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

Bazett, Mark; Stefanov, Anguel N.; Paun, Alexandra; Paradis, Josée; Haston, Christina K.

doi:10.4049/jimmunol.1102425

Cited by 6 publications

(11 citation statements)

References 65 publications

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“…We assumed that a dysfunction in the transcriptional or posttranscriptional controlling mechanisms could partly explain the discrepancies between the IHC and SISH results; still we wanted to explore other genes located on chromosome 7. Chromosome 7 is known to harbor genes whose alteration my play an important role in multiple diseases as cystic fibrosis[27], but also in tumorigenesis [28]with over than 1150 protein- coding genes, 605 of which have been validated by transcript sequences. [29] Nevertheless, three genes; EGFR , MET , and BRAF emerge as of special interest in NSCLC.…”

Section: Discussionmentioning

confidence: 99%

The impact of MET, IGF-1, IGF1R expression and EGFR mutations on survival of patients with non-small-cell lung cancer

Al-Saad¹,

Richardsen²,

Kilvaer³

et al. 2017

PLoS ONE

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IntroductionTo compare the efficacy of silver in situ hybridization (SISH) and immunohistochemistry (IHC) in detecting MET and IGF1R alterations and to investigate their prevalence and prognostic significance. A possible correlation between MET receptor expression, MET gene alterations and the two most frequent occurring EGFR gene mutations was also investigated.Materials and methodsStage I to IIIA tumors from 326 patients with NSCLC were immunohistochemically tested for protein expression of MET and IGF-1. Their cytoplasmic expression was compared with the gene copy number of the MET and IGF1Rgenes by SISH in paraffin-embedded, formalin-fixed material. Correlations were made with the immunohistochemical expression of two frequent EGFR mutations and clinicopathological variables. Univariate and multivariate survival analyses was used to evaluate the prognostic efficacy of the tested markers.ResultsIn univariate analyses, high cytoplasmic MET expression showed a significant negative prognostic effect in adenocarcinoma patients (p = 0.026). MET gene to chromosome 7 ratio was a significant positive prognostic marker (p = 0.005), probably only due to the highly negative prognostic significance of chromosome 7 polysomy (p = 0.002). High IGF1R gene copy number was a negative prognostic marker for all NSCLC patients (p = 0.037). In the multivariate analysis, polysomy of chromosome 7 in tumor cells correlated significantly and independently with a poor prognosis (p = 0.011). In patients with adenocarcinoma, a high cytoplasmic MET expression was an independent negative prognostic marker (p = 0.013). In males a high IGF1R gene copy number to chromosome 15 count ratio was significantly and independently correlated to a poor prognosis (p = 0.018).ConclusionMET protein expression provides superior prognostic information compared with SISH. Polysomy of chromosome 7 is an independent negative prognostic factor in NSCLC patients. This finding has an important implication while examining genes located on chromosome 7 by means of SISH. High IGF1R gene copy number to chromosome 15 count ratio is an independent predictor of inferior survival in male patients with primary NSCLC.

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Section: Discussionmentioning

confidence: 99%

The impact of MET, IGF-1, IGF1R expression and EGFR mutations on survival of patients with non-small-cell lung cancer

Al-Saad¹,

Richardsen²,

Kilvaer³

et al. 2017

PLoS ONE

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“…These mice were bred together to produce Cftr tm1Eur mice and wild-type Cftr +/+ controls and were genotyped as previously described (Paradis et al 2010), Cftr +/tm1UNC heterozygous mice on either C57BL/6 or BALB/c background were used to generate knockout ( Cftr tm1UNC ) mice as previously described (Bazett et al 2012; Haston et al 2006). All mice were bred and maintained at the Meakins-Christie Laboratories of McGill University.…”

Section: Methodsmentioning

confidence: 99%

“…All mice were bred and maintained at the Meakins-Christie Laboratories of McGill University. To circumvent possible premature death due to intestinal disease, all mice (CF and WT) were fed standard chow and received PEGLYTE ® (17.8 mmol/L polyethylene glycol, Pharma Science, DIN:00777838) in their drinking water as described previously (Bazett et al 2012; Clarke et al 1996; Haston et al 2006; Paradis et al 2010). Mice were weaned at 3 weeks of age and grouped in ventilated cages of 1–3 mice based on their sex.…”

Section: Methodsmentioning

confidence: 99%

Cystic fibrosis mouse model-dependent intestinal structure and gut microbiome

et al. 2015

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Mice with a null mutation in the cystic fibrosis transmembrane conductance regulator (Cftr) gene show intestinal structure alterations and bacterial overgrowth. To determine whether these changes are model-dependent and whether the intestinal microbiome is altered in cystic fibrosis (CF) mouse models, we characterized the ileal tissue and intestinal microbiome of mice with the clinically common ΔF508 Cftr mutation (FVB/N Cftrtm1Eur) and with Cftr null mutations (BALB/c Cftrtm1UNC and C57BL/6 Cftrtm1UNC). Intestinal disease in 12-week-old CF mice, relative to wild-type strain controls, was measured histologically. The microbiome was characterized by pyrosequencing of the V4–V6 region of the 16S rRNA gene and intestinal load was measured by RT-PCR of the 16S rRNA gene. The CF-associated increases in ileal crypt to villus axis distention, goblet cell hyperplasia, and muscularis externa thickness were more severe in the BALB/c and C57BL/6 Cftrtm1UNC mice than in the FVB/N Cftrtm1Eur mice. Intestinal bacterial load was significantly increased in all CF models, compared to levels in controls, and positively correlated with circular muscle thickness in CF, but not wild-type, mice. Microbiome profiling identified Bifidobacterium and groups of Lactobacillus to be of altered abundance in the CF mice but overall bacterial frequencies were not common to the three CF strains and were not correlative of major histological changes. In conclusion, intestinal structure alterations, bacterial overgrowth, and dysbiosis were each more severe in BALB/c and C57BL/6 Cftrtm1UNC mice than in the FVB/N Cftrtm1Eur mice. The intestinal microbiome differed among the three CF mouse models.

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“…The CF traits of airway hyperresponsiveness, bone disease and intestinal disease are reflected in mice deficient for Cftr. Specifically, BALB/c Cftr tm1UNC mice, which harbour a null mutation in Cftr , present with an airway hyperresponsive phenotype compared to the lung response of wild-type littermates 17 , as do FVB/N Cftr tm1Eur mice which have the clinically prevalent delF508-Cftr mutation 18 . The airway hyperresponsive phenotype of these CF mouse models occurs in the absence of observable airway remodelling as indicated by a lack of goblet cell hyperplasia or of increased α-smooth muscle actin 17 18 .…”

mentioning

confidence: 99%

“…Specifically, BALB/c Cftr tm1UNC mice, which harbour a null mutation in Cftr , present with an airway hyperresponsive phenotype compared to the lung response of wild-type littermates 17 , as do FVB/N Cftr tm1Eur mice which have the clinically prevalent delF508-Cftr mutation 18 . The airway hyperresponsive phenotype of these CF mouse models occurs in the absence of observable airway remodelling as indicated by a lack of goblet cell hyperplasia or of increased α-smooth muscle actin 17 18 . BALB/c Cftr tm1UNC mice also develop a bone disease that resembles the clinical phenotype in terms of reduced bone mineral density and an altered bone structure 15 19 and intestinal disease has been documented in the majority of CF mouse models 20 , including BALB/c Cftr tm1UNC mice 21 22 23 .…”

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confidence: 99%

Streptomycin treatment alters the intestinal microbiome, pulmonary T cell profile and airway hyperresponsiveness in a cystic fibrosis mouse model

Bazett

Bergeron

Haston

2016

Sci Rep

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Cystic fibrosis transmembrane conductance regulator deficient mouse models develop phenotypes of relevance to clinical cystic fibrosis (CF) including airway hyperresponsiveness, small intestinal bacterial overgrowth and an altered intestinal microbiome. As dysbiosis of the intestinal microbiota has been recognized as an important contributor to many systemic diseases, herein we investigated whether altering the intestinal microbiome of BALB/c Cftrtm1UNC mice and wild-type littermates, through treatment with the antibiotic streptomycin, affects the CF lung, intestinal and bone disease. We demonstrate that streptomycin treatment reduced the intestinal bacterial overgrowth in Cftrtm1UNC mice and altered the intestinal microbiome similarly in Cftrtm1UNC and wild-type mice, principally by affecting Lactobacillus levels. Airway hyperresponsiveness of Cftrtm1UNC mice was ameliorated with streptomycin, and correlated with Lactobacillus abundance in the intestine. Additionally, streptomycin treated Cftrtm1UNC and wild-type mice displayed an increased percentage of pulmonary and mesenteric lymph node Th17, CD8 + IL-17+ and CD8 + IFNγ+ lymphocytes, while the CF-specific increase in respiratory IL-17 producing γδ T cells was decreased in streptomycin treated Cftrtm1UNC mice. Bone disease and intestinal phenotypes were not affected by streptomycin treatment. The airway hyperresponsiveness and lymphocyte profile of BALB/c Cftrtm1UNC mice were affected by streptomycin treatment, revealing a potential intestinal microbiome influence on lung response in BALB/c Cftrtm1UNC mice.

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

Cited by 6 publications

References 65 publications

The impact of MET, IGF-1, IGF1R expression and EGFR mutations on survival of patients with non-small-cell lung cancer

The impact of MET, IGF-1, IGF1R expression and EGFR mutations on survival of patients with non-small-cell lung cancer

Cystic fibrosis mouse model-dependent intestinal structure and gut microbiome

Streptomycin treatment alters the intestinal microbiome, pulmonary T cell profile and airway hyperresponsiveness in a cystic fibrosis mouse model

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