Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Mediated Residual Chloride Secretion Does Not Protect against Early Chronic Pseudomonas aeruginosa Infection in F508del Homozygous Cystic Fibrosis Patients

Derichs, Nico; Mekus, Frauke; Bronsveld, Inez; Bijman, J.; Veeze, Henk J.; Hardt, H. von der; Tümmler, Burkhard; Ballmann, Manfred

doi:10.1203/01.pdr.0000100758.66805.ce

Cited by 18 publications

(12 citation statements)

References 41 publications

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“…For example, Bronsveld and colleagues reported that ΔF508 CFTR maturation and function can be detected in epithelial cells isolated from a subset of human CF subjects homozygous for the ΔF508 CFTR mutation [62]. In other reports [63], ΔF508 CFTR activity correlated with clinical phenotype, and the investigators provided evidence that maturation and function of ΔF508 CFTR likely varies among individuals with the disease. Whether heterogeneity among individuals reflects modifier genes that contribute to ΔF508 CFTR maturation and/or the membrane activity observed in our experiments will require further study, but are certainly suggested by heterogeneous correction with corr-4a in primary airway epithelial cells described here.…”

Section: Discussionmentioning

confidence: 99%

ΔF508 CFTR processing correction and activity in polarized airway and non-airway cell monolayers

Rowe

Pyle

Jurkevante

et al. 2010

Pulmonary Pharmacology & Therapeutics

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We examined the activity of ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) stably expressed in polarized cystic fibrosis bronchial epithelial cells (CFBE41o−) human airway cells and Fisher Rat Thyroid (FRT) cells following treatment with low temperature and a panel of small molecule correctors of ΔF508 CFTR misprocessing. Corr-4a increased ΔF508 CFTR-dependent Cl− conductance in both cell types, whereas treatment with VRT-325 or VRT-640 increased activity only in FRT cells. Total currents stimulated by forskolin and genistein demonstrated similar dose/response effects to Corr-4a treatment in each cell type. When examining the relative contribution of forskolin and genistein to total stimulated current, CFBE41o− cells had smaller forskolin-stimulated Isc following either low temperature or corr-4a treatment (10–30% of the total Isc produced by the combination of both CFTR agonists). In contrast, forskolin consistently contributed greater than 40% of total Isc in ΔF508 CFTR expressing FRT cells corrected with low temperature, and corr-4a treatment preferentially enhanced forskolin dependent currents only in FRT cells (60% of total Isc). ΔF508 CFTR cDNA transcript levels, ΔF508 CFTR C band levels, or cAMP signaling did not account for the reduced forskolin response in CFBE41o− cells. Treatment with non-specific inhibitors of phosphodiesterases (papaverine) or phosphatases (endothall) did not restore ΔF508 CFTR activation by forskolin in CFBE41o− cells, indicating that the Cl− transport defect in airway cells is distal to cAMP or its metabolism. The results identify important differences in ΔF508 CFTR activation in polarizing epithelial models of CF, and have important implications regarding detection of rescued of ΔF508 CFTR in vivo.

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Section: Discussionmentioning

confidence: 99%

ΔF508 CFTR processing correction and activity in polarized airway and non-airway cell monolayers

Rowe

Pyle

Jurkevante

et al. 2010

Pulmonary Pharmacology & Therapeutics

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“…This suggests that these mice have retained some capacity for neutralization of gastric acid. Unlike homozygous ⌬F508 patients, who show no (27) or marginal (2,8) rescue of functional CFTR protein, considerable ⌬F508-CFTR-mediated intestinal chloride secretion is apparent in mutant mice (15-20% of WT level; de Jonge HR, unpublished observations). Accordingly, murine ⌬F508-CFTR may mediate enough residual duodenal bicarbonate secretion to secure a level of gastric acid buffering that permits hydrolysis of all triglyceride.…”

Section: Discussionmentioning

confidence: 99%

Fat absorption in cystic fibrosis mice is impeded by defective lipolysis and post-lipolytic events

Bijvelds

Bronsveld²,

Havinga³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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Cystic fibrosis (CF) is frequently associated with progressive loss of exocrine pancreas function, leading to incomplete digestion and absorption of dietary fat. Supplementing patients with pancreatic lipase reduces fat excretion, but it does not completely correct fat malabsorption, indicating that additional pathological processes affect lipolysis and/or uptake of lipolytic products. To delineate the role of such (post) lipolytic processes in CF-related fat malabsorption, we assessed fat absorption, lipolysis, and fatty acid uptake in two murine CF models by measuring fecal fat excretion and uptake of oleate- and triolein-derived lipid. Pancreatic and biliary function was investigated by determining lipase secretion and biliary bile salt (BS) secretion, respectively. A marked increase in fecal fat excretion was observed in cftr null mice but not in homozygous DeltaF508 mice. Fecal BS loss was enhanced in both CF models, but biliary BS secretion rates were similar. Uptake of free fatty acid was delayed in both CF models, but only in null mice was a specific reduction in lipolytic activity apparent, characterized by strongly reduced triglyceride absorption. Impaired lipolysis was not due to reduced pancreatic lipase secretion. Suppression of gastric acid secretion partially restored lipolytic activity and lipid uptake, indicating that incomplete neutralization of gastric acid impedes fat absorption. We conclude that fat malabsorption in cftr null mice is caused by impairment of lipolysis, which may result from aberrant duodenal pH regulation.

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“…The transepithelial I sc across the tissue was registered in recirculating Ussing chambers as described in detail previously 17 18 21 24. Briefly, superficial rectal suction biopsies were taken without sedation in a standardised procedure, mounted in Ussing chambers and incubated at 37°C with buffer solution.…”

Section: Methodsmentioning

confidence: 99%

Intestinal current measurement for diagnostic classification of patients with questionable cystic fibrosis: validation and reference data

Derichs

Sanz

Känel

et al. 2010

Thorax

125

102

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Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Mediated Residual Chloride Secretion Does Not Protect against Early Chronic Pseudomonas aeruginosa Infection in F508del Homozygous Cystic Fibrosis Patients

Cited by 18 publications

References 41 publications

ΔF508 CFTR processing correction and activity in polarized airway and non-airway cell monolayers

ΔF508 CFTR processing correction and activity in polarized airway and non-airway cell monolayers

Fat absorption in cystic fibrosis mice is impeded by defective lipolysis and post-lipolytic events

Intestinal current measurement for diagnostic classification of patients with questionable cystic fibrosis: validation and reference data

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