Instability of the insertional mutation in Cftr
                     
                        TgH(neoim)Hgu
                     cystic fibrosis mouse model

Charizopoulou, Nikoletta; Jansen, Silke; Dorsch, Martina; Stanke, Frauke; Dorin, Julia R.; Hedrich, Hans-Jürgen; Tümmler, Burkhard

doi:10.1186/1471-2156-5-6

Cited by 20 publications

(8 citation statements)

References 26 publications

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“…B6.129P2(CF/3)- Cftr TgH(neoim)Hgu (CF MHH ) congenic mice were produced by inbreeding the original Cftr TgH (neoim) Hgu mutant mouse, which was generated by insertional mutagenesis in exon 10 of the Cftr gene ( Charizopoulou et al., 2004 , Charizopoulou et al., 2006 ). This congenic Cftr MHH strain was then backcrossed for more than 10 generations into the B6 background.…”

Section: Methodsmentioning

confidence: 99%

β1-Integrin Accumulates in Cystic Fibrosis Luminal Airway Epithelial Membranes and Decreases Sphingosine, Promoting Bacterial Infections

Grassmé

Henry

Ziobro

et al. 2017

Cell Host & Microbe

148

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SummaryChronic pulmonary colonization with bacterial pathogens, particularly Pseudomonas aeruginosa, is the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). We observed that β1-integrins accumulate on the luminal membrane of upper-airway epithelial cells from mice and humans with CF. β1-integrin accumulation is due to increased ceramide and the formation of ceramide platforms that trap β1-integrins on the luminal pole of bronchial epithelial cells. β1-integrins downregulate acid ceramidase expression, resulting in further accumulation of ceramide and consequent reduction of surface sphingosine, a lipid that kills bacteria. Interrupting this vicious cycle by triggering surface β1-integrin internalization via anti-β1-integrin antibodies or the RGD peptide ligand—or by genetic or pharmacological correction of ceramide levels—normalizes β1-integrin distribution and sphingosine levels in CF epithelial cells and prevents P. aeruginosa infection in CF mice. These findings suggest a therapeutic avenue to ameliorate CF-associated bacterial infections.

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Section: Methodsmentioning

confidence: 99%

β1-Integrin Accumulates in Cystic Fibrosis Luminal Airway Epithelial Membranes and Decreases Sphingosine, Promoting Bacterial Infections

Grassmé

Henry

Ziobro

et al. 2017

Cell Host & Microbe

148

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“…In Cftr TgH(neoim)Hgu mice the exon 10 of the Cftr gene had been disrupted by the insertion of the vector pMCIneoPolyA [ 16 ]. Since those mice produced low levels of Cftr [ 17 ] but showed a mixed genetic background [ 24 ], from the original Cftr TgH(neoim)Hgu mutant mouse, CF strain CF/3- Cftr TgH(neoim)Hgu was established at the Institute of Laboratory Animal Science of the Hannover Medical School by brother-sister mating for more than 40 generations. Next, the congenic mouse inbred strain B6.129P2(CF/3)- Cftr TgH(neoim)Hgu , which is used in this study, was generated by 40 backcross generations using CF/3- Cftr TgH(neoim)Hgu as donor strain and C57BL/6J as recipient strain [ 25 ].…”

Section: Methodsmentioning

confidence: 99%

Acute intratracheal Pseudomonas aeruginosa infection in cystic fibrosis mice is age-independent

et al. 2011

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BackgroundSince the discovery of the human CFTR gene in 1989 various mouse models for cystic fibrosis (CF) have been generated and used as a very suitable and popular tool to approach research on this life-threatening disease. Age related changes regarding the course of disease and susceptibility towards pulmonary infections have been discussed in numerous studies.MethodsHere, we investigated CftrTgH(neoim)Hgu and Cftrtm1Unc-Tg(FABPCFTR)1Jaw/J CF mice and their non-CF littermates during an acute lung infection with Pseudomonas aeruginosa for age dependent effects of their lung function and immune response.Mice younger than three or older than six months were intratracheally infected with P. aeruginosa TBCF10839. The infection was monitored by lung function of the animals using non-invasive head-out spirometry and the time course of physiological parameters over 192 hours. Quantitative bacteriology and lung histopathology of a subgroup of animals were used as endpoint parameters.ResultsAge-dependent changes in lung function and characteristic features for CF like a shallower, faster breathing pattern were observed in both CF mouse models in uninfected state. In contrast infected CF mice did not significantly differ from their non-CF littermates in susceptibility and severity of lung infection in both mouse models and age groups. The transgenic Cftrtm1Unc-Tg(FABPCFTR)1Jaw/J and their non-CF littermates showed a milder course of infection than the CftrTgH(neoim)Hgu CF and their congenic C57Bl/6J non-CF mice suggesting that the genetic background was more important for outcome than Cftr dysfunction.ConclusionsPrevious investigations of the same mouse lines have shown a higher airway susceptibility of older CF mice to intranasally applied P. aeruginosa. The different outcome of intranasal and intratracheal instillation of bacteria implies that infected CF epithelium is impaired during the initial colonization of upper airways, but not in the subsequent response of host defense.

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“…This hypothesis is supported by recent studies of the electrophysiology of epithelia generated from mixtures of CFTRϩ͞ϩ and CFTRϪ͞Ϫ human airway cells (19) and from extensive electrophysiological analyses of CF mice models with varied levels of CFTR mRNA expression. In these studies, CFTR expression in a small fraction of cells was sufficient to correct the CF epithelial Cl Ϫ transport defect (20,21).…”

Section: Discussionmentioning

confidence: 99%

Assessment of cystic fibrosis transmembrane conductance regulator (CFTR) activity in CFTR-null mice after bone marrow transplantation

Bruscia¹,

Price²,

Cheng³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Several studies have demonstrated that bone marrow (BM)-derived cells give rise to rare epithelial cells in the gastrointestinal (GI) and respiratory tracts after BM transplantation into myeloablated recipients. We investigate whether, after transplantation of cystic fibrosis transmembrane conductance regulator (CFTR)-positive BM-derived cells, BM-derived GI and airway epithelial cells can provide CFTR activity in the GI tract and nasal epithelium of recipient cystic fibrosis mice. CFTR؊͞؊ mice were transplanted with wild-type BM after receiving different doses of irradiation, and CFTR activity was assessed in vivo in individual mice over time by using rectal and nasal potential difference analyses and in vitro by Ussing chamber analysis. The data suggest that rare BM-derived epithelial cells in the GI and nasal epithelium detected in CFTR؊͞؊ transplanted mice provide a modest level of CFTR-dependent chloride secretion. Detection of CFTR mRNA and protein in tissues of transplanted CFTR؊͞؊ mice supports these data.bone marrow stem cells ͉ chloride channel ͉ epithelial cells

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Instability of the insertional mutation in Cftr TgH(neoim)Hgu cystic fibrosis mouse model

Cited by 20 publications

References 26 publications

β1-Integrin Accumulates in Cystic Fibrosis Luminal Airway Epithelial Membranes and Decreases Sphingosine, Promoting Bacterial Infections

β1-Integrin Accumulates in Cystic Fibrosis Luminal Airway Epithelial Membranes and Decreases Sphingosine, Promoting Bacterial Infections

Acute intratracheal Pseudomonas aeruginosa infection in cystic fibrosis mice is age-independent

Assessment of cystic fibrosis transmembrane conductance regulator (CFTR) activity in CFTR-null mice after bone marrow transplantation

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