Intestinal Epithelial Hyperpermeability

  • M. P. Fink
Conference paper
Part of the Yearbook of Intensive Care and Emergency Medicine book series (YEARBOOK, volume 1997)


The gut serves not only as a portal of entry for nutrients, small ions, and water, but also as a selective barrier preventing systemic contamination by lumen-derived microbes or microbial products. A key component of the gastrointestinal barrier is the epithelium itself. There are only two ways that substances (ions, molecules, or particles) can traverse the epithelium from the lumenal compartment to the basolateral compartment. Permeation can occur via the transcellular pathway (i.e. through cells) or via the paracellular pathway (i.e. between cells).


Tight Junction Intestinal Permeability Reactive Oxygen Intermediate Paracellular Permeability Paracellular Pathway 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gumbiner B (1987) Structure, biochemistry, and assembly of epithelial tight junctions. Am J Physiol 253: C749–C758PubMedGoogle Scholar
  2. 2.
    Anderson JM, Van Itallie CM (1995) Tight junctions and the Molecular basis for regulation of paracellular permeability. Am J Physiol 269: G467–G475PubMedGoogle Scholar
  3. 3.
    Fish EM, Molitoris BA (1994) Alterations in epithelial polarity and the pathogenesis of disease states. N Engl J Med 330: 1580–1588PubMedCrossRefGoogle Scholar
  4. 4.
    Claude P, Goodenough DA (1973) Fracture faces of zonulae occludentes from “tight” and“leaky” epithelia. J Cell Biol 58: 390–400PubMedCrossRefGoogle Scholar
  5. 5.
    Claude P (1978) Morphological factors influencing transepithelial permeability: A model for resistance of the zonula occludens. J Membrane Biol 39: 219–232CrossRefGoogle Scholar
  6. 6.
    Madara JL (1989) Loosening tight junctions: Lessons from the intestine. J Clin Invest 83: 1089–1094PubMedCrossRefGoogle Scholar
  7. 7.
    Riddington DW, Venkatesh B, Boivin CM, et al (1996) Intestinal permeability, gastric intramucosal pH, and systemic endotoxemia in patients undergoing cardiopulmonary bypass. J Am Med Assoc 275: 1007–1012CrossRefGoogle Scholar
  8. 8.
    Bjaranson I, Macpherson A, Hollander D (1995) Intestinal permeability: An overview. Gastroenterol 108: 1566–1581Google Scholar
  9. 9.
    Langkamp-Henken B, Donovan TB, Pate LM, et al (1995) Increased intestinal permeability following blunt and penetrating trauma. Crit Care Med 23: 660–664PubMedCrossRefGoogle Scholar
  10. 10.
    Sinclair DG, Haslam PL, Quinlan GJ, et al (1995) The effect of cardiopulmonary bypass on intestinal and pulmonary endothelial permeability. Chest 108: 718–724PubMedCrossRefGoogle Scholar
  11. 11.
    Ryan CM, Yarmush ML, Burke JF, et al (1992) Increased gut permeability early after burns correlates with the extent of burn injury. Crit Care Med 20: 1508–1512PubMedCrossRefGoogle Scholar
  12. 12.
    Peeters M, Ghoos Y, Maes B, et al (1994) Increased permeability of macroscopically normal small bowel in Crohn’s disease. Digestive Dis Sci 39: 2170–2176CrossRefGoogle Scholar
  13. 13.
    Maxton DG, Bjaranson I, Reynolds AP, et al (1986) 51Cr-EDTA, L-rhamnose, and polyethylene glycol 400 as probe markers for “in vivo” assessment of human intestinal permeability. Clin Sci 71: 71–80Google Scholar
  14. 14.
    Roumen RMH, van der Vliet JA, Wevers RA, et al (1993) Intestinal permeability is increased after major vascular surgery. J Vasc Surg 17: 734–737PubMedCrossRefGoogle Scholar
  15. 15.
    Ohri SK, Bjarnson I, Pathi V, et al (1993) Cardiopulmonary bypass impairs small intestinal transport and increases gut permeability. Ann Thorac Surg 55: 1080–1086PubMedCrossRefGoogle Scholar
  16. 16.
    Madara JL, Barenberg D, Carison S (1986) Effects of cytochalasin D on occluding junctions of intestinal absorptive cells: Further evidence that the cytoskeleton may influence paracellular permeability and junctional charge selectivity. J Cell Biol 102: 2125–2136Google Scholar
  17. 17.
    Madar.a JL, Stafford J, Barenberg D, et al (1988) Functional coupling of tight junctions and microfilaments in T84 monolayers. Am J Physiol 254: G416–G423Google Scholar
  18. 18.
    Madara JL, Moore R, Carlson S (1987) Alteration of intestinal tight junction structure and permeability by cytoskeletal contraction. Am J Physiol 253: C854–C861PubMedGoogle Scholar
  19. 19.
    Kroshian VM, Sheridan AM, Lieberthal W (1994) Functional and cytoskeletal changes induced by sublethal injury in proximal tubular epithelial cells. Am J Physiol 266: F21–F30•Google Scholar
  20. 20.
    Welsh MJ, Shasby DM, Husted RM (1985) Oxidants increase paracellular permeability in a cultured epithelial cell line. J Clin Invest 76: 1155–1168PubMedCrossRefGoogle Scholar
  21. 21.
    Bulsma PB, Peeters RA, Groot JA, et al (1995) Differential in vivo and in vitro intestinal permeability to lactulose and mannitol in animals and humans: A hypothesis. Gastroenterology 108: 687–696Google Scholar
  22. 22.
    Jodal M, Kramer M, Lauterbach I (eds) (1977) The intestinal countercurrent exchanger and its influence on intestinal absorption. In: Intestinal Permeation. Excerpta Medica, Amsterdam, pp 48–55Google Scholar
  23. 23.
    Pappenheimer JR, Reiss KZ (1987) Contribution of solvent drag through intercellular tight junctions to absorption of nutrients by the small intestine in the rat. J Membrane Biol 100: 123–136CrossRefGoogle Scholar
  24. 24.
    Pantzar N, Bergqvist PBF, Bugge M, et al (1995) Small intestinal absorption of polyethylene glycol 400 to 1,000 in the portacaval shunted rat. Hepatology 21: 1167–1173PubMedGoogle Scholar
  25. 25.
    Epstein MD, Tchervenkov JI, Alexander JW, et al (1991) Increased gut permeability following burn trauma. Arch Surg 126: 198–200PubMedCrossRefGoogle Scholar
  26. 26.
    Fink MP,Antonsson JB, Wang H, et al (1991) Increased intestinal permeability in endotoxic pigs: Mesenteric hypoperfusion as an etiologic factor. Arch Surg 126: 211–218Google Scholar
  27. 27.
    Horton JW (1992) Alterations in intestinal permeability and blood flow in a new model of mesenteric ischemia. Circ Shock 36: 134–139PubMedGoogle Scholar
  28. 28.
    Bulkley GB, Kvietys PR, Parks DA, et al (1985) Relationship of blood flow and oxygen consumption to ischemic injury in the canine small intestine. Gastroenterology 89: 852–857PubMedGoogle Scholar
  29. 29.
    Madara JL, Dharmsathaphorn K (1985) Occluding junction structure-function relationships in cultured epithelial monolayer. J Cell Biol 101: 2124–2133PubMedCrossRefGoogle Scholar
  30. 30.
    Ciancio MJ, Vitiritti L, Dhar A, et al (1992) Endotoxin-induced alterations in rat colonic water and electrolyte transport. Gastroenterology 103: 1431–1443Google Scholar
  31. 31.
    Carter EA, Gonnell A, Tompkins RG (1992) Increased transcellular permeability of rat small intestine after thermal injury. Burns 18: 117–120PubMedCrossRefGoogle Scholar
  32. 32.
    Hidalgo IJ, Raub TJ, Borchardt RT (1989) Characterization of human colonic carcinoma cell line (Caco-2) as a model system of intestinal epithelial permeability. Gastroenterology 96: 736–749PubMedGoogle Scholar
  33. 33.
    Menconi MJ, Salzman AL, Unno N, et al (1997) Acidosis induces hyperpermeability in Caco-2BBe cultured intestinal epithelial monolayers. Am J Physiol (In press)Google Scholar
  34. 34.
    Unno N, Menconi MJ, Salzman AL, et al (1996) Hyperpermeability and ATP depletion induced by chronic hypoxia or glycolytic inhibition in Caco-2.., monolayers. Am J Physiol 270: G1010–G1021PubMedGoogle Scholar
  35. 35.
    Unno N, Menconi MJ, Smith M, et al (1995) Nitric oxide mediates interferon-gamma-induced hyperpermeability in cultured human intestinal epithelial monolayers. Crit Care Med 23: 1170–1176PubMedCrossRefGoogle Scholar
  36. 36.
    Salzman AL, Menconi MJ, Unno N, et al (1995) Nitric oxide dilates tight junctions and depletes ATP in cultured Caco-2., intestinal epithelial monolayers. Am J Physiol 268: G361–G373PubMedGoogle Scholar
  37. 37.
    Stenson WF, Easom RA, Riehl TE, et al (1993) Regulation of paracellular permeability in Caco-2 cell monolayers by protein kinase C. Am J Physiol 265: G995–G1062Google Scholar
  38. 38.
    Duffey ME, Hainau B, Ho S, et al (1981) Regulation of epithelial tight junction permeability by cyclic AMP. Nature 294: 451–453PubMedCrossRefGoogle Scholar
  39. 39.
    McRoberts JA, Aranda R, Riley N, et al (1990) Insulin regulates the paracellular permeability of cultured intestinal epithelial cell monolayers. J Clin Invest 85: 1127–1134PubMedCrossRefGoogle Scholar
  40. 40.
    McRoberts JA, Riley NE (1992) Regulation of T84 cell monolayer permeability by insulin-like growth factors. Am J Physiol 262: C207–C213PubMedGoogle Scholar
  41. 41.
    Bentzel CJ, Hainan B, Ho S, et al (1996) Cytoplasmic regulation of tight-junction permeability: Effects of plant cytokinins. Am J Physiol 239: C75–C89Google Scholar
  42. 42.
    Meza I, Obarra G, Sabanero M, et al (1980) Occluding junctions and cytoskeletal components in a cultured transporting epithelium. J Cell Biol 87: 746–754PubMedCrossRefGoogle Scholar
  43. 43.
    Stevenson BR, Begg DA (1994) Concentration-dependent effects of cytochalasin D on tight junctions and actin filaments in MDCK epithelial cells. J Cell Sci 107: 367–375PubMedGoogle Scholar
  44. 44.
    Furuse M, Hirase T, Itoh M, et al (1993) Occludin: A novel integral membrane protein localizing at tight junctions. J Cell Biol 123: 1777–1788Google Scholar
  45. 45.
    Furuse M, Itoh M, Hirase T, et al (1994) Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin in tight junctions. J Cell Biol 127: 1617–1626PubMedCrossRefGoogle Scholar
  46. 46.
    Deitch EA (1990) Intestinal permeability is increased in burn patients shortly after injury. Surgery 107: 411–416PubMedGoogle Scholar
  47. 47.
    Roumen RMH, Hendriks T, Wevers RA, et al (1993) Intestinal permeability after severe trauma and hemorrhagic shock is increased without relation to septic complications. Arch Surg 128: 453–457PubMedCrossRefGoogle Scholar
  48. 48.
    Pape HC, Dwenger A, Regel G, et al (1994) Increased gut permeability after multiple trauma. Br J Surg 81: 850–852PubMedCrossRefGoogle Scholar
  49. 49.
    Ziegler TR, Smith RJ, O’Dwyer ST, et al (1988) Increased intestinal permeability associated with infection in burn patients. Arch Surg 123: 1313–1319PubMedCrossRefGoogle Scholar
  50. 50.
    Johnston JD, Harvey CJ, Menzies IS, et al (1996) Gastrointestinal permeability and absorptive capacity in sepsis. Crit Care Med 24: 1144–1149PubMedCrossRefGoogle Scholar
  51. 51.
    Matthews JB, Smith JA, Tally KJ, et al (1994) “Chemical hypoxia” increases junctional permeability and activates chloride transport in human intestinal epithelial monolayers. Surgery 116: 150–158Google Scholar
  52. 52.
    Unno N, Fink MP (1997) BAPTA inhibits elevation of cytosolic free CaZ+ ([CaZ+],) during chemical hypoxia and ameliorates junctional hyperpermeability in human intestinal epithelial monolayers. Surg Forum (In press)Google Scholar
  53. 53.
    Tsuji Y, Unno N, Menconi MJ, et al (1996) Nitric oxide donors increase cytosolic ionized calcium in cultured human intestinal epithelial cells. Shock 6: 19–24PubMedCrossRefGoogle Scholar
  54. 54.
    Yamaguchi Y, Dalle-Molle E, Hardison WGM (1991) Vasopressin and A23187 stimulate phosphorylation of myosin light chain in isolated rat hepatocytes. Am J Physiol 261: G312–G319PubMedGoogle Scholar
  55. 55.
    Lowe PJ, Miyai K, Steinbach JH, et al (1988) Hormonal regulation of hepatocyte tight junctional permeability. Am J Physiol 255: G454–G461PubMedGoogle Scholar
  56. 56.
    Kan KS, Coleman R (1988) The calcium ionophore A23187 increases the tight-junctional permeability in rat liver. Biochem J 256: 1039–1041PubMedGoogle Scholar
  57. 57.
    Fleming I, Gray GA, Stoclet JC (1993) Influence of endothelium on induction of the Largininenitric oxide pathway in rat aortas. Am J Physiol 264: H1200–H1207PubMedGoogle Scholar
  58. 58.
    Peterson MW, Gruenhaupt D (1990) A23187 increases permeability of MDCK monolayers independent of phospholipase activation. Am J Physiol 259: C69–C76PubMedGoogle Scholar
  59. 59.
    Nathanson MH (1994) Cellular and subcellular calcium signalling in gastrointestinal epithelium. Gastroenterology 106: 1349–1364PubMedGoogle Scholar
  60. 60.
    Clapham DE (1995) Calcium signalling. Cell 80: 259–268PubMedCrossRefGoogle Scholar
  61. 61.
    Nichols DG (1986) Intracellular calcium homeostasis. Br Med Bul 42: 353–358Google Scholar
  62. 62.
    Carafoli E (1992) The Ca’ pump of the plasma membrane. J Biol Chem 267: 2115–2118PubMedGoogle Scholar
  63. 63.
    Strehler EE, Bittar EE, Bittar N (eds) (1995) Sodium-calcium exchangers and calcium pumps. In: Principles of Medical Biology, Vol 3. JAI Press, GreenwichGoogle Scholar
  64. 64.
    McCoy CE, Selvaggio AM, Alexander EA, et al (1988) Adenosine triphosphate depletion induces a rise in cytosolic free calcium in canine renal epithelial cells. J Clin Invest 82: 1326–1332PubMedCrossRefGoogle Scholar
  65. 65.
    Madara JL, Stafford J (1989) Interferony directly affects barrier function of cultured intestinal epithelial monolayers. J Clin Invest 83: 724–727PubMedCrossRefGoogle Scholar
  66. 66.
    Colgan SP, Resnick MB, Parkos CA, et al (1994) IL4 directly modulates function of a model human intestinal epithelium. J Immunol 153: 2122–2129PubMedGoogle Scholar
  67. 67.
    Demling R, Lalonde C, Knox J, et al (1991) Fluid resuscitation with deferoxamine prevents systemic burn-induced oxidant injury. J Trauma 31: 538–544PubMedCrossRefGoogle Scholar
  68. 68.
    Mückter H, Ben-Shaul Y, Bacher A (1987) ATP requirement for induced tight junction formation in HT 29 adenocarcinoma cells. Eur J Cell Biol 44: 258–264PubMedGoogle Scholar
  69. 69.
    Winter M, Wilson JS, Bedell K, et al (1990) The conductance of cultured epithelial cell mono-layers: Oxidants, adenosine triphosphate, and phorbol dibutyrate. Am J Respir Cell Mol Biol 2: 355–364Google Scholar
  70. 70.
    Watanabe H, Kuhne W, Spahr R, et al (1991) Macromolecule permeability of coronary and aortic endothelial monolayers under energy depletion. Am J Physiol 260: H1344–H1352PubMedGoogle Scholar
  71. 71.
    Wilson J, Winter M, Shasby DM (1990) Oxidants, ATP depletion, and endothelial permeability to macromolecules. Blood 76: 2578–2582Google Scholar
  72. 72.
    Gilles RJ, D’Orio V, Ciancabilla F, et al (1994) In vivo 31P nuclear magnetic resonance spectroscopy of skeletal muscle energetics in endotoxemic rats: A prospective, randomized study. Grit Care Med 22: 499–505Google Scholar
  73. 73.
    Granger DN (1988) Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. Am J Physiol 255: H1269–H1275PubMedGoogle Scholar
  74. 74.
    Spragg RG, Hinshaw DB, Hyslop PA, et al (1985) Alterations in adenosine triphosphate and energy charge in cultured endothelial and P388D1 cells after oxidant injury. J Clin Invest 76: 1471–1476PubMedCrossRefGoogle Scholar
  75. 75.
    Hinshaw DB, Armstrong BC, Burger JM, et al (1988) ATP and microfilaments in cellular oxidant injury. Am J Pathol 132: 479–488PubMedGoogle Scholar
  76. 76.
    Hinshaw DB, Burger JM, Armstrong BC, et al (1989) Mechanism of endothelial cell shape change in oxidant injury. J Surg Res 46: 339–349PubMedCrossRefGoogle Scholar
  77. 77.
    Hinshaw DB, Burger JM (1990) Protective effect of glutamine on endothelial cell ATP in oxidant injury. J Surg Res 49: 222–227PubMedCrossRefGoogle Scholar
  78. 78.
    Hyslop PA, Hinshaw DB, Halsey WA Jr, et al (1988) Mechanism of oxidant-mediated cell injury: The glycolytic and mitochondrial pathways of ADP phosphorylation are major intracellular targets inactivated by hydrogen peroxide. J Biol Chem 253: 1665–1675Google Scholar
  79. 79.
    Hausladen A, Fridovich I (1994) Superoxide and peroxynitrite inactivate aconitases, but nitric oxide does not. J Biol Chem 269: 29405–29408PubMedGoogle Scholar
  80. 80.
    Schraufstatter IU, Hinshaw DB, Hyslop PA, et al (1986) Oxidant injury of cells, DNA strand-breaks activate polyadenosine diphosphate-ribose polymerase and lead to depletion of nicotinamide adenine dinucleotide. J Clin Invest 77: 1312–1320Google Scholar
  81. 81.
    Schraufstatter IU, Hyslop PA, Hinshaw DB, et al (1986) Hydrogen peroxide-induced injury of cells and its prevention by inhibitors of poly(ADP-ribose) polymerase. Proc Natl Acad Sci 83: 4908–4912PubMedCrossRefGoogle Scholar
  82. 82.
    Szabo C, Zingarelli B, Salzman AL (1996) Role of poly-ADP ribosyltransferase activation in the vascular contractile and energetic failure elicited by exogenous and endogenous nitric oxide and peroxynitrite. Circ Res 78: 1051–1063PubMedCrossRefGoogle Scholar
  83. 83.
    Castro L, Rodriguez M, Radi R (1994) Aconitase is readily inactivated by peroxynitrite, but not its precursor, nitric oxide. J Biol Chem 269: 29409–29415PubMedGoogle Scholar
  84. 84.
    Szabo C, Zingarelli B, O’Connor M, et al (1996) DNA strand breakage, activation of poly-ADP ribosyl synthetase, and cellular energy depletion are involved in the cytotoxicity in macrophages and smooth muscle cells exposed to peroxynitrite. Proc Natl Acad Sci 93: 1753–1758PubMedCrossRefGoogle Scholar
  85. 85.
    Gores GJ, Nieminen AL, Wray BE, et al (1989) Intracellular pH during “chemical hypoxia” in cultured rat hepatocytes: Protection by intracellular acidosis against the onset of cell death. J Clin Invest 83: 386–396Google Scholar
  86. 86.
    Masaki N, Thomas AP, Hoek JB, et al (1989) Intracellular acidosis protects cultured hepatocytes from the toxic consequences of a loss of mitochondrial energization. Arch Biochem Biophys 272: 152–161PubMedCrossRefGoogle Scholar
  87. 87.
    Bonventre JV, Cheung JY (1985) Effects of metabolic acidosis on viability of cells exposed to anoxia. Am J Physiol249: C149–C159Google Scholar
  88. 88.
    Fish EM, Molitoris B (1994) Extracellular acidosis minimizes actin cytoskeletal alterations during ATP depletion. Am J Physiol 267: F566–F572PubMedGoogle Scholar
  89. 89.
    Oubidar M, Boquillon M, Marie C, et al (1994) Ischemia-induced brain iron delocalization: Effect of iron chelators. Free Rad Biol Med 16: 861–867Google Scholar
  90. 90.
    Rehncrona S, Hauge HN, Siesjo BK (1989) Enhancement of iron-catalyzed free radical formation by acidosis in brain homogenates: Differences in effect by lactic acid and CO2. J Cereb Blood Flow Metab 9: 65–70PubMedCrossRefGoogle Scholar
  91. 91.
    Musleh W, Bruce A, Malfroy B, et al (1994) Effects of EUK-8, a synthetic catalytic superoxide scavenger, on hypoxia-and acidosis-induced damage in hippocampal slices. Neuropharm 33: 929–934CrossRefGoogle Scholar
  92. 92.
    Bralet J, Bouvier C, Schrieber L, et al (1991) Effect of acidosis on lipid peroxidation in brain slices. Brain Res 539: 175–177PubMedCrossRefGoogle Scholar
  93. 93.
    Siesjo BK, Bendek G, Koide T, et al (1985) Influence of acidosis on lipid peroxidation in brain tissues in vitro. J Cereb Blood Flow Metab 5: 253–258PubMedCrossRefGoogle Scholar
  94. 94.
    Rodeheaver DP, Schnellman RG (1993) Extracellular acidosis ameliorates metabolic-inhibitorinduced and potentiates oxidant-induced cell death in renal proximal tubules. J Pharmacol Exp Ther 265: 1355–1360PubMedGoogle Scholar
  95. 95.
    Lundgren J, Zhang H, Agardh CD, et al (1991) Acidosis-induced ischemic brain damage: Are free radicals involved? J Cereb Blood Flow Metab 11: 587–596PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1997

Authors and Affiliations

  • M. P. Fink

There are no affiliations available

Personalised recommendations