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PubMed2006

Evidence of increased flux to n-6 docosapentaenoic acid in phospholipids of pancreas from cftr-/- knockout mice.

An association has been reported between alterations in fatty acid metabolism and cystic fibrosis (CF). We hypothesized that these alterations are specific for a particular lipid component(s) and are the result of a specific metabolic defect. The different lipid classes were examined for fatty acid changes by using pancreatic homogenates and primary cultures of pancreatic acini from cftr(-/-) (CF) and wild-type mice. Lipid classes and phospholipids were separated by aminopropyl column chromatography and high-performance liquid chromatography, and fatty acid methyl esters were analyzed. The results indicate that in CF mice (1) linoleate was decreased in phospholipids but not in neutral lipids; (2) there was an increase in dihomo-gamma-linolenate and in docosapentaenoate, the terminal fatty acid of the n-6 pathway, in total lipids and total phospholipids, but not in the neutral lipid class; and (3) the docosapentaenoate (n-6)/docosahexaenoate (n-3) ratio was significantly elevated in neutral phospholipids. This suggests an enhanced flux through the n-6 pathway beyond arachidonate. This study provides a more in-depth understanding of the fatty acid alterations found in CF, as reflected by the cftr(-/-) mouse model.

Animals↗
PubMed1995

Reduced pancreatic insulin release and reduced peripheral insulin sensitivity contribute to hyperglycaemia in cystic fibrosis.

Traditional opinion holds that patients with cystic fibrosis (CF) develop impaired glucose tolerance or diabetes due to insulinopenia caused by fibrosis of the pancreas. However, studies on the dynamics of insulin secretion and peripheral insulin action have yielded conflicting results. We studied 18 patients with CF (9 male, 9 female, age 15-29 years) and 17 healthy control subjects (8 male, 9 female, 20-32 years). Oral glucose tolerance tests and combined i.v.-glucose-tolbutamide-tests were performed on separate days in fasting subjects. Bergman's "Minimal Model" was used to quantitate both peripheral insulin sensitivity (SI) and insulin-independent glucose disposal (glucose effectiveness; SG). Based on National Diabetes Data Group criteria, 4 patients were classified as diabetic (22%; CF-DM), 3 patients (17%) had impaired glucose tolerance (CF-IGT) while glucose metabolism was normal in 11 patients (61%; CF-NGT). Irrespective of the degree of glucose tolerance, the insulin response to oral glucose was not reduced but delayed, up to 60 min in the CF-IGT/DM group. First-phase insulin release (0-10 min) after i.v.-glucose was significantly lower in CF patients (29% of healthy controls; P < 0.0001), with no difference between the CF-NGT and CF-IGT/DM groups. Insulin release following tolbutamide injection was only marginally reduced in CF patients (64% of controls). In contrast, SI was significantly reduced in the subgroup of CF patients with abnormal glucose metabolism (CF-IGT/DM: 0.97 +/- 0.16 x 10(-4) l/min/pmol; control group: 1.95 +/- 0.25; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

[Ultrasonic evaluation of the upper abdomen in cystic fibrosis].

Abdominal sonography should compulsory be used in patients with cystic fibrosis (CF). It is not difficult to detect early morphologic changes at liver, gall-bladder, pancreas, spleen, and vessels by ultrasound. As a non-invasive method sonography is a very useful tool for a comprehensive special care of outpatients with CF.

Adolescent↗
PubMed1985

Fecal chymotrypsin: a new diagnostic test for exocrine pancreatic insufficiency in children with cystic fibrosis.

The purpose of this report is to evaluate whether a new, simple, non-invasive method for chymotrypsin measurement in stools is useful for the diagnosis of exocrine pancreatic insufficiency in cystic fibrosis (CF). A hundred children aged from 2 months to 12 years were tested: 50 children had been admitted for chronic diarrhoea, 15 for cystic fibrosis and 40 acted as controls. Chymotrypsin in stools was assayed using a kinetic measurement with Succ-Ala-Ala-Pro-Phe-pNa as substrate in a simple photometric assay. In 13 of 15 children with cystic fibrosis, stool enzyme levels were always remarkably low, while all control subjects and all children not presenting cystic fibrosis had normal stool levels of chymotrypsin. Our data suggest that stool chymotrypsin measurement is a simple and reliable "tubeless" test for the evaluation of exocrine pancreatic insufficiency in children with cystic fibrosis.

Child↗
PubMed1997

Cystic fibrosis phenotype associated with pancreatic insufficiency does not always reflect the cAMP-dependent chloride conductive pathway defect. Analysis of C225R-CFTR and R1066C-CFTR.

We have previously screened the cystic fibrosis transmembrane conductance regulator (CFTR) gene and identified new disease-causing mutations. C225R and R1066C are both associated with pancreatic insufficiency, but the former mutation is associated with mild and unusual lung disease, whereas the latter is associated with severe lung disease. In the present study, we expressed these mutants heterologously in HeLa cells, and we analyzed protein synthesis by immunoprecipitation and chloride channel function by using a halide-sensitive fluorescent dye, 6-methoxy-N-ethylquinolinium. Immunoprecipitation and functional studies showed that cells transfected with C225R-CFTR exhibit cAMP-dependent chloride fluxes; C225R-CFTR protein is poorly expressed but fully glycosylated and can be compared with R117H-CFTR. R1066C-CFTR protein is not correctly processed and, unlike DeltaF508-CFTR, this defect cannot be corrected by reduced temperature or overexpression in butyrate-treated cells; defective processing may occur at a different step in the biosynthetic pathway. These results point to two different mechanisms underlying the same pancreatic status and suggest that it is unwise to use pancreatic sufficiency and insufficiency to define mild and severe cystic fibrosis (CF) disease, respectively. Finally, the experimental model described here may be helpful to predict the pulmonary status of CF patients bearing mutations located in putative membrane-spanning domains of the CFTR protein.

Amino Acid Substitution↗
PubMed1992

Levels and molecular forms of immunoreactive trypsin and chymotrypsin in amniotic fluids from normal and cystic fibrosis fetus: evidence for a lack of activation of proteolytic zymogens in cystic fibrosis fetus.

We previously suggested that an activation defect of pancreatic proteolytic zymogens in newborns suffering from cystic fibrosis (CF) might contribute (by an adaptative-like process) to the significant increase of the serum trypsin level observed in the disease at birth. To give support to this hypothesis we studied two pancreatic enzymes: trypsin 1 (IRT) and chymotrypsin A (IRChT) by noncompetitive enzyme immunoassays in amniotic fluids taken at 17-18 weeks of pregnancy. In normal fluids (102), the levels of the two enzymes were widely dispersed between 5 and 100 micrograms/L. A similar pattern was observed for the fluids with a 1 in 4 risk of CF with a normal outcome (24). In contrast, the levels of pancreatic enzymes in the fluids with affected fetus (40) were always below 45 micrograms/L for IRT and 55 micrograms/L for IRChT and most of them were under 20 micrograms/L for both enzymes. The molecular forms of IRT and IRChT in amniotic fluids were studied by gel filtration. In amniotic fluids with affected fetus, a major form of IRT was eluted in a position consistent with the elution of proteins around 25 kDa and two peaks of IRChT were eluted at 75 kDa and 25 kDa. These patterns are similar to those observed in normal serum when zymogens are present and are quite different from the patterns obtained by gel filtration of amniotic fluids with normal outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Amniocentesis↗
PubMed1982

Secretin pancreozymin stimulation test and confirmation of the diagnosis of cystic fibrosis.

We have studied the secretin-pancreozymin stimulation test of pancreatic function with particular regard to its usefulness in the diagnosis of cystic fibrosis patients without gastrointestinal symptoms. We have compared the test results in 38 control individuals, 14 patients with cystic fibrosis and five other patients with problems affecting pancreatic function. Of the cystic fibrosis patients tested, six had no gastrointestinal symptoms and were shown to have normal or raised output of pancreatic enzymes measured (lipase, trypsin, chymotrypsin, and amylase). There was a positive correlation between both volume and bicarbonate measurement versus body weight in all subjects, but this relationship was clearly different in the cystic fibrosis patients compared with others regardless of the cystic fibrosis patients' ability to secrete pancreatic enzymes. Among the cystic fibrosis patients, bicarbonate concentration tended to be higher in those able to secrete a significant amount of pancreatic enzymes. However, the actual output of bicarbonate measured in all cystic fibrosis patients (range 0.001-0.037 mmol/kg/45 min post-stimulation) was below that found in all control patients (range 0.104-0.516 mmol/kg/45 min post-stimulation). Therefore the secretin-pancreozymin test of pancreatic function appears to be useful in the diagnosis of cystic fibrosis even in those patients with adequate enzyme production.

Adolescent↗
PubMed1987

Distal intestinal obstruction syndrome in cystic fibrosis treated by oral intestinal lavage, and a case of recurrent obstruction despite normal pancreatic function.

An oral intestinal lavage solution has been successfully used in the treatment of six patients with chronic distal intestinal obstruction syndrome (previously referred to as meconium ileus equivalent) complicating cystic fibrosis and a further case of recurrent small bowel obstruction. The patient with recurrent obstruction is unusual in having no evidence of pancreatic maldigestion, which previously has been considered a prerequisite for the syndrome.

Acute Disease↗
PubMed1995

Calcium- and CaMKII-dependent chloride secretion induced by the microsomal Ca(2+)-ATPase inhibitor 2,5-di-(tert-butyl)-1,4-hydroquinone in cystic fibrosis pancreatic epithelial cells.

Microsomal Ca(2+)-ATPase inhibitors such as thapsigargin (THG), cyclopiazonic acid (CPA) and 2,5-di-(tert-butyl)-1,4-hydroquinone (DBHQ) have been shown to inhibit Ca2+ reuptake by the intracellular stores and increase cytosolic free Ca2+ ([Ca2+]i). DBHQ is a commercially available non-toxic synthetic compound chemically unrelated to THG and CPA. In this study, we tested the feasibility of utilizing DBHQ to improve Cl- secretion via the Ca(2+)-dependent pathway, in the cystic fibrosis (CF)-derived pancreatic epithelial cell line CFPAC-1. DBHQ stimulated 125I efflux and mobilized intracellular free Ca2+ in a dose-dependent manner. The maximal effects were seen at concentrations of 25-50 microM. DBHQ (25 microM) caused a short-term rise in [Ca2+]i in the absence of ambient Ca2+, and a sustained elevation of [Ca2+]i in cell monolayers bathed in the efflux solution (1.2 mM Ca2+), which was largely attenuated by Ni2+ (5 mM). Bath-application of DBHQ induced an outwardly-rectifying whole-cell Cl- current, which was abolished by pipette addition of BAPTA (5 mM) or CaMK [273-302] (20 microM), an inhibitory peptide of multifunctional Ca2+/calmodulin-dependent protein kinase (CaMKII). Pretreatment of monolayers of CFPAC-1 cells with DBHQ for 4-5 min significantly increased the Ca(2+)-independent or autonomous activity of CaMKII assayed in the cell homogenates. Thus, DBHQ appears to enhance Cl- channel activity via a Ca(2+)-dependent mechanism involving CaMKII. Pretreatment of CFPAC-1 cells with up to 50 microM DBHQ for 6 h did not cause any detectable change in cell viability and did not significantly affect the cell proliferation rate. These results suggest that appropriate selective microsomal Ca(2+)-ATPase inhibitors may be therapeutically useful in improving Cl- secretion in CF epithelial cells.

Calcium↗
PubMed2003

Functional and molecular properties of Na+:HCO-3 cotransporters (NBC).

The sodium bicarbonate cotransporter (NBC) is located on the basolateral membrane of the kidney proximal tubule and is responsible for the reabsorption of the majority of filtered bicarbonate. In secretory epithelia (such as pancreatic duct) NBC is responsible for the transport of bicarbonate from the blood to the cell for the eventual secretion at the apical membrane. As such and due to its versatility, NBC can function in 2 distinct modes of bicarbonate reabsorption or secretion depending on the epithelia. NBC is also present in a wide variety of non-epithelial tissues where it is mainly involved with cell pH regulation. Recent molecular cloning experiments have identified the existence of 4 NBC isoforms (NBC1, 2, 3 and 4) and 2 NBC-related proteins AE4 and NCBE (anion exchanger 4 and sodium-dependent chloride-bicarbonate exchanger). Except for AE4 which does not transport Na, all are presumed to mediate the cotransport of Na+ and HCO(3)-. NBC isoforms show significant homology to each other and to the AE (anion exchange) family. NBC1 shows a limited tissue expression pattern, is electrogenic and plays an important role in bicarbonate reabsorption in kidney proximal tubule. A variant of NBC1 is expressed in pancreatic duct and gastrointestinal tract, and plays an important role in HCO(3)- secretion. NBC2 and NBC3 have a wider tissue distribution than NBC1, are electroneutral, and are involved with cell pH regulation. The electrogenecity of NBC4 may be variant-specific. An NBC related protein called NCBE mediates Na-dependent, Cl-/bicarbonate ex-change. The purpose of this review is to summarize functional and molecular properties of NBC isoforms and related proteins, and discuss their role and regulation in pathophysiologic states.

Acid-Base Imbalance↗