Faculty Opinions recommendation of Ursodeoxycholate modulates bile flow and bile salt pool independently from the cystic fibrosis transmembrane regulator (Cftr) in mice.

2012 ◽  
Author(s):  
Bruno Stieger
Keyword(s):  
Cystic Fibrosis ◽  
Bile Salt ◽  
Bile Flow ◽  
Cystic Fibrosis Transmembrane Regulator ◽  
Cystic Fibrosis Transmembrane

Ursodeoxycholate modulates bile flow and bile salt pool independently from the cystic fibrosis transmembrane regulator (Cftr) in mice

2012 ◽  
Vol 302 (9) ◽  
pp. G1035-G1042 ◽  
Author(s):  
Frank A. J. A. Bodewes ◽  
Marjan Wouthuyzen-Bakker ◽  
Marcel J. Bijvelds ◽  
Rick Havinga ◽  
Hugo R. de Jonge ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Liver Disease ◽  
Bile Salt ◽  
Bile Flow ◽  
Cystic Fibrosis Transmembrane Regulator ◽  
Pool Size ◽  
Therapeutic Action ◽  
Wild Type ◽  
Bile Composition ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis liver disease (CFLD) is treated with ursodeoxycholate (UDCA). Our aim was to evaluate, in cystic fibrosis transmembrane regulator knockout ( Cftr −/−) mice and wild-type controls, whether the supposed therapeutic action of UDCA is mediated via choleretic activity or effects on bile salt metabolism. Cftr −/− mice and controls, under general anesthesia, were intravenously infused with tauroursodeoxycholate (TUDCA) in increasing dosage or were fed either standard or UDCA-enriched chow (0.5% wt/wt) for 3 wk. Bile flow and bile composition were characterized. In chow-fed mice, we analyzed bile salt synthesis and pool size of cholate (CA). In both Cftr −/− and controls intravenous TUDCA stimulated bile flow by ∼250% and dietary UDCA by ∼500%, compared with untreated animals ( P < 0.05). In non-UDCA-treated Cftr −/− mice, the proportion of CA in bile was higher compared with that in controls (61 ± 4 vs. 46 ± 4%; P < 0.05), accompanied by an increased CA synthesis [16 ± 1 vs. 10 ± 2 μmol·h−1·100 g body wt (BW)−1; P < 0.05] and CA pool size (28 ± 3 vs. 19 ± 1 μmol/100 g BW; P < 0.05). In both Cftr −/− and controls, UDCA treatment drastically reduced the proportion of CA in bile below 5% and diminished CA synthesis (2.3 ± 0.3 vs. 2.2 ± 0.4 μmol·day−1·100 g BW−1; nonsignificant) and CA pool size (3.6 ± 0.6 vs. 1.5 ± 0.3 μmol/100 g BW; P < 0.05). Acute TUDCA infusion and chronic UDCA treatment both stimulate bile flow in cystic fibrosis conditions independently from Cftr function. Chronic UDCA treatment reduces the hydrophobicity of the bile salt pool in Cftr −/− mice. These results support a potential beneficial effect of UDCA on bile flow and bile salt metabolism in cystic fibrosis conditions.

CPX, a selective A1-adenosine-receptor antagonist, regulates intracellular pH in cystic fibrosis cells

1995 ◽  
Vol 269 (1) ◽  
pp. C226-C233 ◽  
Author(s):  
V. Casavola ◽  
R. J. Turner ◽  
C. Guay-Broder ◽  
K. A. Jacobson ◽  
O. Eidelman ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Receptor Antagonist ◽  
Intracellular Ph ◽  
Adenosine Receptor ◽  
Ph Regulation ◽  
Cystic Fibrosis Transmembrane Regulator ◽  
Wild Type ◽  
A1 Adenosine Receptor ◽  
Adenosine Receptor Antagonist ◽  
Cystic Fibrosis Transmembrane

The selective A1-adenosine-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (CPX), has been reported to activate Cl- efflux from cystic fibrosis cells, such as pancreatic CFPAC-1 and lung IB3 cells bearing the cystic fibrosis transmembrane regulator(delta F508) mutation, but has little effect on the same process in cells repaired by transfection with wild-type cystic fibrosis transmembrane regulator (O. Eidelman, C. Guay-Broder, P. J. M. van Galen, K. A. Jacobson, C. Fox, R. J. Turner, Z. I. Cabantchik, and H. B. Pollard. Proc. Natl. Acad. Sci. USA 89: 5562-5566, 1992). We report here that CPX downregulates Na+/H+ exchange activity in CFPAC-1 cells but has a much smaller effect on cells repaired with the wild-type gene. CPX also mildly decreases resting intracellular pH. In CFPAC-1 cells, this downregulation is dependent on the presence of adenosine, since pretreatment of the cells with adenosine deaminase blocks the CPX effect. We also show that, by contrast, CPX action on these cells does not lead to alterations in intracellular free Ca2+ concentration. We conclude that CPX affects pH regulation in CFPAC-1 cells, probably by antagonizing the tonic action of endogenous adenosine.

scholarly journals Characterization of Wild-Type and ΔF508 Cystic Fibrosis Transmembrane Regulator in Human Respiratory Epithelia

2005 ◽  
Vol 16 (5) ◽  
pp. 2154-2167 ◽  
Author(s):  
Silvia M. Kreda ◽  
Marcus Mall ◽  
April Mengos ◽  
Lori Rochelle ◽  
James Yankaskas ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Normal Subjects ◽  
Cell Types ◽  
Cystic Fibrosis Transmembrane Regulator ◽  
Ciliated Cells ◽  
Metabolic Fate ◽  
Specific Expression ◽  
Δf508 Cftr ◽  
Cftr Protein ◽  
Cystic Fibrosis Transmembrane

Previous studies in native tissues have produced conflicting data on the localization and metabolic fate of WT and ΔF508 cystic fibrosis transmembrane regulator (CFTR) in the lung. Combining immunocytochemical and biochemical studies utilizing new high-affinity CFTR mAbs with ion transport assays, we examined both 1) the cell type and region specific expression of CFTR in normal airways and 2) the metabolic fate of ΔF508 CFTR and associated ERM proteins in the cystic fibrosis lung. Studies of lungs from a large number of normal subjects revealed that WT CFTR protein localized to the apical membrane of ciliated cells within the superficial epithelium and gland ducts. In contrast, other cell types in the superficial, gland acinar, and alveolar epithelia expressed little WT CFTR protein. No ΔF508 CFTR mature protein or function could be detected in airway specimens freshly excised from a large number of ΔF508 homozygous subjects, despite an intact ERM complex. In sum, our data demonstrate that WT CFTR is predominantly expressed in ciliated cells, and ΔF508 CFTR pathogenesis in native tissues, like heterologous cells, reflects loss of normal protein processing.

S-Nitrosoglutathione Increases Cystic Fibrosis Transmembrane Regulator Maturation

2001 ◽  
Vol 284 (1) ◽  
pp. 65-70 ◽  
Author(s):  
Khalequz Zaman ◽  
Marianne McPherson ◽  
John Vaughan ◽  
John Hunt ◽  
Filipa Mendes ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Cystic Fibrosis Transmembrane Regulator ◽  
Cystic Fibrosis Transmembrane
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