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1 Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; CURE: Digestive Diseases Research Center, Los Angeles, CA, USA; Brentwood Biomedical Research Institute, Los Angeles, CA, USA
2 Department of Chemistry, University of California Los Angeles, Los Angeles, CA, USA
3 Greater Los Angeles Veterans Affairs Healthcare System, University of California Los Angeles, Los Angeles, CA, USA; Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; CURE: Digestive Diseases Research Center, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: jake{at}ucla.edu.
The cystic fibrosis transmembrane conductance regulator (CFTR) plays a crucial role in mediating duodenal HCO3 - secretion (DBS). Although impaired DBS is observed in CF mutant mice and in CF patients, which would predict increased ulcer susceptibility, duodenal injury is rarely observed in CF patients, and is reduced in CF mutant mice. To explain this apparent paradox, we have hypothesized that CFTR dysfunction increases cellular [HCO3 -] and buffering power. To further test this hypothesis, we have examined the effect of a novel, potent, highly selective CFTR inhibitor, CFTRinh-172, on DBS and duodenal ulceration in rats. DBS was measured in situ using a standard loop perfusion model with a pH stat under isoflurane anesthesia. Duodenal ulcers were induced in rats by cysteamine with or without CFTRinh-172 pre-treatment 1hr before cysteamine. Superfusion of CFTRinh-172 (0.1-10 µM) over the duodenal mucosa had no effect on basal DBS, but at 10 µM inhibited acid-induced DBS, suggesting that its effect was limited to CFTR activation. Acid-induced DBS was abolished at 1 and 3 hr and was reduced 24 hr after treatment with CFTRinh-172, although basal DBS was increased at 24 hr. CFTRinh-172 treatment had no effect on gastric acid or HCO3 - secretion. Duodenal ulcers were observed 24 hr after cysteamine treatment, but were reduced in CFTRinh-172-pretreated rats. CFTRinh-172 acutely produces CFTR dysfunction in rodents for up to 24 hr. CFTR inhibition reduces acid-induced DBS, but also prevents duodenal ulcer formation, supporting our hypothesis that intracellular HCO3 - may be an important protective mechanism for duodenal epithelial cells.
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