Skip to main content

Advertisement

SpringerLink
Log in

Transepithelial Leak in Barrett’s Esophagus

  • Original Paper
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Using orally administered sucrose as a probe of gastrointestinal permeability, this study focused on determining whether Barrett’s metaplasia exhibits a paracellular transepithelial leak to small nonelectrolytes. Subjects in five separate classes (nonendoscoped, asymptomatic controls; endoscoped, asymptomatic controls; gastroesophageal reflux disease without mucosal complications; grossly visible esophagitis; and Barrett’s esophagus) consumed a sucrose solution at bedtime and collected all overnight urine. Urine volume was measured and sucrose concentration was determined by high-performance liquid chromatography. Patients with Barrett’s were observed to exhibit a transepithelial leak to sucrose whose mean value was threefold greater than that seen in healthy control subjects or patients with reflux but without any mucosal defect. A parallel study of claudin tight junction proteins in endoscopy biopsy samples showed that whereas Barrett’s metaplasia contains dramatically more claudin-2 and claudin-3 than is found in normal esophageal mucosa, it is markedly lower in claudins 1 and 5, indicating very different tight junction barriers.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Martinez-Palomo A (1970) Ultrastructural modifications of intercellular junctions between tumor cells. In Vitro 6:15–20

    CAS  PubMed  Google Scholar 

  2. Alroy J (1979) Ultrastructure of canine urinary bladder carcinoma. Vet Pathol 16:693–701

    CAS  PubMed  Google Scholar 

  3. Robenek H, Schopper C, Fasske E, Fetting R, Themann H (1981) Structure and function of the junctional complement of spontaneous and transplanted muring mammary carcinomas. J Submicrosc Cytol 13:347–363

    CAS  PubMed  Google Scholar 

  4. Kerjaschki D, Krisch K, Sleyter U, Umrath W, Jakesz R, Depisch D, Kokoschka R, Horandner H (1979) The structure of tight junctions in human thyroid tumors. A systematic freeze-fracture study. Am J Pathol 96:207–225

    CAS  PubMed  Google Scholar 

  5. Polak-Charcon S, Shoham J, Ben-Shaul Y (1980) Tight junctions of epithelial cells of human fetal hindgut, normal colon and colon adenocarcinoma. J Natl Cancer Inst 65:53–57

    CAS  PubMed  Google Scholar 

  6. Aoyagi K, Kohfiji K, Yano S, Murakami N, Hori H, Terasaki Y, Takeda J, Tanaka M, Shirouzu K (2000) Morphological change in the MNNG-treated rat gastric mucosa. Kurume Med J 47:31–36

    CAS  PubMed  Google Scholar 

  7. Saito T (1984) Ultrastructural changes on the junctional complexes in the human urinary bladder carcinoma by thin sectioning and freeze fracture. J Clin Electron Micros 17:201–209

    Google Scholar 

  8. Swift JG, Mukherjee TM, Rowland R (1983) Intercellular junctions in hepatocellular carcinoma. J Submicrosc Cytol 15:799–810

    CAS  PubMed  Google Scholar 

  9. Soler AP, Miller RD, Laughlin KV, Carp NZ, Klurfeld DM, Mullin JM (1999) Increased tight junctional permeability is associated with the development of colon cancer. Carcinogenesis 20:1425–1431

    Article  CAS  PubMed  Google Scholar 

  10. Davies R, Joseph R, Asbun H, Sedwitz M (1989) Detection of the cancer-prone colon, using transepithelial impedance analysis. Arch Surg 124:480–484

    CAS  PubMed  Google Scholar 

  11. Gonzalez-Mariscal L, Betanzos A, Nava P, Jaramillo B (2003) Tight junction proteins. Prog Biophys Mol Biol 81:1–44

    Article  CAS  PubMed  Google Scholar 

  12. Hollander D (1988) Crohn’s disease: a permeability disorder of the tight junction. Gut 29:1621–1624

    CAS  PubMed  Google Scholar 

  13. Soderholm JD, Olaison G, Peterson KH, Franzen LE, Lindmark T, Wiren M, Tagesson C, Sjodahl R (2002) Augmented increase in tight junction permeability by luminal stimuli in the non-inflamed ileum of Crohn’s disease. Gut 50:307–313

    Article  CAS  PubMed  Google Scholar 

  14. Mullin JM, Peralta Soler A, Laughlin KV, Kampherstein JA, Russo LM, Saladik DT, George K, Shurina RD, O’Brien TG (1996) Chronic exposure of LLC-PK1 epithelia to the phorbol ester TPA produces polyp-like foci with leaky tight junctions and altered protein kinase C-alpha expression and localization. Exp Cell Res 227:12–22

    Article  CAS  PubMed  Google Scholar 

  15. Guan Y, Woo P, Rubenstein N, Firestone G (2002) Transforming growth factor-alpha abrogates the glucocorticoid stimulation of tight junction formation and reverses the steroid-induced down-regulation of fascin in rat mammary epithelial tumor cells by a Ras-dependent pathway. Exp Cell Res 273:1–11

    Article  CAS  PubMed  Google Scholar 

  16. Chen Y, Lu Q, Schneeberger E, Goodenough DA (2000) Restoration of tight junction structure and barrier function by down-regulation of the mitogen-activated protein kinase pathway in ras-transformed Madin-Darby canine kidney cells. Mol Biol Cell 11:849–862

    CAS  PubMed  Google Scholar 

  17. Li D, Mrsny RJ (2000) Oncogenic Raf-1 disrupts epithelial tight junctions via downregulation of occludin. J Cell Biol 148:791–800

    Article  CAS  PubMed  Google Scholar 

  18. Mullin JM, Leatherman JM, Valenzano MC, Huerta ER, Verrechio J, Smith DM, Snetselaar K, Liu M, Francis MK, Sell C (2005) Ras mutation impairs epithelial barrier function to a wide range of nonelectrolytes. Mol Biol Cell 16:5538–5550

    Article  CAS  PubMed  Google Scholar 

  19. Nunbhakdi-Craig V, Craig L, Machleidt T, Sontag E (2003) Simian virus 40 small tumor antigen induces deregulation of the actin cytoskeleton and tight junctions in kidney epithelial cells. J Virol 77:2807–2818

    Article  CAS  PubMed  Google Scholar 

  20. Jiang W, Martin T, Matsumoto K, Nakamura T, Mansel R (1999) Hepatocyte growth factor/scatter factor decreases the expression of occluding and transendothelial resistance (TER) and increases paracellular permeability in human vascular endothelial cells. J Cell Physiol 181:319–329

    Article  CAS  PubMed  Google Scholar 

  21. Blanco D, Vicent S, Elizegi E, Pino I, Fraga M, Esteller M, Saffiotti U, Lecanda F, Montuenga L (2004) Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis. Lab Invest 84:999–1012

    Article  CAS  PubMed  Google Scholar 

  22. Resnick MB, Konkin T, Routhier J, Sabo E, Pricolo VE (2004) Claudin-1 is a strong prognostic indicator in stage II colonic cancer: a tissue microarray study. Mod Pathol 18(4):511–518

    Google Scholar 

  23. Tobioka H, Isomura H, Kokai Y, Sawada N (2002) Polarized distribution of carcinoembryonic antigen is associated with a tight junction molecule in human colorectal adenocarcinoma. J Pathol 198:207–212

    Article  CAS  PubMed  Google Scholar 

  24. Tobioka H, Isomura H, Kokai Y, Tokunaga Y, Yamaguchi J, Sawada N (2004) Occludin expression decreases with the progression of human endometrial carcinoma. Hum Pathol 35:159–164

    Article  CAS  PubMed  Google Scholar 

  25. Busch C, Hanssen T, Wagener C, O’Brink B (2002) Down-regulation of CEACAM1 in human prostate cancer: correlation with loss of cell polarity, increased proliferation rate, and Gleason grade 3 to 4 transition. Hum Pathol 33:290–298

    Article  CAS  PubMed  Google Scholar 

  26. Kimura Y, Shiozaki H, Hirao M, Maeno Y, Doki Y, Inoue M, Monden T, Ando-Akatsuka Y, Furuse M, Tsukita S, Monden M (1997) Expression of occludin, tight-junction-associated protein, in human digestive tract. Am J Pathol 151:45–54

    CAS  PubMed  Google Scholar 

  27. Marzioni D, Banita M, Felici A, Paradinas FJ, Newlands E, De Nictolis M, Muhlhauser J, Castellucci M (2001) Expression of ZO-1 and occludin in normal human placenta and in hydatidiform moles. Mol Hum Reprod 7:279–285

    Article  CAS  PubMed  Google Scholar 

  28. Davies R (2002) Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 200:639–646

    Article  CAS  PubMed  Google Scholar 

  29. Papadopoulos MC, Saadoun S, Woodrow CJ, Davies DC, Costa-Martins P, Moss RF, Krishna S, Bell BA (2001) Occludin expression in microvessels of neoplastic and non-neoplastic human brain. Neuropathol Appl Neurobiol. 27:384–395

    Article  CAS  PubMed  Google Scholar 

  30. Furuse M, Sasaki H, Tsukita S (1999) Manner of interaction of heterogeneous claudin species within and between tight junction strands. J Cell Biol 147:891–903

    Article  CAS  PubMed  Google Scholar 

  31. Liebner S, Kniesel U, Kalbacher H, Wolburg H (2000) Correlation of tight junction morphology with the expression of tight junction proteins in blood-brain barrier endothelial cells. Eur J Cell Biol 79:707–717

    Article  CAS  PubMed  Google Scholar 

  32. Kramer F, White K, Kubbies M, Swisshelm K, Weber BH (2000) Genomic organization of claudin-1 and its assessment in hereditary and sporadic breast cancer. Hum Genet 107:249–256

    Article  CAS  PubMed  Google Scholar 

  33. Willott E, Balda MS, Fanning AS, Jameson B, Van Itallie CM, Anderson JM (1993) The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions. Proc Natl Acad Sci USA 90:7834–7838

    Article  CAS  PubMed  Google Scholar 

  34. Miwa N, Furuse M, Tsukita S, Niikawa N, Nakamura Y, Furukawa Y (2000) Involvement of claudin-1 in the beta-catenin/Tcf signaling pathway and its frequent upregulation in human colorectal cancers. Oncol Res 12:469–476

    CAS  Google Scholar 

  35. Folpe A, Billings S, McKenney J, Walsh S, Nusrat A, Weiss S (2002) Expression of claudin-1, a recently described tight junction-associated protein, distinguishes soft tissue perineurioma from potential mimics. Am J Surg Pathol 12:1620–1626

    Article  Google Scholar 

  36. Kominsky SL, Argani P, Korz D, Evron E, Raman V, Garrett E, Rein A, Sauter G, Kallioniemi OP, Sukumar S (2003) Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene 22:2021–2033

    Article  CAS  PubMed  Google Scholar 

  37. Rangel LB, Agarwal R, D’Souza T, Pizer ES, Alo PL, Lancaster WD, Gregoire L, Schwartz DR, Cho KR, Morin PJ (2003) Tight junction proteins claudin-3 and claudin-4 are frequently overexpressed in ovarian cancer but not in ovarian cystadenomas. Clin Cancer Res 9:2567–2575

    CAS  PubMed  Google Scholar 

  38. Brown LM, Devesa SS (2002) Epidemiologic trends in esophageal and gastric cancer in the United States. Surg Oncol Clin North Am 11:235–256

    Article  Google Scholar 

  39. Eloubeidi MA, Homan RK, Martz MD, Theobold KE, Provenzale D (1999) A cost analysis of outpatient care for patients with Barrett’s esophagus in a managed care setting. Am J Gastroenterol 94:2033–2036

    Article  CAS  PubMed  Google Scholar 

  40. Fitzgerald RC (2005) Genetics and prevention of esophageal cancer. Rec Res Cancer Res 166:35–46

    Article  CAS  Google Scholar 

  41. Sampliner RE (2005) Epidemiology, pathophysiology, and treatment of Barrett’s esophagus: reducing mortality from esophageal adenocarcinoma. Med Clin North Am 1989:293–312

    Article  Google Scholar 

  42. Drewitz DJ, Sampliner RE, Garewal HS (1997) The incidence of adenocarcinoma in Barrett’s esophagus: a prospective study of 170 patients followed 4.8 years. Am J Gastroenterol 92:212–215

    CAS  PubMed  Google Scholar 

  43. Shaheen NJ, Crosby MA, Bozymski EM (2000) Is there publication bias in the reporting of cancer risk of Barrett’s esophagus? Gastroenterology 119:333–338

    Article  CAS  PubMed  Google Scholar 

  44. Mullin JM, Kampherstein JA, Laughlin KV, Saladik DT, Peralta Soler A (1997) Transepithelial paracellular leakiness induced by chronic phorbol ester exposure correlates with polyp-like foci and redistribution of protein kinase C-alpha. Carcinogenesis 18:2339–2345

    Article  CAS  PubMed  Google Scholar 

  45. Meddings JB, Sutherland LR, Byles NI, Wallace JL (1993) Sucrose, a novel permeability marker for gastroduodenal disease. Gastroenterology 104:1619–1626

    CAS  PubMed  Google Scholar 

  46. Kawabata H, Meddings JB, Uchida Y, Matsuda K, Sasahara K, Nishioka M (1998) Sucrose permeability as a means of detecting diseases of the upper digestive tract. J Gastroenterol Hepatol 13:1002–1006

    CAS  PubMed  Google Scholar 

  47. Subramanyam K, Patterson M, Gourley WK (1985) Healing of endoscopic biopsy sites in the human rectum. J Clin Gastroenterol 7:266–268

    Article  CAS  PubMed  Google Scholar 

  48. Mullin JM, Agostino N, Rendon-Huerta E, Thornton JJ (2005) Keynote review: epithelial and endothelial barriers in human disease. Drug Discov Today 10:395–408

    Article  CAS  PubMed  Google Scholar 

  49. Rendon-Huerta E, Valenzano MC, Mullin JM, Trembeth SE, Kothari RH, Hameed K, Mercogliano G, Thornton JJ (2003) Comparison of three integral tight junction barrier proteins in Barrett’s epithelium versus normal esophageal epithelium. Am J Gastroenterol 98:1901

    Article  PubMed  Google Scholar 

  50. Munck BG, Rasmussen SN (1977) Paracellular permeability of extracellular space markers across rat jejunum in vitro. Indication of a transepithelial fluid circuit. J Physiol 271: 473–488

    CAS  PubMed  Google Scholar 

  51. Gonzalez-Correa C, Brown B, Smallwood R, Stephenson T, Stoddard C, Bardhan K (2003) Low frequency electrical bioimpedance for the detection of inflammation and dysplasia in Barrett’s oesophagus. Physiol Meas 24:291–296

    Article  CAS  PubMed  Google Scholar 

  52. Tobey NA, Carson JL, Alkiek RA, Orlando RC (1996) Dilated intercellular spaces: a morphological feature of acid reflux-damaged human esophageal epithelium. Gastroenterology 111:1200–1205

    Article  CAS  PubMed  Google Scholar 

  53. Tobey NA, Hosseini SS, Argote CM, Dobrucali AM, Awayda MS, Orlando RC (2004) Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophageal epithelium. Am J Gastroenterol 99:13–22

    Article  CAS  PubMed  Google Scholar 

  54. Calabrese C, Bortolotti M, Fabbri A, Areni A, Cenachi G, Scialpi C, Miglioli M, Di Febo G (2005) Reversibility of GERD Ultrastructural alterations and relief of symptoms after omeprazole treatment. Am J Gastroenterol 100:537–542

    Article  CAS  PubMed  Google Scholar 

  55. Villanacci V, Grigolato PG, Cestari R, Missale G, Cengia G, Klersy C, Rindi G (2001) Dilated intercellular spaces as markers of reflux disease: histology, semiquantitative score and morphometry upon light microscopy. Digestion 64:1–8

    Article  CAS  PubMed  Google Scholar 

  56. Locke GR, Talley NJ, Fett SL, Zinmeister AR, Melton LJ (1997) Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 112:1448–1456

    Article  PubMed  Google Scholar 

  57. Gyorffy H, Holczbauer A, Nagy P, Szabo Z, Kupcsulik P, Paska C, Papp J, Schaff Z, Kiss A (2005) Claudin expression in Barrett’s esophagus and adenocarcinoma. Virchows Arch 447:961–968

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Spencer M. Free, Ph.D., for statistical methodologies and insights of study design. The cooperation of the scheduling secretaries and the nurses, patient care technicians, and anesthesiologists of the Main Line Gastroenterology Associates endoscopy facility is much appreciated. The authors thank Jennifer Swauger, Kathleen Ciavarelli, and Loretta Rossino for assistance in preparation of this manuscript.

Author information

Authors and Affiliations

  1. Lankenau Institute for Medical Research, Director of Research, Division of Gastroenterology, Lankenau Hospital, 100 Lancaster Avenue, Wynnewood, Pennsylvania, USA

    J. M. Mullin & M. C. Valenzano

  2. Division of Gastroenterology, Lankenau Hospital, Wynnewood, Pennsylvania, USA

    J. M. Mullin, S. Trembeth, P. D. Allegretti, J. J. Verrecchio, J. D. Schmidt, G. Mercogliano & J. J. Thornton

  3. Department of Medicine, Lankenau Hospital, Wynnewood, Pennsylvania, USA

    V. Jain

  4. Department of Medicine, University of Alberta School of Medicine, Edmonton, Canada

    J. B. Meddings

Authors
  1. J. M. Mullin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. C. Valenzano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Trembeth
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. D. Allegretti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. J. Verrecchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. D. Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V. Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. B. Meddings
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G. Mercogliano
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J. J. Thornton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. M. Mullin.

Additional information

Support by the Cancer Research and Prevention Foundation, the Sharpe-Strumia Foundation, and the Mary L. Smith Foundation.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mullin, J.M., Valenzano, M.C., Trembeth, S. et al. Transepithelial Leak in Barrett’s Esophagus. Dig Dis Sci 51, 2326–2336 (2006). https://doi.org/10.1007/s10620-006-9478-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-006-9478-5

Keywords

Search

Navigation