Abstract
In the present study, we have investigated the possible consequences of the chloride channel defect in the intestine of cystic fibrosis (CF) patients for electrolyte and water transport in the jejunum in vivo, using a multilumen, double occluding balloon catheter, and an Ag/AgCl intraluminal electrode. During a chloride-free perfusion, to optimize the sensitivity of our measurements, the transmural potential difference (PD) (lumen with reference to serosal side) was found to be significantly higher in the jejunum of CF patients (+8.0 ± 2.1 mV; n = 5) than in healthy control subjects (-2.2 ± 2.0 mV; n = 9). The chloride concentration measured in chloride-free jejunal perfusates of CF patients was significantly lower than in controls (10.9 ± 2.3 and 41.4 ± 8.2 mM, respectively). Possible differences in net chloride and water secretion did not reach statistical significance (chloride secretion controls: -2.1 ± 0.9 mmol/10 cm/h; CF: -0.8 ± 0.2 mmol/10 cm/h; water secretion controls: -0.8 ± 2.5 mL/10 cm/h; CF: -11.7 ± 8.9 mL/10 cm/h). In control subjects, intraluminally applied theophylline stimulated the secretion of water (Δ23.4 ± 4.6 mL/10 cm/h) and chloride (Δ4.1± 1.1 mmol/10 cm/h), but not in CF patients (respectively Δ3.6± 3.3 mL/10 cm/h and Δ1.1 ± 1.1 mmol/10 cm/h). In controls, theophylline caused a significant increase in lumen negativity (PD-10.2 ± 2.6 mV), but no change could be seen in CF patient transmural PD. These observations provide in vivo evidence for a decreased chloride permeability in the jejunum in CF, resulting in a significant reduction in net electrolyte and water secretion in the presence, but not in the absence, of an intestinal secretagogue.
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Main
Intestinal manifestations of CF-the most frequent autosomal recessive inherited disease with a lethal course among Caucasians(1)-can be subdivided into two major groups, characterized by a malabsorptive status(2, 3) and obstructive symptoms(3, 4), respectively. The earliest sign of CF is meconium ileus(1). In 3% of the patients distal intestinal obstruction is a recurrent problem(5).
Malabsorption is in part related to the exocrine pancreatic dysfunction(1), which itself can partly be corrected with enzyme supplementation(6, 7). An intestinal mucosal component of the malabsorption(8) has been deduced from manifest resorptive disorders, as steatorrhea and fecal bile acid excretion remain features of this disease in spite of optimal therapeutic intervention(9). Supplementation of pancreatic enzymes cannot prevent this complication in later life in most patients. This indirect evidence supports the hypothesis that exocrine pancreatic insufficiency is not the single cause of intestinal malabsorption. In vitro studies(9) also support the assumption that a disturbed intestinal chloride secretion is involved in dehydrating the intestinal lumen, which can lead to obstruction and an altered uptake of nutrients.
Obstruction, caused by viscous mucus, is considered to be related to the primary defect in CF(10). This defect is characterized by the inability to perform cAMP-regulated chloride transport across epithelial membranes and is caused by a defective processing or functioning of the mutated CF gene product, the CFTR-chloride channel(11, 12). Enhanced absorption of water and electrolytes(13) by the intestinal villi may also contribute to the abnormal viscosity of the mucous layer in the CF intestine. The viscous mucous layer adjacent to the intestinal wall may affect the absorption of nutrients. Furthermore, it could delay the transit time of the small intestine or even support bacterial overgrowth(14). In this way both malabsorption and obstruction may be interrelated. It is therefore apparent that mucosal chloride secretion is important in maintaining a normal function of the intestine.
The CF defect in intestinal chloride secretion has so far been investigated mainly in vitro, by electrophysiologic measurements in the Ussing chamber(13, 15–18). In vivo measurements of intestinal transport abnormalities in CF patients have been confined to PD measurements in the human rectum(19), colon(20, 21), and jejunum(22). However, the consequences of the CFTR defect for net transport rates of electrolytes and water in the intestinein vivo has not been addressed previously. Considering the paucity of in vivo data on the abnormalities in electrolyte and water transport in the small intestine of CF patients, we thought it important to investigate whether or not the general model of transport dysregulation in CF cells in vitro is indeed applicable to the in vivo situation. In this report we describe the results of water and chloride transport measurements in control and CF jejunum in vivo, in the absence and presence of the secretagogue theophylline (a phosphodiesterase inhibitor). Transmural PD measurements were applied to monitor possible differences in electrogenic ion transport between controls and CF patients. Chloride-free perfusates were used to allow more sensitive measurements of the chloride transport disturbances(23).
METHODS
Chemicals. All chemicals were purchased from Sigma Chemical Co.(St. Louis, MO), except for phenol red, which was obtained from Merck(Darmstadt, Germany). Saline was supplied by Lansberg Medical Supplies (Uden, The Netherlands).
Subjects. None of the control subjects (n = 9) had suffered recently from gastrointestinal problems or had a medical history. Family histories for CF were negative. All CF patients (n = 5) were homozygous for the dF508 mutation. The CF participants used pancreatic enzyme supplementation. Medication was discontinued 12 h prior to the experiments. Mean age of the participants was 22 y in controls (range 20-26), and 20 y in the CF group (range 16-28). All subjects observed an 8-h fasting period before participation.
Procedures. A multilumen, double-occluding balloon catheter was positioned in the proximal jejunum (the 10-cm test segment between both balloons was located distally to the ligament of Treitz) under fluoroscopic guidance. The catheter contained a Ag/AgCl(24) lumen electrode. A reference electrode was connected to the s.c. tissue by means of a saline bridge and a 22-gauge i.v. cannula. PD values were registered on a standard Yew recorder after 10-fold amplification. PD measurements were used as an indicator of electrogenic transport, i.e. a rise in lumen negativity being taken as evidence for increased anion secretion or decreased cation absorption. A separate nasogastric tube (Argyle Salem sump tube Ch 12, Sherwood Medical Co., St. Louis, MO) was used to drain gastric contents. Both balloons on the jejunal catheter were inflated by hand with 30-40 mL of air, guided by the comfort of the subjects. Phenol red (50 mg/L saline) was used to visualize any leakage across the proximal occluding balloon. The test segment was rinsed at 10 mL/min (Hospal-K infusion pumps) with a chloride-free perfusion PBG, until a stable baseline PD was recorded. The perfusion solution contained Na+ 130 mM, gluconate 100 mM, phosphate 10 mM, and mannitol 50 mM. Polyethylene glycol 4000 was added as a nonabsorbable volume marker (1 g/L). Osmolarity was kept at 300 mosmol/L by adjusting the concentration of mannitol. pH was set at 7.4. All perfusion solutions were used at 37 °C. The chloride-free perfusate was used to obtain a higher degree of sensitivity for our chloride transport and PD measurements. The test segment was rinsed first by continuous infusion of perfusate, until a stable PD recording was obtained and samples were optically clear. After such steady state conditions were reached, the effect of theophylline (20 mM) on intestinal ion and water transport was studied during 30-min test periods. Samples (2 mL) were obtained at a 30-min interval (t = 5 and 35 min) by hand drainage.
Calculations. Ion and water transport rates were calculated according to standard equations as described by Fordtran et al.(25). All values are noted as mean ± SEM, for nine control subjects and five CF patients. Calculations were performed with values obtained from duplicate measurements from multiple samples obtained during the observation periods. PD changes were expressed as deviations in millivolts, corrected for drift and offset. A negative sign denotes lumen negativity, when referring to PD measurements, and secretion when referring to water and ion transport. Only final (calculated) values are given for water and ion transport as well as PD measurements. Δ Refers to the calculated change of the corresponding final values.
Analysis. Polyethylene glycol 4000 was determined according to Hyden(26). Phenol red concentration was measured as described by George(27). Sodium and potassium concentrations were determined using an ASTRA-4 Beckmann automat stat routine analyzer, and chloride concentrations were measured with a Corning chloride analyzer. Bicarbonate concentration and pH were measured with an Instrumentation Laboratory OSM3 hemoxymeter.
Serum theophylline concentrations were determined by a HPLC procedure as described elsewhere(28).
Statistics. All values are expressed as mean ± SEM. Mann-Whitney tests were applied to evaluate the results.
Informed consent. The experimental protocol was approved by the University Hospital Medical Ethical Committee. All participants gave their written informed consent.
Theophylline administration. Theophylline was administrated intraluminally in a dosage chosen to obtain a high local (intestinal) concentration, as well as a serum level below the therapeutical range of 20 mg/L. Venous blood samples, obtained from both controls and CF patients 30-45 min after intestinal theophylline administration, averaged, respectively, 7.8± 3.0 and 5.0 ± 2.8 mg/L. These values did not differ significantly.
RESULTS
Jejunal PD Measurements
Basal transport. Perfusion with PBG resulted in a lumen negative PD of -2.2 ± 2.0 mV in controls, and a lumen positive PD of+8.0 ± 2.1 mV in CF patients. This difference is significant atp < 0.005. All further values were compared with these baseline PD values.
Theophylline stimulated transport. In controls, the addition of 20 mM theophylline to the perfusate gave rise to a significant (p< 0.005) drop in PD of -10.2 ± 2.6 mV, whereas the administration of theophylline in CF patients did not affect the PD signal(Figs. 1 and2).
Jejunal Water Transport
Basal transport. In controls, under basal conditions, the small intestinal segment displayed a low rate of net water secretion when perfused with PBG (-0.8 ± 2.5 mL/10 cm/h). CF patients secreted a higher amount of water (-11.7 ± 8.9 mL/10 cm/h), but these values were not statistically different.
Theophylline-stimulated transport. In controls, theophylline induced an increase in water secretion (Δ23.4 ± 4.6 mL/10 cm/h). Compared with the unstimulated water secretion, this increase is significant at p < 0.01. In contrast, administration of theophylline in CF patients did not have a significant effect on water transport (Δ3.6± 3.3 mL/10 cm/h). The change in water transport caused by theophylline in controls compared with CF patients is significant at p < 0.01(Fig. 3).
Electrolyte Transport
Chloride ion concentration. The chloride concentration, accumulated in the perfusate during a 30-min perfusion period, showed a striking difference between controls and CF patients (significant atp < 0.01) before and after theophylline administration. Basal chloride concentration values were: for controls 41.4 ± 8.2 mM and for CF patients 10.9 ± 2.3 mM. Theophylline administration increased the concentration to 59.4 ± 6.2 mM in controls (significant at p< 0.05) but not in CF patients (12.1 ± 2.3 mM)(Fig. 4).
Basal electrolyte transport. During perfusion with the chloride-free solution, there was no significant net transport of sodium (-1.4± 0.8 mmol/10 cm/h) in the control intestine. Sodium transport in the CF small intestine was similar to controls (-1.3 ± 1.3 mmol/10 cm/h). Chloride transport under basal conditions was -2.1 ± 0.9 mmol/10 cm/h in controls, and -0.8 ± 0.2 mmol/10 cm/h in the CF small intestine. Basal potassium and bicarbonate ion transport amounted to -0.2 ± 0.1 mmol/10 cm/h and -0.1 ± 0.1 mmol/10 cm/h in controls, and -0.2 ± 0.1 mmol/10 cm/h and -0.3 ± 0.1 mmol/10 cm/h in CF patients, respectively.
Theophylline-stimulated electrolyte transport. After the addition of theophylline (20 mM), controls showed a significantly increased sodium secretion (Δ3.1 ± 0.8 mmol/10 cm/h), and an increased chloride secretion (Δ4.1 ± 1.1 mmol/10 cm/h; p < 0.05). In CF patients, neither sodium transport (Δ0.4 ± 1.1 mmol/10 cm/h) nor chloride transport (Δ1.1 ± 1.1 mmol/10 cm/h) was significantly altered. Neither controls nor CF patients showed a change in secretion of potassium. Furthermore, the changes in transport of bicarbonate in CF patients were not significant (Δ0.1 ± 0.1 mmol/10 cm/h), whereas in controls a slight but significant increase in bicarbonate secretion was found (Δ0.2 ± 0.1 mmol/10 cm/h; p < 0.05;Figs. 5 and6).
DISCUSSION
Morbidity and mortality in CF are due mostly to pulmonary problems(1). In general, malabsorption has a negative influence on the course of the disease(29). With improving therapeutical interventions, and increased insights into the mechanism underlying the disease, mean life span (now approximately 25 y in The Netherlands) is expected to increase. In turn, this will result in manifestations of a different spectrum of symptoms in CF patients. Amelioration of the malabsorption will become more and more prominent. Because this symptom can be ascribed only in part to the exocrine pancreatic dysfunction(6, 7), an intrinsic enterocyte malfunction(8, 9) or the influence of abnormally viscous intestinal mucus must be considered(15, 30).
The altered state of epithelial water and electrolyte transport may result in increased viscosity of the mucus, which in itself may be responsible for a delayed small intestinal transit time, and a diminished uptake profile of nutrients from the intestinal lumen(31–34). A higher viscosity of mucus in the jejunum of the CF patients was strongly suggested by our observations that the perfusion catheter became obstructed by mucus plugging toward the end of the experimental procedures in all CF patients, but only in one control subject.
Our study was designed to document water and electrolyte secretionin vivo before, and during, a rise in cAMP concentration induced by the phosphodiesterase inhibitor theophylline (20 mM), using a multilumen, double-occluding balloon catheter. Both control and CF jejunum were perfused with a chloride-free solution to accentuate possible difference in chloride secretion. We believe that the PD measurement is a more sensitive and direct technique for monitoring possible differences in electrogenic ion transport between controls and CF patients than is the measurement of basal rates of ion transport which, under nonshort circuit conditions, mainly reflect electroneutral rather than electrogenic transport. The major mechanism contributing to the difference in PD is likely to be the exit of chloride ions through the CFTR-Cl- channel, but indirect effects of the CF condition on paracellular ion movements cannot be ruled out completely.
The results showed no significant difference in basal water and electrolyte transport between the control and the CF jejunum, possibly as a consequence of the considerable variability in individual baseline values. The recorded difference in baseline PD between control and CF jejunum, however, indicates that at least a portion of the CFTR-chloride channels in the control jejunum is in the open state under basal conditions, presumably due to a tonus of endogenous cAMP-linked secretagogues in this tissue, e.g. vasoactive intestinal peptide and prostaglandins(35, 36).
Theophylline induced secretion of water, chloride, sodium, and bicarbonate ions in controls, but not in CF patients. Because serum theophylline concentrations in our controls and CF patients were similar, the lack of resorption of theophylline, through the mucoid contents of the jejunum, could be ruled out as an explanation for the observed differences. Presumably chloride secretion is stimulated through the inhibitory effect of theophylline on phosphodiesterase, and the consequent rise of intracellular cAMP levels. cAMP activates CFTR and causes the increase in transport of chloride ions. The rise in sodium concentration in the test segment is most likely caused by a concomitant isotonic secretion of sodium with chloride across the leaky epithelium of the jejunum(25), as well as by a decreased resorption of sodium due to the inhibition of a Na+/H+ exchange system by theophylline(37). The increase in water secretion most likely results from this isotonic transport as well. In the CF intestine, both the cAMP-induced secretion of chloride through the (defective) CFTR-chloride channel and the parallel secretion of sodium are disturbed. One explanation for the lack of theophylline effects on sodium transport in the CF jejunum could be that the theophylline-sensitive Na+/H+ antiporter no longer contributes significantly to transepithelial sodium movement in the absence of theophylline, at least not under virtually chloride-free conditions (PBG medium, lack of chloride, and bicarbonate accumulation) in the CF intestine. Provided that a certain minimal level of luminal chloride or bicarbonate ions would be required to allow sodium ion transport by the Na+/H+ antiporter, the contribution of this theophylline-inhibitable pathway for sodium absorption is expected to be much lower in CF jejunum compared with that of controls, perhaps explaining the loss of theophylline sensitivity of sodium absorption.
Alternatively, the loss of theophylline sensitivity of sodium absorption may indicate that the intestinal Na+/H+ antiporter is no longer inhibitable by theophylline/cAMP under CF conditions(38), implying that wild type CFTR may play an additional role in salt absorption. The latter interpretation would also offer a plausible explanation for the enhanced absorption of electrolytes by intestinal villi in CF intestine measured in Ussing chambers(13). The increase of absorption most likely is caused by the loss of cAMP inhibition of electroneutral sodium absorption through Na+/H+ exchange (because electrogenic sodium channels are not expressed in human small intestine)(38), and thus is not expected to generate a shift in PD. The possible role of CFTR in electroneutral sodium absorption is in line with recent observations by O'Loughlin et al.(39), showing evidence for CFTR expression and CFTR-related changes in intracellular ion concentrations in villi of resected human jejunum.
Interestingly, controls showed a small but significant increase in bicarbonate ion transport in response to theophylline. The lack of increase in bicarbonate ion transport after application of theophylline in the CF jejunum may therefore also indicate that, in this tissue, this ion, at least, exits the epithelial cell partially through the CFTR-chloride channel, as was recently demonstrated in pulmonary tissue(40, 42).
Summarizing our data, we were unable to stimulate water or chloride ion secretion in the CF jejunum. The increase in lumen negativity in the jejunum, indicative mainly of chloride secretion, was absent in CF patients. This supports the hypothesis that in CF jejunum chloride transport is diminished, due to the defective incorporation of CFTR in the enterocyte mucosal membrane. Our study also provides some evidence for the transport of negatively charged ions (bicarbonate), other than chloride alone through the CFTR-chloride channel(40, 42). Considering the clear difference in theophylline effects on in vivo ion and water transport in the intestine of control and dF508 CF homozygotes, the perfusion technique described offers a promising tool for verifying one possible explanation for the “heterozygote advantage” in dF508 carriers, i.e. the hypothesis that a partial depletion of CFTR offers protection against severe loss of salt and water as occurs in secretory diarrhea, including cholera(41–44).
Abbreviations
- CF:
-
cystic fibrosis
- CFTR:
-
cystic fibrosis transmembrane conductance regulator
- PBG:
-
phosphate-buffered gluconate solution
- PD:
-
potential difference
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Acknowledgements
Dr. D. J. J. Halley of the Department of Clinical Genetics, Erasmus University, Rotterdam, provided data on the genetic status of the CF patients. Dr. S. E. Overbeek and Dr. E. C. Groeninx van Zoelen, Department of Respiratory Diseases, University Hospital Rotterdam/Dijkzigt Hospital, aided this study by motivating the CF patients. We thank Dr. M. Meradji and Dr. S. G. F. Robben, Department of Radiology, Sophia Childrens Hospital, for their help with the positioning of the catheters. We are indebted to all participating CF patients and control subjects.
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Supported in part by the Dutch Liver Gut Foundation.
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Teune, T., Timmers-Reker, A., Bouquet, J. et al. In Vivo Measurement of Chloride and Water Secretion in the Jejunum of Cystic Fibrosis Patients. Pediatr Res 40, 522–527 (1996). https://doi.org/10.1203/00006450-199610000-00002
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DOI: https://doi.org/10.1203/00006450-199610000-00002