Skip to main content

CFTR: A New Horizon in the Pathomechanism and Treatment of Pancreatitis

  • Chapter
  • First Online:
Reviews of Physiology, Biochemistry and Pharmacology Vol. 170

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that conducts chloride and bicarbonate ions across epithelial cell membranes. Mutations in the CFTR gene diminish the ion channel function and lead to impaired epithelial fluid transport in multiple organs such as the lung and the pancreas resulting in cystic fibrosis. Heterozygous carriers of CFTR mutations do not develop cystic fibrosis but exhibit increased risk for pancreatitis and associated pancreatic damage characterized by elevated mucus levels, fibrosis, and cyst formation. Importantly, recent studies demonstrated that pancreatitis causing insults, such as alcohol, smoking, or bile acids, strongly inhibit CFTR function. Furthermore, human studies showed reduced levels of CFTR expression and function in all forms of pancreatitis. These findings indicate that impairment of CFTR is critical in the development of pancreatitis; therefore, correcting CFTR function could be the first specific therapy in pancreatitis. In this review, we summarize recent advances in the field and discuss new possibilities for the treatment of pancreatitis.

Conflict of Interest Statement: The authors have no conflict of interest to declare.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Abu-El-Haija M et al (2012) Pancreatic damage in fetal and newborn cystic fibrosis pigs involves the activation of inflammatory and remodeling pathways. Am J Pathol 181(2):499–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allen-Mersh TG (1985) What is the significance of pancreatic ductal mucinous hyperplasia? Gut 26(8):825–833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alton EW et al (2015) Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med 3(9):684–691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andersen DH (1938) Cystic fibrosis of the pancreas and its relation to celiac disease: clinical and pathological study. Am J Dis Child 56:344–399

    Article  Google Scholar 

  • Apaja PM, Lukacs GL (2014) Protein homeostasis at the plasma membrane. Physiology (Bethesda) 29(4):265–277

    CAS  Google Scholar 

  • Arduino C et al (1999) Polyvariant mutant CFTR genes in patients with chronic pancreatitis. Clin Genet 56(5):400–404

    Article  CAS  PubMed  Google Scholar 

  • Bagheri-Hanson A et al (2014) Intestinal current measurement versus nasal potential difference measurements for diagnosis of cystic fibrosis: a case–control study. BMC Pulm Med 14:156

    Article  PubMed  PubMed Central  Google Scholar 

  • Baker JM et al (2007) CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices. Nat Struct Mol Biol 14(8):738–745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balch WE,Roth DM, Hutt DM, (2011) Emergent properties of proteostasis in managing cystic fibrosis. Cold Spring Harb Perspect Biol 3(2). 10.1101/cshperspect.a004499

    Google Scholar 

  • Bedwell DM et al (1997) Suppression of a CFTR premature stop mutation in a bronchial epithelial cell line. Nat Med 3(11):1280–1284

    Article  CAS  PubMed  Google Scholar 

  • Bertin C et al (2012) Pancreas divisum is not a cause of pancreatitis by itself but acts as a partner of genetic mutations. Am J Gastroenterol 107(2):311–317

    Article  CAS  PubMed  Google Scholar 

  • Bishop MD et al (2005) The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis. Hum Genet 118(3-4):372–381

    Article  CAS  PubMed  Google Scholar 

  • Bomberger JM, Barnaby RL, Stanton BA (2009) The deubiquitinating enzyme USP10 regulates the post-endocytic sorting of cystic fibrosis transmembrane conductance regulator in airway epithelial cells. J Biol Chem 284(28):18778–18789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheung JC et al (2008) Molecular basis for the ATPase activity of CFTR. Arch Biochem Biophys 476(1):95–100

    Article  CAS  PubMed  Google Scholar 

  • Chong PA et al (2013) Dynamics intrinsic to cystic fibrosis transmembrane conductance regulator function and stability. Cold Spring Harb Perspect Med 3(3):a009522

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chu CS et al (1993) Genetic basis of variable exon 9 skipping in cystic fibrosis transmembrane conductance regulator mRNA. Nat Genet 3(2):151–156

    Article  CAS  PubMed  Google Scholar 

  • Clancy JP et al (2001) Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis. Am J Respir Crit Care Med 163(7):1683–1692

    Article  CAS  PubMed  Google Scholar 

  • Clarke LL et al (1992) Defective epithelial chloride transport in a gene-targeted mouse model of cystic fibrosis. Science 257(5073):1125–1128

    Article  CAS  PubMed  Google Scholar 

  • Clunes LA et al (2012) Cigarette smoke exposure induces CFTR internalization and insolubility, leading to airway surface liquid dehydration. FASEB J 26(2):533–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS (1998) Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 339:653–658

    Article  CAS  PubMed  Google Scholar 

  • Cohn JA et al (2005) Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. Hum Mutat 26(4):303–307

    Article  CAS  PubMed  Google Scholar 

  • Criddle DN et al (2004) Ethanol toxicity in pancreatic acinar cells: mediation by nonoxidative fatty acid metabolites. Proc Natl Acad Sci U S A 101(29):10738–10743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Criddle DN et al (2006) Fatty acid ethyl esters cause pancreatic calcium toxicity via inositol trisphosphate receptors and loss of ATP synthesis. Gastroenterology 130(3):781–793

    Article  CAS  PubMed  Google Scholar 

  • Cuppens H et al (1998) Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation. J Clin Invest 101(2):487–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Boeck K et al (2005) Pancreatitis among patients with cystic fibrosis: correlation with pancreatic status and genotype. Pediatrics 115(4):e463–e469

    Article  PubMed  Google Scholar 

  • De Boeck K et al (2014) Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros 13(6):674–680

    Article  PubMed  CAS  Google Scholar 

  • DiMagno MJ et al (2005) A proinflammatory, antiapoptotic phenotype underlies the susceptibility to acute pancreatitis in cystic fibrosis transmembrane regulator (-/-) mice. Gastroenterology 129(2):665–681

    Article  PubMed  Google Scholar 

  • DiMagno MJ et al (2010) Inhibition of acinar apoptosis occurs during acute pancreatitis in the human homologue DeltaF508 cystic fibrosis mouse. Am J Physiol Gastrointest Liver Physiol 299(2):G400–G412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du K, Lukacs GL (2009) Cooperative assembly and misfolding of CFTR domains in vivo. Mol Biol Cell 20(7):1903–1915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du M et al (2008) PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Proc Natl Acad Sci U S A 105(6):2064–2069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Durno C et al (2002) Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. Gastroenterology 123(6):1857–1864

    Article  PubMed  Google Scholar 

  • Farinha CM, Matos P, Amaral MD (2013) Control of cystic fibrosis transmembrane conductance regulator membrane trafficking: not just from the endoplasmic reticulum to the Golgi. FEBS J 280(18):4396–4406

    Article  CAS  PubMed  Google Scholar 

  • Gadsby DC, Vergani P, Csanady L (2006) The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature 440(7083):477–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerasimenko JV et al (2013) Ca2+ release-activated Ca2+ channel blockade as a potential tool in antipancreatitis therapy. Proc Natl Acad Sci U S A 110(32):13186–13191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gould NS et al (2012) CFTR is the primary known apical glutathione transporter involved in cigarette smoke-induced adaptive responses in the lung. Free Radic Biol Med 52(7):1201–1206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gray MA et al (1994) CFTR and calcium-activated chloride currents in pancreatic duct cells of a transgenic CF mouse. Am J Physiol 266(1 Pt 1):C213–C221

    CAS  PubMed  Google Scholar 

  • Groman JD et al (2004) Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign. Am J Hum Genet 74(1):176–179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hassan F et al (2014) Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels. Respir Res 15:69

    Article  PubMed  PubMed Central  Google Scholar 

  • He L et al (2008) Multiple membrane-cytoplasmic domain contacts in the cystic fibrosis transmembrane conductance regulator (CFTR) mediate regulation of channel gating. J Biol Chem 283(39):26383–26390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hegyi P, Petersen OH (2013) The exocrine pancreas: the acinar-ductal tango in physiology and pathophysiology. Rev Physiol Biochem Pharmacol 165:1–30

    CAS  PubMed  Google Scholar 

  • Hermann T (2007) Aminoglycoside antibiotics: old drugs and new therapeutic approaches. Cell Mol Life Sci 64(14):1841–1852

    Article  CAS  PubMed  Google Scholar 

  • Howard M, Frizzell RA, Bedwell DM (1996) Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med 2(4):467–469

    Article  CAS  PubMed  Google Scholar 

  • Huang W et al (2014) Fatty acid ethyl ester synthase inhibition ameliorates ethanol-induced Ca2+-dependent mitochondrial dysfunction and acute pancreatitis. Gut 63(8):1313–1324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hwang TC, Sheppard DN (2009) Gating of the CFTR Cl-channel by ATP-driven nucleotide-binding domain dimerisation. J Physiol 587(Pt 10):2151–2161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ignáth I et al (2009) CFTR expression but not Cl-transport is involved in the stimulatory effect of bile acids on apical Cl-/HCO3-exchange activity in human pancreatic duct cells. Pancreas 38(8):921–929

    Article  PubMed  CAS  Google Scholar 

  • Judák L et al (2014) Ethanol and its non-oxidative metabolites profoundly inhibit CFTR function in pancreatic epithelial cells which is prevented by ATP supplementation. Pflugers Arch 466(3):549–562

    Article  PubMed  CAS  Google Scholar 

  • Kadiyala V et al (2013) Cigarette smoking impairs pancreatic duct cell bicarbonate secretion. JOP 14(1):31–38

    PubMed  PubMed Central  Google Scholar 

  • Kerem B, Chiba-Falek O, Kerem E (1997) Cystic fibrosis in Jews: frequency and mutation distribution. Genet Test 1(1):35–39

    CAS  PubMed  Google Scholar 

  • Kerem E et al (2008) Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 372(9640):719–727

    Article  CAS  PubMed  Google Scholar 

  • Kerem E et al (2014) Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med 2(7):539–547

    Article  CAS  PubMed  Google Scholar 

  • Kim SJ, Skach WR (2012) Mechanisms of CFTR folding at the endoplasmic reticulum. Front Pharmacol 3:201

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ko SB et al (2010) Corticosteroids correct aberrant CFTR localization in the duct and regenerate acinar cells in autoimmune pancreatitis. Gastroenterology 138(5):1988–1996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ko SB et al (2012) Molecular mechanisms of pancreatic stone formation in chronic pancreatitis. Front Physiol 3:415

    Article  PubMed  PubMed Central  Google Scholar 

  • Kopelman H et al (1985) Pancreatic fluid secretion and protein hyperconcentration in cystic fibrosis. N Engl J Med 312(6):329–334

    Article  CAS  PubMed  Google Scholar 

  • Kristidis P et al (1992) Genetic determination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet 50(6):1178–1184

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lambert JA et al (2014) Cystic fibrosis transmembrane conductance regulator activation by roflumilast contributes to therapeutic benefit in chronic bronchitis. Am J Respir Cell Mol Biol 50(3):549–558

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • LaRusch J et al (2014) Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet 10(7), e1004376

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lee MG et al (2012) Molecular mechanism of pancreatic and salivary gland fluid and HCO3 secretion. Physiol Rev 92(1):39–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Linde L et al (2007) Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin. J Clin Invest 117(3):683–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lukacs GL, Verkman AS (2012) CFTR: folding, misfolding and correcting the DeltaF508 conformational defect. Trends Mol Med 18(2):81–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maléth J et al (2011) Non-conjugated chenodeoxycholate induces severe mitochondrial damage and inhibits bicarbonate transport in pancreatic duct cells. Gut 60(1):136–138

    Article  PubMed  Google Scholar 

  • Maléth J et al (2015) Alcohol disrupts levels and function of the cystic fibrosis transmembrane conductance regulator to promote development of pancreatitis. Gastroenterology 148(2):427–439, e16

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Masson E et al (2013) A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One 8(8), e73522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinez B, Heller M, Gaitch N, Hubert D, Burgel PR, Levy P, Girodon E, Bienvenu T (2014) p.Arg75Gln, a CFTR variant involved in the risk of CFTR-related disorders? J Hum Genet 59:206–210

    Article  CAS  PubMed  Google Scholar 

  • Mense M et al (2006) In vivo phosphorylation of CFTR promotes formation of a nucleotide-binding domain heterodimer. EMBO J 25(20):4728–4739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mu TW, Fowler DM, Kelly JW (2008) Partial restoration of mutant enzyme homeostasis in three distinct lysosomal storage disease cell lines by altering calcium homeostasis. PLoS Biol 6(2), e26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Navis A, Bagnat M (2015) Loss of cftr function leads to pancreatic destruction in larval zebrafish. Dev Biol 399(2):237–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Noone PG et al (2001) Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations. Gastroenterology 121(6):1310–1319

    Article  CAS  PubMed  Google Scholar 

  • Ockenga J, Stuhrmann M, Ballmann M, Teich N, Keim V, Dörk T, Manns MP (2000) Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis. Am J Gastroenterol 95:2061–206

    Article  CAS  PubMed  Google Scholar 

  • Okiyoneda T, Apaja PM, Lukacs GL (2011) Protein quality control at the plasma membrane. Curr Opin Cell Biol 23(4):483–491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okiyoneda T et al (2013) Mechanism-based corrector combination restores DeltaF508-CFTR folding and function. Nat Chem Biol 9(7):444–454

    Article  CAS  PubMed  Google Scholar 

  • Olivier AK et al (2012) Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets. J Clin Invest 122(10):3755–3768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olivier AK, Gibson-Corley KN, Meyerholz DK (2015) Animal models of gastrointestinal and liver diseases. Animal models of cystic fibrosis: gastrointestinal, pancreatic, and hepatobiliary disease and pathophysiology. Am J Physiol Gastrointest Liver Physiol 308(6):G459–G471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ooi CY, Durie PR (2012) Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros 11(5):355–362

    Article  CAS  PubMed  Google Scholar 

  • Ooi CY et al (2011) Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis. Gastroenterology 140(1):153–161

    Article  CAS  PubMed  Google Scholar 

  • Pallagi P et al (2014) The role of pancreatic ductal secretion in protection against acute pancreatitis in mice. Crit Care Med 42(3):e177–e188

    Article  CAS  PubMed  Google Scholar 

  • Pedemonte N et al (2005) Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening. J Clin Invest 115(9):2564–2571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rab A et al (2013) Cigarette smoke and CFTR: implications in the pathogenesis of COPD. Am J Physiol Lung Cell Mol Physiol 305(8):L530–L541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raju SV et al (2013) Cigarette smoke induces systemic defects in cystic fibrosis transmembrane conductance regulator function. Am J Respir Crit Care Med 188(11):1321–1330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raju SV et al (2014) Impact of heterozygote CFTR mutations in COPD patients with chronic bronchitis. Respir Res 15:18

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ramsey BW et al (2011) A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 365(18):1663–1672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ren HY et al (2013) VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol Biol Cell 24(19):3016–3024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riordan JR (2005) Assembly of functional CFTR chloride channels. Annu Rev Physiol 67:701–718

    Article  CAS  PubMed  Google Scholar 

  • Riordan JR (2008) CFTR function and prospects for therapy. Annu Rev Biochem 77:701–726

    Article  CAS  PubMed  Google Scholar 

  • Rogers CS et al (2008) Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science 321(5897):1837–1841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosendahl J et al (2013) CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut 62(4):582–592

    Article  CAS  PubMed  Google Scholar 

  • Sarles H et al (1965) Observations on 205 confirmed cases of acute pancreatitis, recurring pancreatitis, and chronic pancreatitis. Gut 6(6):545–559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sermet-Gaudelus I et al (2007) In vitro prediction of stop-codon suppression by intravenous gentamicin in patients with cystic fibrosis: a pilot study. BMC Med 5:5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sermet-Gaudelus I et al (2010) Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis. Am J Respir Crit Care Med 182(10):1262–1272

    Article  CAS  PubMed  Google Scholar 

  • Sharer N et al (1998) Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 339(10):645–652

    Article  CAS  PubMed  Google Scholar 

  • Shwachman H, Lebenthal E, Khaw KT (1975) Recurrent acute pancreatitis in patients with cystic fibrosis with normal pancreatic enzymes. Pediatrics 55(1):86–95

    CAS  PubMed  Google Scholar 

  • Sloane PA et al (2012) A pharmacologic approach to acquired cystic fibrosis transmembrane conductance regulator dysfunction in smoking related lung disease. PLoS One 7(6), e39809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Snouwaert JN et al (1992) An animal model for cystic fibrosis made by gene targeting. Science 257(5073):1083–1088

    Article  CAS  PubMed  Google Scholar 

  • Steiner B et al (2011) Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat 32(8):912–920

    Article  CAS  PubMed  Google Scholar 

  • Sun X et al (2010) Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis. J Clin Invest 120(9):3149–3160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takács T et al (2013) Intraductal acidosis in acute biliary pancreatitis. Pancreatology 13(4):333–335

    Article  PubMed  Google Scholar 

  • Truninger K, Malik N, Ammann RW, Muellhaupt B, Seifert B, Müller HJ, Blum HE (2001) Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. Am J Gastroenterol 96:2657–2661

    Article  CAS  PubMed  Google Scholar 

  • Tuggle KL et al (2014) PLoS One 9(3):e91253

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Uc A et al (2012) Pancreatic and biliary secretion are both altered in cystic fibrosis pigs. Am J Physiol Gastrointest Liver Physiol 303(8):G961–G968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uc A et al (2015) Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass. Clin Sci (Lond) 128(2):131–142

    Article  CAS  Google Scholar 

  • Van Goor F et al (2009) Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A 106(44):18825–18830

    Article  PubMed  PubMed Central  Google Scholar 

  • Van Goor F et al (2011) Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A 108(46):18843–18848

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Van Goor F et al (2014) Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros 13(1):29–36

    Article  PubMed  CAS  Google Scholar 

  • Varga K et al (2008) Enhanced cell-surface stability of rescued DeltaF508 cystic fibrosis transmembrane conductance regulator (CFTR) by pharmacological chaperones. Biochem J 410(3):555–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Venglovecz V et al (2008) Effects of bile acids on pancreatic ductal bicarbonate secretion in guinea pig. Gut 57(8):1102–1112

    Article  CAS  PubMed  Google Scholar 

  • Wainwright CE et al (2015) Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 373(3):220–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weiss FU et al (2005) Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls. Gut 54(10):1456–1460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Welch EM et al (2007) PTC124 targets genetic disorders caused by nonsense mutations. Nature 447(7140):87–91

    Article  CAS  PubMed  Google Scholar 

  • Wilschanski M et al (2000) A pilot study of the effect of gentamicin on nasal potential difference measurements in cystic fibrosis patients carrying stop mutations. Am J Respir Crit Care Med 161(3 Pt 1):860–865

    Article  CAS  PubMed  Google Scholar 

  • Wilschanski M et al (2003) Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N Engl J Med 349(15):1433–1441

    Article  CAS  PubMed  Google Scholar 

  • Wilschanski M et al (2006) Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med 174(7):787–794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilschanski M et al (2011) Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis. Eur Respir J 38(1):59–69

    Article  CAS  PubMed  Google Scholar 

  • Wittel UA et al (2006) Cigarette smoke-induced differential expression of the genes involved in exocrine function of the rat pancreas. Pancreas 33(4):364–370

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto A et al (2003) Ethanol induces fluid hypersecretion from guinea-pig pancreatic duct cells. J Physiol 551(Pt 3):917–926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zielenski J (2000) Genotype and phenotype in cystic fibrosis. Respiration 67:117–133

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Our research was supported by the Hungarian Scientific Research Fund (PD115974 (JM), K116634 (PH), NF101116 (ZR)); the Momentum Grant of the Hungarian Academy of Sciences (LP2014-10/2014); the Cystic Fibrosis Canada (GL), NIH R01-DK75302 (GL); and the Canadian Institute of Health Research (GL), the NIH DK096327 (AU), NIH DK097820 (AU), NIH DK096518 (JE), Cystic Fibrosis Trust (UK) INOVCF- SRC003 (MAG), National Pancreas Foundation Grant (AU), NIH/NIDCR intramural grant DE000735 (SM), NIH R01-DK058088 (MST), and GL is a recipient of a Canada Research Chair.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Péter Hegyi .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Hegyi, P. et al. (2016). CFTR: A New Horizon in the Pathomechanism and Treatment of Pancreatitis. In: Nilius, B., de Tombe, P., Gudermann, T., Jahn, R., Lill, R., Petersen, O. (eds) Reviews of Physiology, Biochemistry and Pharmacology Vol. 170. Reviews of Physiology, Biochemistry and Pharmacology, vol 170. Springer, Cham. https://doi.org/10.1007/112_2015_5002

Download citation

Publish with us

Policies and ethics