Low linoleic and high docosahexaenoic acids in a severe phenotype of transgenic cystic fibrosis mice.
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ABSTRACT:
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]
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Project description:Cystic fibrosis transmembrane conductance regulator (Cftr) knockout mice present the clinical features of low body weight and intestinal disease permitting an assessment of the interrelatedness of these phenotypes in a controlled environment. To identify intestinal alterations which affect body weight in CF mice the histological phenotypes of crypt-villus axis height, goblet cell hyperplasia, and mast cell infiltrate were measured, cardiac blood samples assessed, and gene expression profiling of the ileum was completed for 12 week old (C57BL/6xBALB) F2 Cftrtm1UNC and non-CF mice presenting a range of body weight. Crypt-villus axis height decreased with increasing weight in CF, but not control, mice. Goblet cell hyperplasia and mast cell infiltration in the submucosa and muscularis externa layers of the CF intestine, were identified to be independent of bodyweight. Blood triglyceride levels were found to be significantly lower in CF mice than control mice (p = 3.02 x 10-5) but were not dependent on CF mouse body weight. By expression profiling, genes of DNA replication and lipid metabolism were among those altered in CF mice relative to non-CF controls; and no differences in gene expression were measured between samples from CF mice in the 25th and 75th percentile for weight. This study indicates that the absence of Cftr leads to altered morphology in the CF intestine the extent of which is correlated with body weight in CF mice while CF related changes in blood triglyceride levels and in the intestinal gene expression profile were not dependent on body weight in this model. Keywords: disease state analysis
2007-05-21 | GSE5715 | GEO
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.
| S-EPMC2323021 | biostudies-literature
Project description:This multi-center study will compare multi-target DNA and quantitative FIT stool-based testing to colonoscopy in individuals with Cystic Fibrosis (CF) undergoing colon cancer screening with colonoscopy. The primary endpoint is detection of any adenomas, including advanced adenomas and colorectal cancer (CRC).
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| S-EPMC3774510 | biostudies-literature
Project description:BackgroundCystic 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.MethodsCftr(tm1UNC) (CF) and wildtype (WT) littermate mice on the C57BL/6J background were used. Lubiprostone (10 μg/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.ResultsCrypt 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.ConclusionsThese 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.
| S-EPMC2945989 | biostudies-literature
Project description:The opportunistic pathogen Pseudomonas aeruginosa is responsible for much of the morbidity and mortality associated with cystic fibrosis (CF), a condition that predisposes patients to chronic lung infections. P. aeruginosa lung infections are difficult to treat because P. aeruginosa adapts to the CF lung, can develop multidrug resistance, and can form biofilms. Despite the clinical significance of P. aeruginosa, modeling P. aeruginosa infections in CF has been challenging. Here, we characterize Scnn1b-transgenic (Tg) BALB/c mice as P. aeruginosa lung infection models. Scnn1b-Tg mice overexpress the epithelial Na+ channel (ENaC) in their lungs, driving increased sodium absorption that causes lung pathology similar to CF. We intranasally infected Scnn1b-Tg mice and wild-type littermates with the laboratory P. aeruginosa strain PAO1 and CF clinical isolates and then assessed differences in bacterial clearance, cytokine responses, and histological features up to 12 days postinfection. Scnn1b-Tg mice carried higher bacterial burdens when infected with biofilm-grown rather than planktonic PAO1; Scnn1b-Tg mice also cleared infections more slowly than their wild-type littermates. Infection with PAO1 elicited significant increases in proinflammatory and Th17-linked cytokines on day 3. Scnn1b-Tg mice infected with nonmucoid early CF isolates maintained bacterial burdens and mounted immune responses similar to those of PAO1-infected Scnn1b-Tg mice. In contrast, Scnn1b-Tg mice infected with a mucoid CF isolate carried high bacterial burdens, produced significantly more interleukin 1β (IL-1β), IL-13, IL-17, IL-22, and KC, and showed severe immune cell infiltration into the bronchioles. Taken together, these results show the promise of Scnn1b-Tg mice as models of early P. aeruginosa colonization in the CF lung.
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Project description:Gene transfer could provide a novel therapeutic approach for cystic fibrosis (CF), and adeno-associated virus (AAV) is a promising vector. However, the packaging capacity of AAV limits inclusion of the full-length cystic fibrosis transmembrane conductance regulator (CFTR) cDNA together with other regulatory and structural elements. To overcome AAV size constraints, we recently developed a shortened CFTR missing the N-terminal portion of the R domain (residues 708-759, CFTRΔR) and found that it retained regulated anion channel activity in vitro. To test the hypothesis that CFTRΔR could correct in vivo defects, we generated CFTR(-/-) mice bearing a transgene with a fatty acid binding protein promoter driving expression of human CFTRΔR in the intestine (CFTR(-/-);TgΔR). We found that intestinal crypts of CFTR(-/-);TgΔR mice expressed CFTRΔR and the intestine appeared histologically similar to that of WT mice. Moreover, like full-length CFTR transgene, the CFTRΔR transgene produced CFTR Cl(-) currents and rescued the CFTR(-/-) intestinal phenotype. These results indicate that the N-terminal part of the CFTR R domain is dispensable for in vivo intestinal physiology. Thus, CFTRΔR may have utility for AAV-mediated gene transfer in CF.
| S-EPMC3041073 | biostudies-other
Project description:Cystic fibrosis (CF) mouse models exhibit exocrine pancreatic function yet do not develop adipose stores to the levels of non-CF mice. CF mice homozygous for the Cftr mutation (F508del) at 3 weeks (post-weaning) and 6 weeks (young adult) of age had markedly less adipose tissue than non-CF mice. Both 3- and 6-week old mice had dietary lipid absorption and fecal lipid excretion comparable to non-CF controls. Fractional hepatic de novo synthesis of palmitate and stearate (de novo lipogenesis, DNL) as determined by deuterium incorporation was reduced in CF mice. At 3 weeks of age, F508del mice had significantly decreased DNL of palmitate and stearate, by 83% and 80%, respectively. By 6 weeks of age, DNL rates in non-CF mice remained unchanged as compared to 3-week old mice, while DNL rates of F508del mice were still reduced, by 33% and 40%, respectively. Adipose tissue fatty acid profiles were comparable in CF and non-CF mice, indicating that adipose differences are quantitative, not qualitative. A correspondingly lower content of deuterium-labeled fatty acids was found in CF adipose tissue, consistent with reduced deposition of newly made hepatic triglycerides and/or decreased adipose tissue lipogenesis. Hepatic transcriptome analysis revealed lower mRNA expression from several genes involved in fatty acid biosynthesis, suggesting down-regulation of several enzymes in fatty acids synthesis as a mechanism for the reduced lipogenesis. These novel data provide a model for altered fat and fatty acid metabolism in CF, independent of malabsorption, and may partly explain the inability of pancreatic enzyme replacement therapy to completely restore normal body mass to CF patients ∆F508 CF mice and its WT littermates (3-weeks old females, C57BL/6J) were examined. RNA extracted from snapped-frozen livers, 4 replicates per genotype.
2012-06-17 | E-GEOD-33319 | biostudies-arrayexpress
Project description:Purpose: Pseudomonas aeruginosa is a major cause of morbidity and mortality in patients with cystic fibrosis (CF). We provide an insight to the DNA auxotrophy of P. aeruginosa PASS4 isolate. Better understanding of P. aeruginosa adaptations in the CF lung environment can have a great impact in the development of specialised treatment regimes aimed at the eradications of P. aeruginosa infections. Methods: P. aeruginosa strains PAO1 and PASS4 were grown in minimal medium with either L-Asparagine or DNA as a carbon source, in biological triplicates. RNA was extracted and sequenced on Illumina HiSeq 1000 platform. The sequence reads that passed quality filters were analyzed using EdgePro and DESeq packages, as well as the Rockhopper tool. Results: We mapped > 10 million paired sequence reads per sample to the genome of P. aeruginosa PAO1 and identified a total of 576 genes differentially expressed by PASS4 when grown in DNA (P value < 0.01, log2 fold-change 1< to < -1), with 322 genes upregulated and 254 genes downregulated. There were a total of 423 genes differentially expressed by PAO1 when grown in DNA (P value < 0.01, log2 fold-change 1< to <-1), with 359 genes upregulated and 64 genes downregulated . A total of 129 transcripts displayed similar expression patterns in both organisms, with 112 being upregulated and 17 down-regulated. Conclusions: Our study identified that P. aeruginosa PASS4 was a purine auxotroph. Purine auxotropy may represent a viable microbial strategy for adaptation to DNA rich environments such as the CF lung.
2019-06-16 | GSE100287 | GEO