Gastroenterology

Gastroenterology

Volume 119, Issue 1, July 2000, Pages 32-40
Gastroenterology

Alimentary Tract
Residual chloride secretion in intestinal tissue of ΔF508 homozygous twins and siblings with cystic fibrosis,☆☆

https://doi.org/10.1053/gast.2000.8524Get rights and content

Abstract

Background & Aims: Cholinergic stimulation of chloride secretion is impaired in the intestines of patients with cystic fibrosis (CF). However, intestinal chloride secretion has been observed in patients with mild CF mutations. The aim of this study was to investigate residual Cl secretion in the intestine of ΔF508 homozygous CF patients, and examine the contribution of cystic fibrosis transmembrane conductance regulator (CFTR) and alternative Cl conductances. Twins and siblings with identical CFTR genotypes were investigated to determine the impact of factors other than CFTR on chloride secretion. Methods: Chloride secretion in rectal tissue was investigated by applying Ca2+ and adenosine 3',5'-cyclic monophosphate (cAMP)-linked agonists before and after the inhibition of alternative Cl conductances with 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). Results: cAMP-mediated Cl secretion was observed in 73% of patients, and 20% showed DIDS-sensitive Ca2+-activated Cl secretion. This DIDS-sensitive alternative chloride conductance was seen only in CF patients who also responded to cAMP agonists. Chloride secretion was more concordant within monozygous twins than within dizygous pairs. Conclusions: These results suggest the presence of CFTR-mediated Cl secretion in a subgroup of patients, implying that a portion of ΔF508 CFTR can be processed in vivo and function as a chloride channel in the apical membrane of intestinal cells. Moreover, a considerable number of ΔF508 homozygous patients express chloride conductances other than CFTR in their intestinal epithelia.

GASTROENTEROLOGY 2000;119:32-40

Section snippets

Subjects

Twin and sibling pairs with CF with different genotypes were enrolled for the European Cystic Fibrosis Twin and Sibling Study. For the study described here, only subjects homozygous for the CFTR gene mutation ΔF508 were selected. We invited 72 patients belonging to dizygous twin or sibling pairs and 26 patients belonging to monozygous twin pairs. Patients were investigated in or near their home countries at selected CF core centers in Hannover, Innsbruck, London, Rotterdam, and Verona.

Chloride-secretory response in CF intestine

Of the participating patients belonging to a sibling or dizygous twin pair, 49 responses to 8-bromo-cAMP + forskolin, 56 to carbachol, and 41 to histamine could be determined. Eighteen 8-bromo-cAMP + forskolin, 20 carbachol, and 14 histamine responses from participating patients of monozygous twin pairs were collected. The mean basal transepithelial resistance of the rectal biopsy specimens of our group of ΔF508 homozygous CF patients was 27 Ω·cm2. The mean basal Isc was 20 μA/cm2.

Patients for

Discussion

This study investigated the presence and frequency of chloride-secretory responses in the rectal tissue of ΔF508 homozygous CF twins and siblings upon stimulation with cAMP- and Ca2+-linked agonists, before and after incubation of the tissue with DIDS. Forty (73%) of the ΔF508 homozygotes expressed a cAMP-stimulated chloride-secretory response in their intestinal tissue. Because cAMP-regulated chloride conductance is indicative of CFTR,2, 3, 27 this finding suggests the presence of some active

Acknowledgements

The authors thank the collaborating patients, parents, physicians and scientists for their cooperation, particularly H. Ellemunter (Innsbruck), G. Mastella (Verona), S. Thomas (London), J. Versloot, H. Otten, and R. Samlal-Soedhoe (The Netherlands).

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    Address requests for reprints to: Inez Bronsveld, Laboratory of Pediatrics, rm Ee-1500, Erasmus University Rotterdam, P.O. Box 1738, 3000 Rotterdam, The Netherlands. e-mail: [email protected]; fax: (31) 20-8706751.

    ☆☆

    This work was executed as part of the European Cystic Fibrosis Twin and Sibling Study and supported by the BIOMED II program of the EU, the Deutsche Forschungsgemeinschaft, the Deutsche Fördergesellschaft für die Mukoviszidoseforschung eV, and the Mukoviszidose eV.

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