Altered Eicosanoid Metabolism in the Cystic Fibrosis Mouse Small Intestine

Lisle, Robert C. De; Meldi, Lauren; Flynn, Maureen; Jansson, Kyle

doi:10.1097/mpg.0b013e31817e0f2c

Cited by 25 publications

(23 citation statements)

References 67 publications

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“…It has been shown that cytosolic PLA 2 is increased in lungs of CF mice and that challenge with lipopolysaccharide or arachidonic acid increases Muc5AC, whereas PLA 2 inhibition blocks this effect (15). At least two PLA 2 genes have increased expression in the adult CF mouse small intestine [(16) and the current study], which is accompanied by excessive mucus accumulation.…”

Section: Introductionmentioning

confidence: 86%

Intestinal Smooth Muscle Dysfunction Develops Postnatally in Cystic Fibrosis Mice

Lisle

Meldi²,

Mueller³

2012

J. pediatr. gastroenterol. nutr.

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Objectives Intestinal dysmotility is one of the effects of cystic fibrosis (CF) but when and how this develops is not well understood. The goal of this study was to use the Cftr knockout mouse to determine when in development circular smooth muscle of the small intestine becomes dysfunctional. Methods Wild type (WT) and CF mice were used at postnatal day 5 (P5) through adult. Pieces of small intestine were used to measure contractile activity of the circular muscle. Bacterial overgrowth was measured by quantitative PCR of the bacterial 16S gene. Intestinal gene expression was determined by quantitative RT-PCR. Prostaglandin E2 (PGE2) and its metabolites were measured by enzyme immunoassay. Results CF circular muscle response to cholinergic stimulation was similar to WT at P5, became somewhat impaired at P7, and was severely impaired by P14. In the CF intestine, bacterial overgrowth occurred by P4 and was maintained into adulthood. Eicosanoid metabolic gene expression in the CF intestine did not differ from WT shortly after birth. The phospholipase A2 genes, Pla2g4c and Pla2g5 exhibited increased expression in CF mice at P24. Prostaglandin degradative genes, Hpgd and Ptgr1, showed lower expression in CF as compared to WT at P16 and P24, respectively. PGE2 levels were significantly greater in CF mice at most ages from P7 through adulthood. Conclusions The results clearly demonstrate that lack of CFTR itself does not cause smooth muscle dysfunction, as the circular muscle from P5 CF mice had normal activity and dysfunction developed between P7-P14.

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Section: Introductionmentioning

confidence: 86%

Intestinal Smooth Muscle Dysfunction Develops Postnatally in Cystic Fibrosis Mice

Lisle

Meldi²,

Mueller³

2012

J. pediatr. gastroenterol. nutr.

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“…AA is a precursor of bioactive oxygenated metabolites known as eicosanoids, which include prostaglandins and leukotrienes. Production of these metabolites is known to be increased in CF, and several studies have drawn a connection between eicosanoid alterations and disease pathogenesis (54)(55)(56)(57)(58)(59). It is plausible that the observed benefi t of n-3 fatty acid therapy in the CF mouse model ( 6 ) and in a small subset of human trials ( 29,30 ) is due to its ability to normalize AA levels and, consequently, reduce excessive production of eicosanoids.…”

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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“…EFA deficiency in itself can cause fat malabsorption by affecting the absorption capacity of the intestine [74]. Apart from reduced LA and DHA levels, increased levels of AA in the CF intestine could also (indirectly) affect fat absorption, by contributing to intestinal inflammation, mucus secretion and intestinal smooth muscle relaxation [79]. It has been shown that EFA deficiency affects both the intra-luminal and intra-cellular process of fat absorption, as exemplified in (non-CF) animal models [69].…”

Section: Relation With Cfpfmmentioning

confidence: 99%

Persistent fat malabsorption in cystic fibrosis; lessons from patients and mice

Wouthuyzen-Bakker

Bodewes

Verkade

2011

Journal of Cystic Fibrosis

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Fat malabsorption in pancreatic insufficient cystic fibrosis (CF) patients is classically treated with pancreatic enzyme replacement therapy (PERT). Despite PERT, intestinal fat absorption remains insufficient in most CF patients. Several factors have been suggested to contribute to the persistent fat malabsorption in CF (CFPFM). We reviewed the current insights concerning the proposed causes of CFPFM and the corresponding intervention studies. Most data are obtained from studies in CF patients and CF mice. Based on the reviewed literature, we conclude that alterations in intestinal pH and intestinal mucosal abnormalities are most likely to contribute to CFPFM. The presently available data indicate that acid suppressive drugs and broad spectrum antibiotics could be helpful in individual CF patients for optimizing fat absorption and/or nutritional status.

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Altered Eicosanoid Metabolism in the Cystic Fibrosis Mouse Small Intestine

Abstract: 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.

Cited by 25 publications

References 67 publications

Intestinal Smooth Muscle Dysfunction Develops Postnatally in Cystic Fibrosis Mice

Intestinal Smooth Muscle Dysfunction Develops Postnatally in Cystic Fibrosis Mice

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

Persistent fat malabsorption in cystic fibrosis; lessons from patients and mice

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