Impact of Nutrition on Phenotype in CFTR-deficient Mice

Cottart, Charles‐Henry; Bonvin, Elise; Rey, Colette; Wendum, Dominique; Bernaudin, Jean-François; Dumont, Sylvie; Lasnier, Elisabeth; Debray, Dominique; Clément, Annick; Housset, Chantal; Bonora, M.

doi:10.1203/pdr.0b013e318155a61d

Cited by 26 publications

(21 citation statements)

References 29 publications

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“…The absence of altered lung function in B6 Cftr tm1UNC mice agrees with previous airway response phenotyping of this strain (47), although changes in breathing rate and minute volume (48,49) have been reported for B6 Cftr tm1UNC mice; therefore, lung function changes apart from airway hyperresponsiveness may exist in this strain. We are not aware of prior reports of the lung function in BALB Cftr tm1UNC mice.…”

Section: Discussionsupporting

confidence: 90%

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Bazett

Stefanov

Paun

et al. 2012

The Journal of Immunology

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We previously observed the lungs of naive BALB/cJ Cftrtm1UNC mice to have greater numbers of lymphocytes, by immunohistochemical staining, than did BALB wild type littermates or C57BL/6J Cftrtm1UNC mice. In the present study, we initially investigated whether this mutation in Cftr alters the adaptive immunity phenotype by measuring the lymphocyte populations in the lungs and spleens by FACS and by evaluating CD3-stimulated cytokine secretion, proliferation, and apoptosis responses. Next, we assessed a potential influence of this lymphocyte phenotype on lung function through airway resistance measures. Finally, we mapped the phenotype of pulmonary lymphocyte counts in BALB × C57BL/6J F2 Cftrtm1UNC mice and reviewed positional candidate genes. By FACS analysis, both the lungs and spleens of BALB Cftrtm1UNC mice had more CD3+ (both CD4+ and CD8+) cells than did littermates or C57BL/6J Cftrtm1UNC mice. Cftrtm1UNC and littermate mice of either strain did not differ in anti-CD3–stimulated apoptosis or proliferation levels. Lymphocytes from BALB Cftrtm1UNC mice produced more IL-4 and IL-5 and reduced levels of IFN-γ than did littermates, whereas lymphocytes from C57BL/6J Cftrtm1UNC mice demonstrated increased Il-17 secretion. BALB Cftrtm1UNC mice presented an enhanced airway hyperresponsiveness to methacholine challenge compared with littermates and C57BL/6J Cftrtm1UNC mice. A chromosome 7 locus was identified to be linked to lymphocyte numbers, and genetic evaluation of the interval suggests Itgal and Il4ra as candidate genes for this trait. We conclude that the pulmonary phenotype of BALB Cftrtm1UNC mice includes airway hyperresponsiveness and increased lymphocyte numbers, with the latter trait being influenced by a chromosome 7 locus.

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Section: Discussionsupporting

confidence: 90%

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Bazett

Stefanov

Paun

et al. 2012

The Journal of Immunology

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“…Surprisingly, HFD feeding did not result in significant weight gain. At the same time, certain studies revealed even a decreased body weight in weanling animals fed a high-fat diet [25]. The absence of significant changes in serum adiponectin levels also indicates that the experimental animals were not characterized by adipocyte dysfunction [26] that is characteristic for severe obesity [27].…”

Section: Discussionmentioning

confidence: 96%

Early High-Fat Feeding Induces Alteration of Trace Element Content in Tissues of Juvenile Male Wistar Rats

Tinkov

Gatiatulina

Popova

et al. 2016

Biol Trace Elem Res

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The primary objective of the current study was to assess the influence of early high-fat feeding on tissue trace element content in young male Wistar rats. Twenty weanling male Wistar rats were divided into two groups fed standard (STD) or high-fat diet (HFD) containing 10 and 31.6 % of total calories from fat, respectively, for 1 month. Serum lipid spectrum, apolipoproteins, glucose, insulin, adiponectin, and leptin levels were assessed. The level of trace elements was estimated using inductively coupled plasma mass spectrometry. High-fat feeding significantly increased epidydimal (EDAT) and retroperitoneal adipose tissue (RPAT), as well as total adipose tissue mass by 34, 103, and 59 %, respectively. Serum leptin levels in HFD animals were twofold higher than those in the control rats. No significant difference in serum lipid spectrum, apolipoproteins, glucose, adiponectin, and insulin was detected between the groups. HFD significantly altered tissue trace element content. In particular, HFD-fed animals were characterized by significantly lower levels of Cu, I, Mn, Se, and Zn in the liver; Cr, V, Co, Cu, Fe, and I content of EDAT; Co, Cu, I, Cr, V, Fe, and Zn concentration in RPAT samples. At the same time, only serum Cu was significantly depressed in HFD-fed animals as compared to the control ones. Hair Co, Mn, Si, and V levels were significantly increased in comparison to the control values, whereas Se and I content was decreased. HFD feeding induced excessive adiposity and altered tissue trace element content in rats without insulin resistance, adiponectin deficiency, and proatherogenic state. Hypothetically, trace element disbalance may precede obesity-associated metabolic disturbances.

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“…These levels are too low to alter the activity of the Asm as demonstrated in the present study, however when CF mice are fed the Peptamen R diet, cholesterol concentrations increase to such levels that Asm is severely affected. The increase in cholesterol concentrations is due to an impressive consumption of the diet by the mice (~75% of body weight in a 24-hour cycle) leading to liver steatosis 38,39 . It is obvious that such a consumption is hard to achieve in humans, with the result that cholesterol levels will not increase in humans and, hence, Asm levels will not be changed.…”

Section: Accumulation Of Ceramide In Cf-mice Is Reduced By a Dietmentioning

confidence: 99%

Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis

Teichgräber

Ulrich

Endlich

et al. 2008

Nat Med

499

586

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Microbial lung infections are the major cause of morbidity and mortality in the hereditary metabolic disorder cystic fibrosis, yet the molecular mechanisms leading from the mutation of cystic fibrosis transmembrane conductance regulator (CFTR) to lung infection are still unclear. Here, we show that ceramide age-dependently accumulates in the respiratory tract of uninfected Cftr-deficient mice owing to an alkalinization of intracellular vesicles in Cftr-deficient cells. This change in pH results in an imbalance between acid sphingomyelinase (Asm) cleavage of sphingomyelin to ceramide and acid ceramidase consumption of ceramide, resulting in the higher levels of ceramide. The accumulation of ceramide causes Cftr-deficient mice to suffer from constitutive age-dependent pulmonary inflammation, death of respiratory epithelial cells, deposits of DNA in bronchi and high susceptibility to severe Pseudomonas aeruginosa infections. Partial genetic deficiency of Asm in Cftr(-/-)Smpd1(+/-) mice or pharmacological treatment of Cftr-deficient mice with the Asm blocker amitriptyline normalizes pulmonary ceramide and prevents all pathological findings, including susceptibility to infection. These data suggest inhibition of Asm as a new treatment strategy for cystic fibrosis.-1 - infection. These data suggest inhibition of Asm as a novel treatment strategy in CF. Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis-4 -

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Impact of Nutrition on Phenotype in CFTR-deficient Mice

Cited by 26 publications

References 29 publications

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Early High-Fat Feeding Induces Alteration of Trace Element Content in Tissues of Juvenile Male Wistar Rats

Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis

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