Roles of ion channels and water channels in the development of chronic pancreatitis

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[Background and aim]Chronic pancreatitis is a progressive inflammatory disease of the pancreas. Cystic Fibrosis Transmembrane conductance Regulator(CFTR)is a cyclic AMP-regulated chloride channel expressed in the apical plasma membrane of human pancreatic duct cells. Recent evidence suggest that mutation(s) in CFTR is one of the risk factors in developing chronic pancreatitis. The aim of this project was to educidate the roles of ion and water channels in the development of chronic pancreatitis.[Methods] (1) Genomic DNA was extracted from the leukocytes of the patients. CFTR mutations was identified by direct sequencing. Each exon fragments were amplified by polymerase chain reaction. (2) Genonic DNA of Guinea-pig was isolated from the small intestine. Fragments of guinea pig CFTR was amplified by PCR and directly sequenced. PCR primer sets were designed based on the consensus sequence among human, rat and mouse CFTR. Interlobular ducts were isoloated from the Guinea pig pancreas and cultured overnight. RNA interference was used to reduce the expression of CFTR in guinea pig interlobular ducts.[Results] (1) In Japanese patient with alcoholic chronic pancreatitis, new mutation in CFTR (L1156F) was identified. L1156F CFTR showed the reduced HCO3- permeability in Xenopus oocytes. (2) Guinea pig CFTR consists of 1481 amino acid residues. Fluid secretary rate in isolated guinea pig pancreatic ducts with CFTR specific RNAi was decreased to half of the rate in control ducts with scrambled RNAi.[Conclusion] These evidence sugget that reduced expression of CFTR due to the mutations or polymorphisms causes the pancreatic ductal dysfunction and might be the cause of chronic pancreatitis in Japanese.