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Low linoleic and high docosahexaenoic acids in a severe phenotype of transgenic cystic fibrosis mice.

ABSTRACT: Low linoleic acid concentration is a common finding in patients with cystic fibrosis and associated with severe clinical phenotype. Low docosahexaenoic and arachidonic acids are more inconsistently found in patients, but arachidonic/docosahexaenoic ratio is usually high. In animal models with cftr mutations or KO animals for the cftr gene, linoleic acid deficiency has not been consistently reported and some report docosahexaenoic deficiency as the major fatty acid abnormality. We hereby describe fatty acid profile in a severe clinical cystic fibrosis phenotype in mice with a duplication of exon 3 generated in the cystic fibrosis gene of C57B1/6J mice ( cftr^m¹^Bay allele). In 43/50 animals, plasma phospholipid fatty acids were repeatedly analyzed (mean three times/animal) covering ages between 7 and 235 days. Linoleic acid concentrations were significantly lower in cftr-/- mice compared to heterozygotes ( P?=?0.03) and wild type mice ( P?

SUBMITTER: Strandvik B

PROVIDER: S-EPMC5882031 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Low linoleic and high docosahexaenoic acids in a severe phenotype of transgenic cystic fibrosis mice.

Strandvik Birgitta B O Neal Wanda K WK Ali Mohamed A MA Hammar Ulf U

Experimental biology and medicine (Maywood, N.J.) 20180301 5

Low linoleic acid concentration is a common finding in patients with cystic fibrosis and associated with severe clinical phenotype. Low docosahexaenoic and arachidonic acids are more inconsistently found in patients, but arachidonic/docosahexaenoic ratio is usually high. In animal models with cftr mutations or KO animals for the cftr gene, linoleic acid deficiency has not been consistently reported and some report docosahexaenoic deficiency as the major fatty acid abnormality. We hereby describe ...[more]

PMID: 29513100

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Project description:BackgroundA major boost to cystic fibrosis disease research was given by the generation of various mouse models using gene targeting in embryonal stem cells. Moreover, the introduction of the same mutation on different inbred strains generating congenic strains facilitated the search for modifier genes. From the original CftrTgH(neoim)Hgu mouse model with a divergent genetic background (129/Sv, C57BL/6, HsdOla:MF1) two inbred mutant mouse strains CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu had been generated using strict brother x sister mating. CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu mice were fertile and showed normal growth and lifespan. In this work the CftrTgH(neoim)Hgu insertional mutation was backcrossed from CF/3-CftrTgH(neoim)Hgu onto the inbred backgrounds C57BL/6J and DBA/2J generating congenic animals in order to clarify the differential impact of the Cftr mutation and the genetic background on the disease phenotype of the cystic fibrosis mutant mice. Clinical and electrophysiological features of the two congenic strains were compared with those of CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu and wild type controls.ResultsUnder the standardized housing conditions of the animal facility, the four mouse strains CF/1-CftrTgH(neoim)Hgu, CF/3-CftrTgH(neoim)Hgu, D2.129P2(CF/3)-CftrTgH(neoim)Hgu and B6.129P2(CF/3)-CftrTgH(neoim)Hgu exhibited normal life expectancy. Growth of congenic cystic fibrosis mice was comparable with that of wild type controls. All mice but D2.129P2(CF/3)-CftrTgH(neoim)Hgu females were fertile. Short circuit current measurements revealed characteristic response profiles of the HsdOla:MF1, DBA/2J and C57BL/6J backgrounds in nose, ileum and colon. All cystic fibrosis mouse lines showed the disease-typical hyperresponsiveness to amiloride in the respiratory epithelium. The mean chloride secretory responses to carbachol or forskolin were 15-100% of those of the cognate wild type control animals.ConclusionThe amelioration of the clinical features and of the basic defect that had emerged during the generation of CF/3-CftrTgH(neoim)Hgu mice was retained in the congenic mice indicating that the Cftr linkage group or other loci shared between the inbred strains contain(s) the major modifier(s) of attenuation of cystic fibrosis symptoms.

Project description:Cystic fibrosis (CF) is caused by mutations in the CFTR gene that impair the function of CFTR, a cAMP-regulated anion channel. In the small intestine loss of CFTR function creates a dehydrated, acidic luminal environment which is believed to cause an accumulation of mucus, a phenotype characteristic of CF. CF mice have small intestinal bacterial overgrowth, an altered innate immune response, and impaired intestinal transit. We investigated whether lubiprostone, which can activate the CLC2 Cl- channel, would improve the intestinal phenotype in CF mice.Cftr(tm1UNC) (CF) and wildtype (WT) littermate mice on the C57BL/6J background were used. Lubiprostone (10 ?g/kg-day) was administered by gavage for two weeks. Mucus accumulation was estimated from crypt lumen widths in periodic acid-Schiff base, Alcian blue stained sections. Luminal bacterial load was measured by qPCR for the bacterial 16S gene. Gastric emptying and small intestinal transit in fasted mice were assessed using gavaged rhodamine dextran. Gene expression was evaluated by Affymetrix Mouse430 2.0 microarray and qRT-PCR.Crypt width in control CF mice was 700% that of WT mice (P < 0.001). Lubiprostone did not affect WT crypt width but, unexpectedly, increased CF crypt width 22% (P = 0.001). Lubiprostone increased bacterial load in WT mice to 490% of WT control levels (P = 0.008). Conversely, lubiprostone decreased bacterial overgrowth in CF mice by 60% (P = 0.005). Lubiprostone increased gastric emptying at 20 min postgavage in both WT (P < 0.001) and CF mice (P < 0.001). Lubiprostone enhanced small intestinal transit in WT mice (P = 0.024) but not in CF mice (P = 0.377). Among other innate immune markers, expression of mast cell genes was elevated 4-to 40-fold in the CF intestine as compared to WT, and lubiprostone treatment of CF mice decreased expression to WT control levels.These results indicate that lubiprostone has some benefits for the CF intestinal phenotype, especially on bacterial overgrowth and the innate immune response. The unexpected observation of increased mucus accumulation in the crypts of lubiprostone-treated CF mice suggests the possibility that lubiprostone increases mucus secretion.

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Low linoleic and high docosahexaenoic acids in a severe phenotype of transgenic cystic fibrosis mice.

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Low linoleic and high docosahexaenoic acids in a severe phenotype of transgenic cystic fibrosis mice.

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