Animal models of cystic fibrosis

Scholte, Bob J.; Davidson, Donald J.; Wilke, Martina; Jonge, Hugo R. de

doi:10.1016/j.jcf.2004.05.039

Cited by 77 publications

(81 citation statements)

References 73 publications

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“…This could be done with a technique pioneered by Capecchi (Thomas &Capecchi 1987, Ledermann 2000) which uses homologous recombination in mouse to target a mutation to a specific site in the chromosome. The resulting ES cells are injected into blastocysts to produce chimeric mice and subsequently a mutant strain through germ-line transmission of the mutant allele (Scholte et al 2004). The initial CF KO and residual CF function mouse models contained mutations that resulted in a complete loss of function by using a 'replacement strategy' to produce an interruption of the CFTR gene and create absolute nulls and no CFTR protein production.…”

Section: Cf Micementioning

confidence: 99%

“…Chronic pulmonary infection with P. aeruginosa is the primary concern with the characteristic transition of this organism to mucoid phenotype clearly correlating with poor prognosis and clinical decline (Parad et al 1999). However, it remains unclear whether CFTR dysfunction results directly in an increased predisposition to infection with this organism or a broader susceptibility resulting in repeated infections with organisms such as S. aureus or respiratory syncytial virus and inappropriate inflammatory responses generating a lung environment that favours subsequent infections with P. aeruginosa (Scholte et al 2004).…”

Section: Pathophysiology Of Airway Epithelium In Cf Micementioning

confidence: 99%

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Animal models of chronic lung infection with Pseudomonas aeruginosa: useful tools for cystic fibrosis studies

Kukavica-Ibrulj

Levesque

2008

Lab Anim

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SummaryCystic fibrosis (CF) is caused by a defect in the transmembrane conductance regulator (CFTR) protein that functions as a chloride channel. Dysfunction of the CFTR protein results in salty sweat, pancreatic insufficiency, intestinal obstruction, male infertility and severe pulmonary disease. In most patients with CF life expectancy is limited due to a progressive loss of functional lung tissue. Early in life a persistent neutrophylic inflammation can be demonstrated in the airways. The cause of this inflammation, the role of CFTR and the cause of lung morbidity by different CF-specific bacteria, mostly Pseudomonas aeruginosa, are not well understood. The lack of an appropriate animal model with multi-organ pathology having the characteristics of the human form of CF has hampered our understanding of the pathobiology and chronic lung infections of the disease for many years. This review summarizes the main characteristics of CF and focuses on several available animal models that have been frequently used in CF research. A better understanding of the chronic lung infection caused particularly by P. aeruginosa, the pathophysiology of lung inflammation and the pathogenesis of lung disease necessitates animal models to understand CF, and to develop and improve treatment.

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Section: Cf Micementioning

confidence: 99%

Section: Pathophysiology Of Airway Epithelium In Cf Micementioning

confidence: 99%

Animal models of chronic lung infection with Pseudomonas aeruginosa: useful tools for cystic fibrosis studies

Kukavica-Ibrulj

Levesque

2008

Lab Anim

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“…Rotterdam delF508/delF508-CFTR mice (Cftr ) were used [22,23]. Muscle-stripped ileal mucosa was incubated in William's E-Glutamax medium supplemented with insulin (10 lg/ml) and dexamethasone (20 lg/ml).…”

Section: Ex Vivo Studiesmentioning

confidence: 99%

Rescue of functional delF508‐CFTR channels in cystic fibrosis epithelial cells by the α‐glucosidase inhibitor miglustat

et al. 2006

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In the disease cystic fibrosis (CF), the most common mutation delF508 results in endoplasmic reticulum retention of misfolded CF gene proteins (CFTR). We show that the a-1,2-glucosidase inhibitor miglustat (N-butyldeoxynojirimycin, NB-DNJ) prevents delF508-CFTR/calnexin interaction and restores cAMP-activated chloride current in epithelial CF cells. Moreover, miglustat rescues a mature and functional delF508-CFTR in the intestinal crypts of ileal mucosa from delF508 mice. Since miglustat is an orally active orphan drug (Zavesca Ò ) prescribed for the treatment of Gaucher disease, our findings provide the basis for future clinical evaluation of miglustat in CF patients.

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“…Several studies indicate that submucosal glands are the major sites of CFTR expression in human and murine airways (Engelhardt et al 1992;Kälin et al 1999;Doucet et al 2003), where it is thought to control the composition and depth of the ASL (Verkman et al 2003). It is widely accepted that the airway pathology in CF patients is largely due to CFTR dysfunction in these glands, and the different anatomy between submucosal airway glands in humans and those in mice has been proposed to contribute to the lack of airway pathology in mice (Scholte et al 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Although several relevant biochemical, electrophysiological, and cellular aspects of the disease have been studied in these models, they all fail to develop the complex human CF pathology, especially the typical CF lung disease including secondary bacterial and viral infections (Scholte et al 2004). Instead, the murine CF phenotype is mostly dominated by intestinal disease.…”

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confidence: 99%

Tissue and Cellular Expression Patterns of Porcine CFTR: Similarities to and Differences From Human CFTR

Plog

Mundhenk

Bothe

et al. 2010

J Histochem Cytochem.

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Emerging porcine models of cystic fibrosis (CF) are expected to mimic the human disease more closely than current mouse models do. However, little is known of the tissue and cellular expression patterns of the porcine CF transmembrane conductance regulator (pCFTR) and possible differences from human CFTR (hCFTR). Here, the expression pattern of pCFTR was systematically established on the mRNA and protein levels. Using specific anti-pCFTR antibodies, the majority of the protein was immunohistochemically detected on paraffin-embedded sections and on cryostate sections in the apical cytosol of intestinal crypt epithelial cells, nasal, tracheal, and bronchial epithelial cells, and other select, mostly glandular epithelial cells. Confocal laser scanning microscopy with co-localization of the Golgi marker 58K localized the protein in the cytosol between the Golgi apparatus and the apical cell membrane with occasional punctate or diffuse staining of the apical membrane. The tissue and cellular distribution patterns were confirmed by RT-PCR from whole tissue lysates or select cells after laser capture microdissection. Thus, expression of pCFTR was found to largely resemble that of hCFTR except for the kidney, brain, and cutaneous glands, which lack expression in pigs. Species-specific differences between pCFTR and hCFTR may become relevant for future interpretations of the CF phenotype in pig models.

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Animal models of cystic fibrosis

Cited by 77 publications

References 73 publications

Animal models of chronic lung infection with Pseudomonas aeruginosa: useful tools for cystic fibrosis studies

Animal models of chronic lung infection with Pseudomonas aeruginosa: useful tools for cystic fibrosis studies

Rescue of functional delF508‐CFTR channels in cystic fibrosis epithelial cells by the α‐glucosidase inhibitor miglustat

Tissue and Cellular Expression Patterns of Porcine CFTR: Similarities to and Differences From Human CFTR

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