Roles of CFTR chloride channel in the pathogenesis of chronic pancreatitis

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1. We have investigated whether mutations of the CFTR (cystic fibrosis transmembrane conductance regulator) gene are related to chronic pancreatitis in Japanese.2. To estimate the function of CFTR, we established a simple and non-invasive method to measure Cl^- concentrations in the sweat. Of 25 patients with chronic pancreatitis, 56% had sweat Cl^- levels over 60 mmol/L, a level consistent with the diagnosis of cystic fibrosis. This suggests that the impaired CFTR function underlies about a half of chronic pancreatitis in Japanese.3. None of 20 major mutations in Caucasians were found in healthy subjects and patients with chronic pancreatitis. Polymorphisms at the junction of intron8 and exon9 (TG) repeats were unique to Japanese, which may explain CFTR dysfunction in patients with chronic pancreatitis.4. To investigate the secretory mechanism of HCO_3^- from pancreatic duct cells, we have measured intracellular concentrations of HCO_3^- and Cl^- and membrane potential in interlobular ducts isolated from guinea-pig pancreas. We proposed a new model ; (a) when the luminal HCO_3^- concentration is below-70 mM, HCO_3^- secretion is supported by Cl^--HCO_3^- exchange and (b) when the luminal HCO_3^- concentration is higher than 70 mM, it is mediated by a HCO_3^- conductance, most likely CFTR.5. CFTR and SLC26 family of transporters were co-expressed in Xenopus oocytes or HEK (Human Embryonic Kidney) 293 cells. We found that the SLC26 transporters work as electrogenic Cl^-HCO_3^- exchangers and are regulated by CFTR.6. RT-PCR analysis of isolated ducts from rat pancreas revealed the expression of AQP1 in pancreatic duct cells. The osmotic water permeability of the ductal epithelium was reduced by either basolateral or luminal. application of HgCl_2. AQP1 of the known water channels appears to be the main water pathway in pancreatic ductal epithelium. Immunohistochemistry revealed heterogeneous expression of AQP1 in rat duct cells.