of factors such as small population sample sizes, inappropriate age-matching controls, different blood compartments, and analytical techniques (8 ).…”

Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis

“…9,11,12,14,15 In common with all of the reported viral or nonviral clinical studies there was no correction of the CF sodium ion transport defect. Interestingly, treatment of CF mice with a pharmacological agent shown to stimulate epithelial chloride secretion 26 corrects several CF pathological features (including a predisposition for lung inflammation), 27 suggesting that even correction of the CF chloride defect alone following gene transfer, may improve CF prognosis.…”