Animal models of gastrointestinal and liver diseases. Animal models of cystic fibrosis: Gastrointestinal, pancreatic, and hepatobiliary disease and pathophysiology

American Journal of Physiology - Gastrointestinal and Liver Physiology

Volumn 308, Issue 6, 2015, Pages G459-G471

  Olivier, Alicia K ^a   Gibson Corley, Katherine N ^a   Meyerholz, David K ^a  

^a UNIVERSITY OF IOWA   (United States)

Author keywords

Cystic fibrosis; Cystic fibrosis transmembrane conductance regulator; Gastrointestinal tract; Liver; Pancreas

Indexed keywords

CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR;

ANIMAL MODEL; ARTICLE; BILIARY CIRRHOSIS; BIOLOGICAL MODEL; COLON DIVERTICULOSIS; CONSTIPATION; CYSTIC FIBROSIS; DYSBIOSIS; EARLY DIAGNOSIS; FERRET MODEL; FOCAL BILIARY CIRRHOSIS; GASTROESOPHAGEAL REFLUX; GASTROINTESTINAL DISEASE; GASTROINTESTINAL TRACT; GENE MUTATION; GENETIC ANALYSIS; HEPATOBILIARY DISEASE; HUMAN; INTESTINAL SECRETIONS; INTESTINE ATRESIA; INTESTINE MOTILITY; INTESTINE OBSTRUCTION; LIVER DISEASE; MECONIUM ILEUS; MOUSE MODEL; MULTILOBULAR BILIARY CIRRHOSIS; NONHUMAN; PANCREAS; PANCREAS DISEASE; PATHOPHYSIOLOGY; PORCINE MODEL; PORTAL HYPERTENSION; PRIORITY JOURNAL; PROTEIN EXPRESSION; RAT MODEL; RECTUM PROLAPSE; ANIMAL; BILIARY TRACT DISEASES; COMPLICATION; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR MOUSE; DISEASE MODEL; GASTROINTESTINAL DISEASES; GENETIC PREDISPOSITION; GENETICS; LIVER DISEASES; METABOLISM; MUTATION; PANCREATIC DISEASES; PHENOTYPE; SPECIES DIFFERENCE;

ANIMALS; BILIARY TRACT DISEASES; CYSTIC FIBROSIS; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; DISEASE MODELS, ANIMAL; GASTROINTESTINAL DISEASES; GENETIC PREDISPOSITION TO DISEASE; HUMANS; LIVER DISEASES; MICE, INBRED CFTR; MUTATION; PANCREATIC DISEASES; PHENOTYPE; SPECIES SPECIFICITY;

EID: 84929584853     PISSN: 01931857     EISSN: 15221547     Source Type: Journal    
DOI: 10.1152/ajpgi.00146.2014     Document Type: Article

References (135)

1. Abou Alaiwa MH, Reznikov LR, Gansemer ND, Sheets KA, Horswill AR, Stoltz DA, Zabner J, Welsh MJ. pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37. Proc Natl Acad Sci USA 111: 18703–18708, 2014
2. Abramson SJ, Baker DH, Amodio JB, Berdon WE. Gastrointestinal manifestations of cystic fibrosis. Semin Roentgenol 22: 97–113, 1987
3. Abu-El-Haija M, Ramachandran S, Meyerholz DK, Abu-El-Haija M, Griffin M, Giriyappa RL, Stoltz DA, Welsh MJ, McCray PB Jr, Uc A. Pancreatic damage in fetal and newborn cystic fibrosis pigs involves the activation of inflammatory and remodeling pathways. Am J Pathol 181: 499–507, 2012
4. Abu-El-Haija M, Sinkora M, Meyerholz DK, Welsh MJ, McCray PB Jr, Butler J, Uc A. An activated immune and inflammatory response targets the pancreas of newborn pigs with cystic fibrosis. Pancreatology 11: 506–515, 2011
5. Agrons GA, Corse WR, Markowitz RI, Suarez ES, Perry DR. Gastrointestinal manifestations of cystic fibrosis: radiologic-pathologic correlation. Radiographics 16: 871–893, 1996
6. Ahmed N, Corey M, Forstner G, Zielenski J, Tsui LC, Ellis L, Tullis E, Durie P. Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas. Gut 52: 1159–1164, 2003
7. Augarten A, Ben Tov A, Madgar I, Barak A, Akons H, Laufer J, Efrati O, Aviram M, Bentur L, Blau H, Paret G, Wilschanski M, Kerem BS, Yahav Y. The changing face of the exocrine pancreas in cystic fibrosis: the correlation between pancreatic status, pancreatitis and cystic fibrosis genotype. Eur J Gastroenterol Hepatol 20: 164–168, 2008
8. Bali A, Stableforth DE, Asquith P. Prolonged small-intestinal transit time in cystic fibrosis. Br Med J 287: 1011–1013, 1983
9. Bartlett JR, Friedman KJ, Ling SC, Pace RG, Bell SC, Bourke B, Castaldo G, Castellani C, Cipolli M, Colombo C, Colombo JL, Debray D, Fernandez A, Lacaille F, Macek M Jr, Rowland M, Salvatore F, Taylor CJ, Wainwright C, Wilschanski M, Zemkova D, Hannah WB, Phillips MJ, Corey M, Zielenski J, Dorfman R, Wang Y, Zou F, Silverman LM, Drumm ML, Wright FA, Lange EM, Durie PR, Knowles MR, Gene Modifier Study Group. Genetic modifiers of liver disease in cystic fibrosis. JAMA 302: 1076–1083, 2009
10. Benedetti A, Alvaro D, Bassotti C, Gigliozzi A, Ferretti G, La Rosa T, Di Sario A, Baiocchi L, Jezequel AM. Cytotoxicity of bile salts against biliary epithelium: a study in isolated bile ductule fragments and isolated perfused rat liver. Hepatology 26: 9–21, 1997
11. Benya EC, Nussbaum-Blask AR, Selby DM. Colonic diverticulitis causing partial bowel obstruction in a child with cystic fibrosis. Pediatr Radiol 27: 918–919, 1997
12. Bishop MD, Freedman SD, Zielenski J, Ahmed N, Dupuis A, Martin S, Ellis L, Shea J, Hopper I, Corey M, Kortan P, Haber G, Ross C, Tzountzouris J, Steele L, Ray PN, Tsui LC, Durie PR. The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis. Hum Genet 118: 372–381, 2005
13. Blackman SM, Deering-Brose R, McWilliams R, Naughton K, Coleman B, Lai T, Algire M, Beck S, Hoover-Fong J, Hamosh A, Fallin MD, West K, Arking DE, Chakravarti A, Cutler DJ, Cutting GR. Relative contribution of genetic and nongenetic modifiers to intestinal obstruction in cystic fibrosis. Gastroenterology 131: 1030–1039, 2006
14. Bodewes FA, Wouthuyzen-Bakker M, Bijvelds MJ, Havinga R, de Jonge HR, Verkade HJ. Ursodeoxycholate modulates bile flow and bile salt pool independently from the cystic fibrosis transmembrane regulator (Cftr) in mice. Am J Physiol Gastrointest Liver Physiol 302: G1035–G1042, 2012
15. Bodian M. Fibrocystic Disease of the Pancreas: A Congenital Disorder of Mucus Production-Mucosis. New York: Grune & Stratton, 1953
16. Bonfield TL, Hodges CA, Cotton CU, Drumm ML. Absence of the cystic fibrosis transmembrane regulator (Cftr) from myeloid-derived cells slows resolution of inflammation and infection. J Leukoc Biol 92: 1111–1122, 2012
17. Borowitz D, Durie PR, Clarke LL, Werlin SL, Taylor CJ, Semler J, De Lisle RC, Lewindon P, Lichtman SM, Sinaasappel M, Baker RD, Baker SS, Verkade HJ, Lowe ME, Stallings VA, Janghorbani M, Butler R, Heubi J. Gastrointestinal outcomes and confounders in cystic fibrosis. J Pediatr Gastroenterol Nutr 41: 273–285, 2005
18. Boucher RC. Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu Rev Med 58: 157–170, 2007
19. Braun J, Mundhenk L, Range F, Gruber AD. Quantitative expression analyses of candidates for alternative anion conductance in cystic fibrosis mouse models. J Cyst Fibros 9: 351–364, 2010
20. Buchanan DJ, Rapoport S. Chemical comparison of normal meconium and meconium from a patient with meconium ileus. Pediatrics 9: 304–310, 1952
21. Canani RB, Cirillo P, Roggero P, Romano C, Malamisura B, Terrin G, Passariello A, Manguso F, Morelli L, Guarino AM, Sinkora M, Meyerholz DK, Welsh MJ, McCray PB Jr, Butler J, Uc A, Working Group on Intestinal Infections of the Italian Society of Pediatric Gastroenterology and Nutrition. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics 117: e817–e820, 2006
22. Chen JH, Stoltz DA, Karp PH, Ernst SE, Pezzulo AA, Moninger TO, Rector MV, Reznikov LR, Launspach JL, Chaloner K, Zabner J, Welsh MJ. Loss of anion transport without increased sodium absorption characterizes newborn porcine cystic fibrosis airway epithelia. Cell 143: 911–923, 2010
23. Cheng K, Ashby D, Smyth RL. Ursodeoxycholic acid for cystic fibrosis-related liver disease. Cochrane Database Syst Rev 10: CD000222, 2012
24. Choi JY, Muallem D, Kiselyov K, Lee MG, Thomas PJ, Muallem S. Aberrant CFTR-dependent HCO3 _ transport in mutations associated with cystic fibrosis. Nature 410: 94–97, 2001
25. Clarke LL, Gawenis LR, Bradford EM, Judd LM, Boyle KT, Simpson JE, Shull GE, Tanabe H, Ouellette AJ, Franklin CL, Walker NM. Abnormal Paneth cell granule dissolution and compromised resistance to bacterial colonization in the intestine of CF mice. Am J Physiol Gastrointest Liver Physiol 286: G1050–G1058, 2004
26. Clarke LL, Grubb BR, Yankaskas JR, Cotton CU, McKenzie A, Boucher RC. Relationship of a non-cystic fibrosis transmembrane conductance regulator-mediated chloride conductance to organ-level disease in Cftr-/- mice. Proc Natl Acad Sci USA 91: 479–483, 1994
27. Cohn JA, Strong TV, Picciotto MR, Nairn AC, Collins FS, Fitz JG. Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells. Gastroenterology 105: 1857–1864, 1993
28. Colombo C, Battezzati PM, Crosignani A, Morabito A, Costantini D, Padoan R, Giunta A. Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome. Hepatology 36: 1374–1382, 2002
29. Davis PB. Cystic fibrosis since 1938. Am J Respir Crit Care Med 173: 475–482, 2006
30. De Boeck K, Weren M, Proesmans M, Kerem E. Pancreatitis among patients with cystic fibrosis: correlation with pancreatic status and genotype. Pediatrics 115: e463–e469, 2005
31. De Lisle RC. Increased expression of sulfated gp300 and acinar tissue pathology in pancreas of CFTR-/- mice. Am J Physiol Gastrointest Liver Physiol 268: G717–G723, 1995
32. De Lisle RC, Meldi L, Mueller R. Intestinal smooth muscle dysfunction develops postnatally in cystic fibrosis mice. J Pediatr Gastroenterol Nutr 55: 689–694, 2012
33. de Lisle RC, Sewell R, Meldi L. Enteric circular muscle dysfunction in the cystic fibrosis mouse small intestine. Neurogastroenterol Motil 22: e341–e387, 2010
34. Debray D, Kelly D, Houwen R, Strandvik B, Colombo C. Best practice guidance for the diagnosis and management of cystic fibrosisassociated liver disease. J Cyst Fibros 10 Suppl 2: S29–S36, 2011
35. Debray D, Rainteau D, Barbu V, Rouahi M, El Mourabit H, Lerondel S, Rey C, Humbert L, Wendum D, Cottart CH, Dawson P, Chignard N, Housset C. Defects in gallbladder emptying and bile acid homeostasis in mice with cystic fibrosis transmembrane conductance regulator deficiencies. Gastroenterology 142: 1581–1591, 2012
36. Del Campo R, Garriga M, Perez-Aragon A, Guallarte P, Lamas A, Maiz L, Bayon C, Roy G, Canton R, Zamora J, Baquero F, Suarez L. Improvement of digestive health and reduction in proteobacterial populations in the gut microbiota of cystic fibrosis patients using a Lactobacillus reuteri probiotic preparation: a double blind prospective study. J Cyst Fibros 13: 716–722, 2014
37. Dimango E, Walker P, Keating C, Berdella M, Robinson N, Langfelder- Schwind E, Levy D, Liu X. Effect of esomeprazole versus placebo on pulmonary exacerbations in cystic fibrosis. BMC Pulm Med 14: 21, 2014
38. Durie PR, Forstner GG. Pathophysiology of the exocrine pancreas in cystic fibrosis. J R Soc Med 82 Suppl 16: 2–10, 1989
39. Durie PR, Kent G, Phillips MJ, Ackerley CA. Characteristic multiorgan pathology of cystic fibrosis in a long-living cystic fibrosis transmembrane regulator knockout murine model. Am J Pathol 164: 1481–1493, 2004
40. Durno C, Corey M, Zielenski J, Tullis E, Tsui LC, Durie P. Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis. Gastroenterology 123: 1857–1864, 2002
41. Farrelly PJ, Charlesworth C, Lee S, Southern KW, Baillie CT. Gastrointestinal surgery in cystic fibrosis: a 20-year review. J Pediatr Surg 49: 280–283, 2014
42. Fiorotto R, Scirpo R, Trauner M, Fabris L, Hoque R, Spirli C, Strazzabosco M. Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-κB-mediated inflammatory response in mice. Gastroenterology 141: 1498–1508, 2011
43. Fisher JT, Tyler SR, Zhang Y, Lee BJ, Liu X, Sun X, Sui H, Liang B, Luo M, Xie W, Yi Y, Zhou W, Song Y, Keiser N, Wang K, de Jonge HR, Engelhardt JF. Bioelectric characterization of epithelia from neonatal CFTR knockout ferrets. Am J Respir Cell Mol Biol 49: 837–844, 2013
44. Fisichella PM, Jalilvand A. The role of impaired esophageal and gastric motility in end-stage lung diseases and after lung transplantation. J Surg Res 186: 201–206, 2014
45. Flass T, Narkewicz MR. Cirrhosis and other liver disease in cystic fibrosis. J Cyst Fibros 12: 116–124, 2013
46. Freudenberg F, Broderick AL, Yu BB, Leonard MR, Glickman JN, Carey MC. Pathophysiological basis of liver disease in cystic fibrosis employing a ΔF508 mouse model. Am J Physiol Gastrointest Liver Physiol 294: G1411–G1420, 2008
47. Frizzell RA, Hanrahan JW. Physiology of epithelial chloride and fluid secretion. Cold Spring Harbor Perspect Med 2: a009563, 2012
48. Gallagher AM, Gottlieb RA. Proliferation, not apoptosis, alters epithelial cell migration in small intestine of CFTR null mice. Am J Physiol Gastrointest Liver Physiol 281: G681–G687, 2001
49. Garcia MA, Yang N, Quinton PM. Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion. J Clin Invest 119: 2613–2622, 2009
50. Gelfond D, Ma C, Semler J, Borowitz D. Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule. Dig Dis Sci 58: 2275–2281, 2013
51. George DH. Diverticulosis of the vermiform appendix in patients with cystic fibrosis. Hum Pathol 18: 75–79, 1987
52. Gouyer V, Leir SH, Tetaert D, Liu Y, Gottrand F, Harris A, Desseyn JL. The characterization of the first anti-mouse Muc6 antibody shows an increased expression of the mucin in pancreatic tissue of Cftr-knockout mice. Histochem Cell Biol 133: 517–525, 2010
53. Gray MA, Winpenny JP, Porteous DJ, Dorin JR, Argent BE. CFTR and calcium-activated chloride currents in pancreatic duct cells of a transgenic CF mouse. Am J Physiol Cell Physiol 266: C213–C221, 1994
54. Grubb BR. Ion transport across the jejunum in normal and cystic fibrosis mice. Am J Physiol Gastrointest Liver Physiol 268: G505–G513, 1995
55. Grubb BR, Gabriel SE. Intestinal physiology and pathology in genetargeted mouse models of cystic fibrosis. Am J Physiol Gastrointest Liver Physiol 273: G258–G266, 1997
56. Hedsund C, Gregersen T, Joensson IM, Olesen HV, Krogh K. Gastrointestinal transit times and motility in patients with cystic fibrosis. Scand J Gastroenterol 47: 920–926, 2012
57. Helm JF, Dodds WJ, Riedel DR, Teeter BC, Hogan WJ, Arndorfer RC. Determinants of esophageal acid clearance in normal subjects. Gastroenterology 85: 607–612, 1983
58. Henderson LB, Doshi VK, Blackman SM, Naughton KM, Pace RG, Moskovitz J, Knowles MR, Durie PR, Drumm ML, Cutting GR. Variation in MSRA modifies risk of neonatal intestinal obstruction in cystic fibrosis. PLos Genet 8: e1002580, 2012
59. Hodges CA, Cotton CU, Palmert MR, Drumm ML. Generation of a conditional null allele for Cftr in mice. Genesis 46: 546–552, 2008
60. Hodges CA, Grady BR, Mishra K, Cotton CU, Drumm ML. Cystic fibrosis growth retardation is not correlated with loss of Cftr in the intestinal epithelium. Am J Physiol Gastrointest Liver Physiol 301: G528–G536, 2011
61. Hoegger MJ, Fischer AJ, McMenimen JD, Ostedgaard LS, Tucker AJ, Awadalla MA, Moninger TO, Michalski AS, Hoffman EA, Zabner J, Stoltz DA, Welsh MJ. Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis. Science 345: 818–822, 2014
62. Houwen RH, van der Doef HP, Sermet I, Munck A, Hauser B, Walkowiak J, Robberecht E, Colombo C, Sinaasappel M, Wilschanski M, ESPGHAN Cystic Fibrosis Working Group. Defining DIOS and constipation in cystic fibrosis with a multicentre study on the incidence, characteristics, and treatment of DIOS. J Pediatr Gastroenterol Nutr 50: 38–42, 2010
63. Imrie JR, Fagan DG, Sturgess JM. Quantitative evaluation of the development of the exocrine pancreas in cystic fibrosis and control infants. Am J Pathol 95: 697–708, 1979
64. Ip WF, Bronsveld I, Kent G, Corey M, Durie PR. Exocrine pancreatic alterations in long-lived surviving cystic fibrosis mice. Pediatr Res 40: 242–249, 1996
65. Karlas T, Neuschulz M, Oltmanns A, Wirtz H, Keim V, Wiegand J. ARFI and transient elastography for characterization of cystic fibrosis related liver disease: first longitudinal follow-up data in adult patients. J Cyst Fibros 12: 826–827, 2013
66. Lamireau T, Monnereau S, Martin S, Marcotte JE, Winnock M, Alvarez F. Epidemiology of liver disease in cystic fibrosis: a longitudinal study. J Hepatol 41: 920–925, 2004
67. Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345: 1247125, 2014
68. Leeuwen L, Magoffin AK, Fitzgerald DA, Cipolli M, Gaskin KJ. Cholestasis and meconium ileus in infants with cystic fibrosis and their clinical outcomes. Arch Dis Child 99: 443–447, 2014
69. Lewindon PJ, Pereira TN, Hoskins AC, Bridle KR, Williamson RM, Shepherd RW, Ramm GA. The role of hepatic stellate cells and transforming growth factor- 1 in cystic fibrosis liver disease. Am J Pathol 160: 1705–1715, 2002
70. Lewindon PJ, Shepherd RW, Walsh MJ, Greer RM, Williamson R, Pereira TN, Frawley K, Bell SC, Smith JL, Ramm GA. Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy. Hepatology 53: 193–201, 2011
71. Lindblad A, Glaumann H, Strandvik B. Natural history of liver disease in cystic fibrosis. Hepatology 30: 1151–1158, 1999
72. Lisowska A, Madry E, Pogorzelski A, Szydlowski J, Radzikowski A, Walkowiak J. Small intestine bacterial overgrowth does not correspond to intestinal inflammation in cystic fibrosis. Scand J Clin Lab Invest 70: 322–326, 2010
73. Lisowska A, Wojtowicz J, Walkowiak J. Small intestine bacterial overgrowth is frequent in cystic fibrosis: combined hydrogen and methane measurements are required for its detection. Acta Biochim Pol 56: 631–634, 2009
74. Liu J, Walker NM, Cook MT, Ootani A, Clarke LL. Functional Cftr in crypt epithelium of organotypic enteroid cultures from murine small intestine. Am J Physiol Cell Physiol 302: C1492–C1503, 2012
75. Loser C, Mollgaard A, Folsch UR. Faecal elastase 1: a novel, highly sensitive, and specific tubeless pancreatic function test. Gut 39: 580–586, 1996
76. Lynch SV, Goldfarb KC, Wild YK, Kong W, De Lisle RC, Brodie EL. Cystic fibrosis transmembrane conductance regulator knockout mice exhibit aberrant gastrointestinal microbiota. Gut Microbes 4: 41–47, 2013
77. Maisonneuve P, Marshall BC, Knapp EA, Lowenfels AB. Cancer risk in cystic fibrosis: a 20-year nationwide study from the United States. J Natl Cancer Inst 105: 122–129, 2013
78. Makris K, Tsiotos GG, Stafyla V, Sakorafas GH. Small intestinal nonmeckelian diverticulosis. J Clin Gastroenterol 43: 201–207, 2009
79. Marx V. Models: stretching the skills of cell lines and mice. Nat Methods 11: 617–620, 2014
80. Meyerholz DK, Stoltz DA, Pezzulo AA, Welsh MJ. Pathology of gastrointestinal organs in a porcine model of cystic fibrosis. Am J Pathol 176: 1377–1389, 2010
81. Meyers RL, Orlando RC. In vivo bicarbonate secretion by human esophagus. Gastroenterology 103: 1174–1178, 1992
82. Murshed R, Spitz L, Kiely E, Drake D. Meconium ileus: a ten-year review of thirty-six patients. Eur J Pediatr Surg 7: 275–277, 1997
83. Neglia JP, FitzSimmons SC, Maisonneuve P, Schoni MH, Schoni- Affolter F, Corey M, Lowenfels AB. The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group. N Engl J Med 332: 494–499, 1995
84. Nousia-Arvanitakis S, Fotoulaki M, Economou H, Xefteri M, Galli- Tsinopoulou A. Long-term prospective study of the effect of ursodeoxycholic acid on cystic fibrosis-related liver disease. J Clin Gastroenterol 32: 324–328, 2001
85. Olivier AK, Yi Y, Sun X, Sui H, Liang B, Hu S, Xie W, Fisher JT, Keiser NW, Lei D, Zhou W, Yan Z, Li G, Evans TI, Meyerholz DK, Wang K, Stewart ZA, Norris AW, Engelhardt JF. Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets. J Clin Invest 122: 3755–3768, 2012
86. Ooi CY, Dorfman R, Cipolli M, Gonska T, Castellani C, Keenan K, Freedman SD, Zielenski J, Berthiaume Y, Corey M, Schibli S, Tullis E, Durie PR. Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis. Gastroenterology 140: 153–161, 2011
87. Oppenheimer EH, Esterly JR. Observations in cystic fibrosis of the pancreas. II. Neonatal intestinal obstruction. Bull Johns Hopkins Hosp 111: 1–13, 1962
88. Ostedgaard LS, Meyerholz DK, Chen JH, Pezzulo AA, Karp PH, Rokhlina T, Ernst SE, Hanfland RA, Reznikov LR, Ludwig PS, Rogan MP, Davis GJ, Dohrn CL, Wohlford-Lenane C, Taft PJ, Rector MV, Hornick E, Nassar BS, Samuel M, Zhang Y, Richter SS, Uc A, Shilyansky J, Prather RS, McCray PB Jr, Zabner J, Welsh MJ, Stoltz DA. The _F508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs. Sci Transl Med 3: 74ra24, 2011
89. Ostedgaard LS, Meyerholz DK, Vermeer DW, Karp PH, Schneider L, Sigmund CD, Welsh MJ. Cystic fibrosis transmembrane conductance regulator with a shortened R domain rescues the intestinal phenotype of CFTR-/- mice. Proc Natl Acad Sci USA 108: 2921–2926, 2011
90. Pascua P, Garcia M, Fernandez-Salazar MP, Hernandez-Lorenzo MP, Calvo JJ, Colledge WH, Case RM, Steward MC, San Roman JI. Ducts isolated from the pancreas of CFTR-null mice secrete fluid. Pflügers Arch 459: 203–214, 2009
91. Patricolo M, Noia G, Rossi L, Zangari A, Pomini F, Catesini C, Filippetti R, Galli T, Iacobelli BD, Capuano LG, Romano D, Mancuso S, Rivosecchi M. An experimental animal model of intestinal obstruction to simulate in utero therapy for jejunoileal atresia. Fetal Diagn Ther 13: 298–301, 1998
92. Poulsen JH, Fischer H, Illek B, Machen TE. Bicarbonate conductance and pH regulatory capability of cystic fibrosis transmembrane conductance regulator. Proc Natl Acad Sci USA 91: 5340–5344, 1994
93. Quinton PM. Physiological basis of cystic fibrosis: a historical perspective. Physiol Rev 79: S3–S22, 1999
94. Ramm GA, Shepherd RW, Hoskins AC, Greco SA, Ney AD, Pereira TN, Bridle KR, Doecke JD, Meikle PJ, Turlin B, Lewindon PJ. Fibrogenesis in pediatric cholestatic liver disease: role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment. Hepatology 49: 533–544, 2009
95. Ratcliff R, Evans MJ, Cuthbert AW, MacVinish LJ, Foster D, Anderson JR, Colledge WH. Production of a severe cystic fibrosis mutation in mice by gene targeting. Nat Genet 4: 35–41, 1993
96. Reid CJ, Hyde K, Ho SB, Harris A. Cystic fibrosis of the pancreas: involvement of MUC6 mucin in obstruction of pancreatic ducts. Mol Med 3: 403–411, 1997
97. Rescorla FJ, Grosfeld JL, West KJ, Vane DW. Changing patterns of treatment and survival in neonates with meconium ileus. Arch Surg 124: 837–840, 1989
98. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245: 1066–1073, 1989
99. Risse PA, Kachmar L, Matusovsky OS, Novali M, Gil FR, Javeshghani S, Keary R, Haston CK, Michoud MC, Martin JG, Lauzon AM. Ileal smooth muscle dysfunction and remodeling in cystic fibrosis. Am J Physiol Gastrointest Liver Physiol 303: G1–G8, 2012
100. Roberts HE, Cragan JD, Cono J, Khoury MJ, Weatherly MR, Moore CA. Increased frequency of cystic fibrosis among infants with jejunoileal atresia. Am J Med Genet 78: 446–449, 1998
101. Rogers CS, Stoltz DA, Meyerholz DK, Ostedgaard LS, Rokhlina T, Taft PJ, Rogan MP, Pezzulo AA, Karp PH, Itani OA, Kabel AC, Wohlford-Lenane CL, Davis GJ, Hanfland RA, Smith TL, Samuel M, Wax D, Murphy CN, Rieke A, Whitworth K, Uc A, Starner TD, Brogden KA, Shilyansky J, McCray PB Jr, Zabner J, Prather RS, Welsh MJ. Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science 321: 1837–1841, 2008
102. Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med 352: 1992–2001, 2005
103. Rowntree RK, Harris A. The phenotypic consequences of CFTR mutations. Ann Hum Genet 67: 471–485, 2003
104. Scheele GA, Fukuoka SI, Kern HF, Freedman SD. Pancreatic dysfunction in cystic fibrosis occurs as a result of impairments in luminal pH, apical trafficking of zymogen granule membranes, and solubilization of secretory enzymes. Pancreas 12: 1–9, 1996
105. Schippa S, Iebba V, Santangelo F, Gagliardi A, De Biase RV, Stamato A, Bertasi S, Lucarelli M, Conte MP, Quattrucci S. Cystic fibrosis transmembrane conductance regulator (CFTR) allelic variants relate to shifts in faecal microbiota of cystic fibrosis patients. PLos One 8: e61176, 2013
106. Scott-Jupp R, Lama M, Tanner MS. Prevalence of liver disease in cystic fibrosis. Arch Dis Child 66: 698–701, 1991
107. Scott RB, O’Loughlin EV, Gall DG. Gastroesophageal reflux in patients with cystic fibrosis. J Pediatr 106: 223–227, 1985
108. Sharer N, Schwarz M, Malone G, Howarth A, Painter J, Super M, Braganza J. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 339: 645–652, 1998
109. Sheppard DN, Welsh MJ. Structure and function of the CFTR chloride channel. Physiol Rev 79: S23–S45, 1999
110. Siafakas C, Vottler TP, Andersen JM. Rectal prolapse in pediatrics. Clin Pediatr 38: 63–72, 1999
111. Siddiqui MM, Burge DM. Neonatal spontaneous colonic perforation due to cystic fibrosis. Pediatr Surg Int 24: 863–864, 2008
112. Snouwaert JN, Brigman KK, Latour AM, Malouf NN, Boucher RC, Smithies O, Koller BH. An animal model for cystic fibrosis made by gene targeting. Science 257: 1083–1088, 1992
113. Sontag MK, Corey M, Hokanson JE, Marshall JA, Sommer SS, Zerbe GO, Accurso FJ. Genetic and physiologic correlates of longitudinal immunoreactive trypsinogen decline in infants with cystic fibrosis identified through newborn screening. J Pediatr 149: 650–657, 2006
114. Stoltz DA, Meyerholz DK, Pezzulo AA, Ramachandran S, Rogan MP, Davis GJ, Hanfland RA, Wohlford-Lenane C, Dohrn CL, Bartlett JA, Nelson GA, Chang EH, Taft PJ, Ludwig PS, Estin M, Hornick EE, Launspach JL, Samuel M, Rokhlina T, Karp PH, Ostedgaard LS, Uc A, Starner TD, Horswill AR, Brogden KA, Prather RS, Richter SS, Shilyansky J, McCray PB Jr, Zabner J, Welsh MJ. Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth. Sci Transl Med 2: 29ra31, 2010
115. Stoltz DA, Meyerholz DK, Welsh MJ. Origins of cystic fibrosis lung disease. N Engl J Med 372: 351–362, 2015
116. Stoltz DA, Rokhlina T, Ernst SE, Pezzulo AA, Ostedgaard LS, Karp PH, Samuel MS, Reznikov LR, Rector MV, Gansemer ND, Bouzek DC, Alaiwa MH, Hoegger MJ, Ludwig PS, Taft PJ, Wallen TJ, Wohlford-Lenane C, McMenimen JD, Chen JH, Bogan KL, Adam RJ, Hornick EE, Nelson GA, Hoffman EA, Chang EH, Zabner J, McCray PB Jr, Prather RS, Meyerholz DK, Welsh MJ. Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs. J Clin Invest 123: 2685–2693, 2013
117. Strobel O, Dor Y, Alsina J, Stirman A, Lauwers G, Trainor A, Castillo CF, Warshaw AL, Thayer SP. In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia. Gastroenterology 133: 1999–2009, 2007
118. Strong TV, Boehm K, Collins FS. Localization of cystic fibrosis transmembrane conductance regulator mRNA in the human gastrointestinal tract by in situ hybridization. J Clin Invest 93: 347–354, 1994
119. Subhi R, Ooi R, Finlayson F, Kotsimbos T, Wilson J, Lee WR, Wale R, Warrier S. Distal intestinal obstruction syndrome in cystic fibrosis: presentation, outcome and management in a tertiary hospital (2007–2012). ANZ J Surg 84: 740–744, 2014
120. Sun X, Olivier AK, Liang B, Yi Y, Sui H, Evans TI, Zhang Y, Zhou W, Tyler SR, Fisher JT, Keiser NW, Liu X, Yan Z, Song Y, Goeken JA, Kinyon JM, Fligg D, Wang X, Xie W, Lynch TJ, Kaminsky PM, Stewart ZA, Pope RM, Frana T, Meyerholz DK, Parekh K, Engelhardt JF. Lung phenotype of juvenile and adult cystic fibrosis transmembrane conductance regulator-knockout ferrets. Am J Respir Cell Mol Biol 50: 502–512, 2014
121. Sun X, Olivier AK, Yi Y, Pope CE, Hayden HS, Liang B, Sui H, Zhou W, Hager KR, Zhang Y, Liu X, Yan Z, Fisher JT, Keiser NW, Song Y, Tyler SR, Goeken JA, Kinyon JM, Radey MC, Fligg D, Wang X, Xie W, Lynch TJ, Kaminsky PM, Brittnacher MJ, Miller SI, Parekh K, Meyerholz DK, Hoffman LR, Frana T, Stewart ZA, Engelhardt JF. Gastrointestinal pathology in juvenile and adult CFTR-knockout ferrets. Am J Pathol 184: 1309–1322, 2014
122. Sun X, Sui H, Fisher JT, Yan Z, Liu X, Cho HJ, Joo NS, Zhang Y, Zhou W, Yi Y, Kinyon JM, Lei-Butters DC, Griffin MA, Naumann P, Luo M, Ascher J, Wang K, Frana T, Wine JJ, Meyerholz DK, Engelhardt JF. Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis. J Clin Invest 120: 3149–3160, 2010
123. Thiagarajah JR, Verkman AS. CFTR pharmacology and its role in intestinal fluid secretion. Curr Opin Pharmacol 3: 594–599, 2003
124. Tucker JA, Spock A, Spicer SS, Shelburne JD, Bradford W. Inspissation of pancreatic zymogen material in cystic fibrosis. Ultrastruct Pathol 27: 323–335, 2003
125. Tuggle KL, Birket SE, Cui X, Hong J, Warren J, Reid L, Chambers A, Ji D, Gamber K, Chu KK, Tearney G, Tang LP, Fortenberry JA, Du M, Cadillac JM, Bedwell DM, Rowe SM, Sorscher EJ, Fanucchi MV. Characterization of defects in ion transport and tissue development in cystic fibrosis transmembrane conductance regulator (CFTR)-knockout rats. PLos One 9: e91253, 2014
126. Uc A, Giriyappa R, Meyerholz DK, Griffin M, Ostedgaard LS, Tang XX, Abu-El-Haija M, Stoltz DA, Ludwig P, Pezzulo A, Abu-El-Haija M, Taft P, Welsh MJ. Pancreatic and biliary secretion are both altered in cystic fibrosis pigs. Am J Physiol Gastrointest Liver Physiol 303: G961–G968, 2012
127. van der Doef HP, Kokke FT, Beek FJ, Woestenenk JW, Froeling SP, Houwen RH. Constipation in pediatric cystic fibrosis patients: an underestimated medical condition. J Cystic Fibrosis 9: 59–63, 2010
128. van der Doef HP, Kokke FT, van der Ent CK, Houwen RH. Intestinal obstruction syndromes in cystic fibrosis: meconium ileus, distal intestinal obstruction syndrome, and constipation. Curr Gastroenterol Rep 13: 265–270, 2011
129. Walkowiak J, Sands D, Nowakowska A, Piotrowski R, Zybert K, Herzig KH, Milanowski A. Early decline of pancreatic function in cystic fibrosis patients with class 1 or 2 CFTR mutations. J Pediatr Gastroenterol Nutr 40: 199–201, 2005
130. Welsh MJ, Ramsey BW, Accurso F, Cutting GR. Cystic fibrosis. In: The Metabolic and Molecular Basis of Inherited Disease, edited by Scriver CR, Beaudet AL, Sly WS, Valle D. New York: McGraw-Hill, 2001, p. 5121–5189
131. Wilke M, Buijs-Offerman RM, Aarbiou J, Colledge WH, Sheppard DN, Touqui L, Bot A, Jorna H, de Jonge HR, Scholte BJ. Mouse models of cystic fibrosis: phenotypic analysis and research applications. J Cystic Fibrosis 10 Suppl 2: S152–S171, 2011
132. Wilschanski M, Durie PR. Patterns of GI disease in adulthood associated with mutations in the CFTR gene. Gut 56: 1153–1163, 2007
133. Woodley FW, Machado RS, Hayes D Jr, Di Lorenzo C, Kaul A, Skaggs B, McCoy K, Patel A, Mousa H. Children with cystic fibrosis have prolonged chemical clearance of acid reflux compared with symptomatic children without cystic fibrosis. Dig Dis Sci 59: 623–630, 2014
134. Zhou L, Dey CR, Wert SE, DuVall MD, Frizzell RA, Whitsett JA. Correction of lethal intestinal defect in a mouse model of cystic fibrosis by human CFTR. Science 266: 1705–1708, 1994
135. Zuelzer WW, Newton WA Jr. The pathogenesis of fibrocystic disease of the pancreas: a study of 36 cases with special reference to the pulmonary lesions. Pediatrics 4: 53–69, 1949.