Very mild disease phenotype of congenic Cftr
                TgH(neoim)Hgu
              cystic fibrosis mice

Tóth, Balázs; Wilke, Martina; Stanke, Frauke; Dorsch, Martina; Jansen, Silke; Wedekind, Dirk; Charizopoulou, Nikoletta; Bot, A.; Burmester, Marion; Leonhard-Marek, S.; Jonge, Hugo R. de; Hedrich, Hans-Jürgen; Breves, Gerhard; Tümmler, Burkhard

doi:10.1186/1471-2156-9-28

Cited by 6 publications

(7 citation statements)

References 33 publications

(41 reference statements)

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“…We have previously investigated the CF phenotype of trachea and upper airways of Cftr MHH mice [ 21 , 25 ]. Like in humans, the nasal epithelium of the CF mice exhibited the basic defect of Na + hyperabsorption and Cl - hyposecretion [ 25 ] and the trachea had accumulated ceramide [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…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 ]. Following the nomenclature of Teichgräber et al [ 19 ] this strain is called Cftr MHH , syngenic C57BL6/J mice are called B6 and served as controls.…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2011

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“…Because those mice produced low levels of Cftr (8) but showed a mixed genetic background (3) 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 (37). In the following, D2.129P2(CF/3)-Cftr TgH(neoim)Hgu /B6.129P2(CF/3)-Cftr TgH(neoim)Hgu are called CftrϪ/Ϫ mice, and syngenic C57BL/6J/DBA/2J mice are called B6/D2 and served as controls.…”

Section: Methodsmentioning

confidence: 99%

Impaired TLR4 and HIF expression in cystic fibrosis bronchial epithelial cells downregulates hemeoxygenase-1 and alters iron homeostasis in vitro

Chillappagari

Venkatesan

Garapati

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Hemeoxygenase-1 (HO-1), an inducible heat shock protein, is upregulated in response to multiple cellular insults via oxidative stress, lipopolysaccharides (LPS), and hypoxia. In this study, we investigated in vitro the role of Toll-like receptor 4 (TLR4), hypoxia-inducible factor 1α (HIF-1α), and iron on HO-1 expression in cystic fibrosis (CF). Immunohistochemical analysis of TLR4, HO-1, ferritin, and HIF-1α were performed on lung sections of CFTR-/- and wild-type mice. CFBE41o- and 16HBE14o- cell lines were employed for in vitro analysis via immunoblotting, immunofluorescence, real-time PCR, luciferase reporter gene analysis, and iron quantification. We observed a reduced TLR4, HIF-1α, HO-1, and ferritin in CFBE41o- cell line and CF mice. Knockdown studies using TLR4-siRNA in 16HBE14o- revealed significant decrease of HO-1, confirming the role of TLR4 in HO-1 downregulation. Inhibition of HO-1 using tin protoporphyrin in 16HBE14o- cells resulted in increased iron levels, suggesting a probable role of HO-1 in iron accumulation. Additionally, sequestration of excess iron using iron chelators resulted in increased hypoxia response element response in CFBE41o- and 16HBE14o-, implicating a role of iron in HIF-1α stabilization and HO-1. To conclude, our in vitro results demonstrate that multiple regulatory factors, such as impaired TLR4 surface expression, increased intracellular iron, and decreased HIF-1α, downregulate HO-1 expression in CFBE41o- cells.

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“…(c) Although knockout of CFTR abolishes Ca 2+ -activated Cl -currents in many mouse strains, several inbred strains of mice have been described in which Ca 2+ -activated Cl -secretion is present even though the CFTR gene has been disrupted. This suggests that CaCC channel expression might be strain specific (36)(37)(38). (d) A subset of human cystic fibrosis patients exhibit residual colonic Cl -conductance that is likely mediated by CaCCs (39).…”

Section: Discussionmentioning

confidence: 99%

Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon

et al. 2010

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Anion transport by the colonic mucosa maintains the hydration and pH of the colonic lumen, and its disruption causes a variety of diarrheal diseases. Cholinergic agonists raise cytosolic Ca 2+ levels and stimulate anion secretion, but the mechanisms underlying this effect remain unclear. Cholinergic stimulation of anion secretion may occur via activation of Ca 2+ -activated Cl -channels (CaCCs) or an increase in the Cl -driving force through CFTR after activation of Ca 2+ -dependent K + channels. Here we investigated the role of a candidate CaCC protein, bestrophin-2 (Best2), using Best2 -/-mice. Cholinergic stimulation of anion current was greatly reduced in Best2 -/-mice, consistent with our proposed role for Best2 as a CaCC. However, immunostaining revealed Best2 localized to the basolateral membrane of mucin-secreting colonic goblet cells, not the apical membrane of Cl --secreting enterocytes. In addition, in the absence of HCO 3 -, cholinergic-activated current was identical in control and Best2 -/-tissue preparations, which suggests that most of the Best2 current was carried by HCO 3 -. These data delineate an alternative model of cholinergic regulation of colonic anion secretion in which goblet cells play a critical role in HCO 3 -homeostasis. We therefore propose that Best2 is a HCO 3 -channel that works in concert with a Cl:HCO 3 -exchanger in the apical membrane to affect transcellular HCO 3 -transport. Furthermore, previous models implicating CFTR in cholinergic Cl -secretion may be explained by substantial downregulation of Best2 in Cftr -/-mice.

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Very mild disease phenotype of congenic Cftr TgH(neoim)Hgu cystic fibrosis mice

Cited by 6 publications

References 33 publications

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

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

Impaired TLR4 and HIF expression in cystic fibrosis bronchial epithelial cells downregulates hemeoxygenase-1 and alters iron homeostasis in vitro

Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon

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