Residual chloride secretion in intestinal tissue of ΔF508 homozygous twins and siblings with cystic fibrosis

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 Delta F508 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 Delta F508 CFTR can be processed in vivo and function as a chloride channel in the apical membrane of intestinal cells. Moreover, a considerable number of Delta F508 homozygous patients express chloride conductances other than CFTR in their intestinal epithelia.