The absorption and effect of dietary supplementation with omega‐3 fatty acids on serum leukotriene B<sub>4</sub>, in patients with cystic fibrosis

Kurlandsky, Lawrence E.; Bennink, Maurice R.; Webb, Phyllis M.; Ulrich, Pamela J.; Baer, Lawrence J.

doi:10.1002/ppul.1950180404

Cited by 62 publications

(35 citation statements)

References 58 publications

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“…This is corroborated by our data demonstrating that the administration of DHA, and not of precursor fatty acids, is required to correct the lipid abnormality as well as the pathologic changes observed in cftr Ϫ͞Ϫ mice. Formulations containing DHA (e.g., fish oil) have been given to CF patients in an effort to down-regulate AA levels and decrease inflammation (31)(32)(33). No statistically significant clinical improvements were found in these studies between control and CF patients.…”

Section: Discussionmentioning

confidence: 99%

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

Freedman

Katz

Parker

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

272

239

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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...

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Section: Discussionmentioning

confidence: 99%

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

Freedman

Katz

Parker

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

272

239

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“…The fi ndings are representative of at least three independent experiments. by guest, on May 9, 2018 www.jlr.org Downloaded from several of these trials (39)(40)(41). More extensive studies in animal models and CF patients are required to confi rm these early observations.…”

Section: Discussionmentioning

confidence: 99%

“…The reason for this difference is unclear. Human trials ( 39 ) have shown differences in metabolism using EPA alone or combinations of EPA and DHA ( 29,30,40,41 ). However, the individual effects of EPA and DHA are diffi cult to disaggregate, as supplementation with either of these fatty acids increases concentrations of the other.…”

Section: Discussionmentioning

confidence: 99%

DHA and EPA reverse cystic fibrosis-related FA abnormalities by suppressing FA desaturase expression and activity

Njoroge

Laposata²,

Katrangi³

et al. 2012

Journal of Lipid Research

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in the United States to 37 years ( 2 ). Among the phenotypic manifestations of CF patients are abnormalities in blood and tissue polyunsaturated fatty acid (PUFA) levels that are independent of absorption and nutritional status (reviewed in Refs. [3][4][5]. The most consistent of these abnormalities are decreased linoleate (LA; 18:2n-6) and docosahexaenate (DHA; 22:6n-3). In addition, some studies have shown increased arachidonate (AA; 20:4n-6), palmitoleate (16:1n-7), oleate (18:1n-9), and Mead acid (20:3n-9). Similar fi ndings are seen in animal ( 6-9 ) and cell culture ( 10, 11 ) models of CF. The magnitude of fatty acid alterations in CF patients correlates with disease severity, suggesting a role for fatty acid metabolism in CF pathophysiology ( 12-17 ).There is increasing evidence that these abnormalities are due to differences in fatty acid metabolism in CF. PUFAs of the n-3 and n-6 series are metabolized in a stepwise fashion along parallel pathways (reviewed in Ref. 18 ). A common set of desaturase and elongase enzymes catalyzes the conversion of LA through multiple steps to AA and ultimately to docosapentaenoate (DPA; 22:5n-6). The same enzymes convert linolenate (LNA; 18:3n-3) to eicosapentaenoate (EPA; 20:5n-3) and subsequently to DHA. Multiple studies have demonstrated increased conversion of AA to eicosanoids (19)(20)(21)(22), stimulating increased metabolism of LA to maintain AA ( 7, 10, 11 ) and accounting for the decreased LA and increased AA levels seen in CF.Recent studies in our laboratory have uncovered a potential mechanism accounting for these metabolic changes ( 23 ). In cell culture models of CF, decreased LA and increased AA and EPA levels in CF cells correlated with increased expression and activity of the ⌬ 5-and ⌬ 6-desaturase enzymes that catalyze conversion of LA to AA and LNA to EPA. Similar increases in ⌬ 9-desaturase and elongase-6Abstract Patients and models of cystic fi brosis (CF) exhibit consistent abnormalities of polyunsaturated fatty acid composition, including decreased linoleate (LA) and docosahexaenoate (DHA) and variably increased arachidonate (AA), related in part to increased expression and activity of fatty acid desaturases. These abnormalities and the consequent CF-related pathologic manifestations can be reversed in CF mouse models by dietary supplementation with DHA. However, the mechanism is unknown. This study investigates this mechanism by measuring the effect of exogenous DHA and eicosapentaenoate (EPA) supplementation on fatty acid composition and metabolism, as well as on metabolic enzyme expression, in a cell culture model of CF. We found that both DHA and EPA suppress the expression and activity of ⌬ 5-and ⌬ 6-desaturases, leading to decreased fl ux through the n-3 and n-6 PUFA metabolic pathways and decreased production of AA. The fi ndings also uncover other metabolic abnormalities, including increased fatty acid uptake and markedly increased retroconversion of DHA to EPA, in CF cells. These results indicate that the fatty acid abnormalities of CF are ...

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“…There is increasing evidence that n-3 fatty acids supplementation improve the clinical status of patients with rheumatoid arthritis [32]. In CF, n-3 fatty acid administration decreased serum LTB 4 [33, 34]. n-3 Fatty acids exert anti-inflammatory properties competing with n-6 FA in the biosynthesis of inflammatory products and affecting cellular transcriptional process.…”

Section: Lipids and Growthmentioning

confidence: 99%

Nutrition and Growth in Cystic Fibrosis

2002

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Malnutrition is a common complication of chronic diseases in children and may lead to growth impairment (stunting). Malnutrition in cystic fibrosis (CF) results from increased energy expenditure, decreased energy intakes, malabsorption of ingested nutrients because of pancreatic insufficiency and chronic inflammation. Malnutrition and high levels of inflammatory cytokines affect IGF-1 production through interrelated mechanisms. Nutritional support was shown to improve both nutritional status and outcome in CF. However, some nutrients have a direct effect on the disease. n-3 fatty acids supplementation is able to correct lipid abnormalities resulting from a primary mechanism. Moreover, n-3 fatty acids have a direct effect on the inflammatory response, decreasing eicosanoid synthesis and modulating nuclear transcriptional factors nuclear factor ĸB and peroxisome proliferator-activated receptors γ. Nutritional support may be considered part of the care of the CF patient together with antibiotics, pancreatic enzymes and physiotherapy, influencing significantly the evolution of the disease.

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The absorption and effect of dietary supplementation with omega‐3 fatty acids on serum leukotriene B₄, in patients with cystic fibrosis

Cited by 62 publications

References 58 publications

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

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

DHA and EPA reverse cystic fibrosis-related FA abnormalities by suppressing FA desaturase expression and activity

Nutrition and Growth in Cystic Fibrosis

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The absorption and effect of dietary supplementation with omega‐3 fatty acids on serum leukotriene B4, in patients with cystic fibrosis

Cited by 62 publications

References 58 publications

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

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

DHA and EPA reverse cystic fibrosis-related FA abnormalities by suppressing FA desaturase expression and activity

Nutrition and Growth in Cystic Fibrosis

Contact Info

Product

Resources

About

The absorption and effect of dietary supplementation with omega‐3 fatty acids on serum leukotriene B₄, in patients with cystic fibrosis

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

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